Parkinsonism and Related Disorders 76 (2020) 63–71

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Review article

Clinical implications of gastric complications on levodopa treatment in T

Parkinson's disease
Ronald F. Pfeiffera,∗, Stuart H. Isaacsonb, Rajesh Pahwac
a
Department of Neurology, Oregon Health and Science University, Portland, OR, USA
b
Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA
c
Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA

ARTICLE INFO ABSTRACT

Keywords: Disorders of the gastrointestinal (GI) tract are common and distressing nonmotor symptoms of Parkinson's
Delayed gastric emptying disease (PD) that can adversely affect levodopa absorption and lead to OFF periods, also known as motor
Helicobacter pylori fluctuations. Gastroparesis, which is primarily defined as delayed gastric emptying (DGE), and Helicobacter pylori
Gastroparesis infection, which is present with increased frequency in PD, are among the most common and important GI
Levodopa
disorders reported in PD that may impair oral levodopa absorption and increase OFF time. Symptoms of gas-
Motor fluctuations
troparesis include nausea, vomiting, postprandial bloating, fullness, early satiety, abdominal pain, and weight
OFF periods
Parkinson's disease loss. DGE has been reported in a substantial fraction of individuals with PD. Symptoms of H. pylori infection
include gastritis and peptic ulcers. Studies have found that DGE and H. pylori infection are correlated with
delayed peak levodopa plasma levels and increased incidence of motor fluctuations.
Therapeutic strategies devised to minimize the potential that gastric complications will impair oral levodopa
absorption and efficacy in PD patients include treatments that circumvent the GI tract, such as apomorphine
injection, levodopa intestinal gel delivery, levodopa inhalation powder, and deep brain stimulation. Other
strategies aim at improving gastric emptying in PD patients, primarily including prokinetic agents.

1. Introduction
Gastrointestinal (GI) disorders are among the most common and
distressing nonmotor symptoms of Parkinson's disease (PD) [1–3]. In
his 1817 treatise, James Parkinson noted among the symptoms of this
disease “torpidity” of the bowels, great difficulty in defecation, and
impairment and agitation of muscles of the tongue and throat, leading
to problems in chewing and swallowing [4,5]. Motor symptoms of PD
became the primary focus of clinicians and researchers over the sub-
sequent 200 years, but recently the topic of PD-associated GI dysfunc-
tion has received growing attention [5]. GI symptoms may already be
present in prodromal PD [6] and approximately 60–80% of patients
with PD eventually experience GI symptoms, as indicated by cross-
sectional [7,8] and autopsy cohort studies [9], and in an analysis em-
ploying a large US claims database in which the incidence of GI dis-
orders reached 65% by 4 years post-PD diagnosis [10].
The spectrum of PD-associated GI dysfunction includes dental pro-
blems; excessive saliva with drooling as a consequence of reduced
swallowing frequency and efficiency; oral/pharyngeal/esophageal
dysphagia; aspiration pneumonia; gastroesophageal reflux;
gastroparesis with nausea, vomiting, early satiety, abdominal pain, and
bloating; and bowel dysfunction with reduced frequency, defecatory
dysfunction, and occasionally, fecal incontinence [2,3,11] (Fig. 1). GI
symptoms, particularly constipation, may develop up to 20 years before
development of motor symptoms and diagnosis of PD [2,12–14]. In
addition to causing patient distress, PD-associated GI problems are as-
sociated with malnutrition and weight loss, decreased quality of life
(QoL), and increased overall disability [1,15–17]. Aspiration pneu-
monia associated with dysphagia is a leading cause of morbidity, hos-
pitalization, and mortality in PD patients [18,19].
Oral levodopa is absorbed in the proximal small intestine, and GI
manifestations are likely to interfere with its absorption, potentially
impairing its efficacy [1]. Although levodopa is the gold standard of
treatment for PD, it is associated with motor complications that occur in
more than half of patients within ~5 years of treatment initiation
[20–22]. These complications are characterized by dyskinesias and
motor fluctuations or OFF periods, resulting in patients spending more
time throughout the day with breakthrough PD symptoms, which may
significantly reduce QoL and impair function [23]. Risk factors for
motor complications identified in studies include PD severity, duration,

∗
Corresponding author. Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
E-mail address: pfeiffro@ohsu.edu (R.F. Pfeiffer).

https://doi.org/10.1016/j.parkreldis.2020.05.001
Received 7 January 2020; Received in revised form 9 April 2020; Accepted 1 May 2020
Available online 11 May 2020
1353-8020/ © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
R.F. Pfeiffer, et al.
Fig. 1. Gastrointestinal dysfunctions and symptoms in Parkinson's disease. Adapted with permission from R.F. Pfeiffer, Lancet Neurol. 2 (2) (2003) 107–116 [45].
and cumulative levodopa dose [21,22], but there is increasing re-
cognition that PD-associated GI disorders also may delay, reduce, or
block the absorption and uptake of oral levodopa, with potential delay
or negation of its effects [1,24–26]. Gastroparesis and alterations of the
microbiome are present in animal models of PD utilizing rotenone [27]
and MPTP [28]. Small intestinal bacterial overgrowth is characterized
by alteration in both number and identity of bacteria in the small in-
testine [29]. Such alterations in the microbiome may impair availability
of levodopa to the absorption site [5,30], which may lead to fluctuating
levodopa plasma levels and dose failure, resulting in OFF periods and
motor complications [24,25,31,32].
Gastric complications including gastroparesis and Helicobacter pylori
infection are among the most common and important GI disorders of PD
that can impair oral levodopa absorption and efficacy [24]. Gastro-
paresis is defined clinically as delayed gastric emptying (DGE), which is
chiefly characterized by reduced stomach motility in the absence of
mechanical obstruction [24,33]. Multiple therapeutic strategies have
been used or are under development to counteract the adverse effects of
gastric complications on levodopa therapy. Following a brief overview
of the current understanding of the pathophysiology of GI disorders in
PD, this review will focus on the effects of gastric complications on
levodopa uptake and effectiveness and the current and emerging ther-
apeutic strategies to address this problem in PD treatment.
2. Methods
In this narrative review we searched the National Library of
Medicine PubMed database for studies and reviews pertaining to the
following main keyword/topic areas: gastroparesis, delayed gastric
emptying, levodopa absorption/pharmacokinetics, gastrointestinal
dysfunction, motor fluctuations, nonmotor symptoms, Helicobactor py-
lori, small intestinal bacterial overgrowth, and Parkinson's disease.
From these initial search results, and from papers cited within the re-
turned papers from the searches, we obtained the 146 papers we con-
sidered relevant to the effects of gastric complications on levodopa
uptake and effectiveness, and current and emerging therapeutic stra-
tegies.
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Parkinsonism and Related Disorders 76 (2020) 63–71
3. Proposed pathophysiology of GI disorders in PD
The presence of Lewy bodies in the enteric nervous system (ENS) of
patients with PD was first documented in the 1980s [34,35]. Braak
et al. subsequently reported that the deposition of α-synuclein appeared
within the ENS before it was observed in the central nervous system
(CNS). Based in part on these findings, it was proposed that the pa-
thogenesis of idiopathic PD may start with ingestion of an external
pathogen that provokes local inflammation, producing leakiness in the
mucosal barrier, which then permits entry and ongoing damage in the
nasal cavity and gut, with deposition of α-synuclein in the ENS [36–38].
The α-synuclein then may spread via two routes—from the nasal pas-
sage and the gut—in ascending, prion-like fashion via postganglionic
pathways of the dorsal motor nucleus of the vagus nerve to affect the
CNS [24,36,37,39–41].
Hypothesized pathogenic mechanisms in this process include α-sy-
nuclein misfolding and accumulation, initially in the submucosal
plexus, and formation of Lewy bodies (which primarily contain phos-
phorylated aggregates of α-synuclein) in the ENS and CNS [37,39]. The
concentration of phosphorylated α-synuclein in the GI tract appears to
occur on a rostrocaudal gradient, with the highest density in the lower
esophagus and submandibular gland, and the lowest in the colon and
rectum [39]. An autopsy study in 95 colon samples found that all
subjects with PD were positive for α-synuclein deposition, and that
prevalence and grade of deposition was significantly higher versus
controls (P = 0.001 and P = 0.003 for each comparison, respectively),
while subjects with Alzheimer's disease were no different versus con-
trols for the same parameters [42]. However, researchers note that
numerous questions and gaps of evidence in the Braak hypothesis re-
main to be clarified or confirmed [38,41,43]. Independent of the pro-
posed mechanism of the origin and spread of PD pathology within the
nervous system, several of the multiple GI manifestations associated
with PD are able to impair levodopa absorption, uptake, and clinical
effectiveness [1].
4. Levodopa pharmacokinetics and pharmacodynamics
Over the more than 50 years following its introduction as PD
therapy, levodopa pharmacokinetics and pharmacodynamics have been
R.F. Pfeiffer, et al.
extensively investigated but understanding remains incomplete. It is
clear that both peripheral and central factors contribute to the devel-
opment of motor fluctuations as a consequence of levodopa therapy.
This review addresses some of the peripheral factors that can lead to
delayed, unpredictable, and even failed responses to levodopa, but it is
important to remember that changes within the CNS at presynaptic,
synaptic, and postsynaptic levels may also play a role in the appearance
of motor fluctuations and dyskinesia [44].
5. Gastroparesis
Clinical symptoms of gastroparesis include nausea, vomiting, post-
prandial bloating, fullness, early satiety, abdominal pain, and weight
loss [33,45]. Formal diagnosis requires the combination of symptoms
and DGE [25,33], which most frequently is confirmed with scintigraphy
following administration of a radiolabeled test meal [46]. Gastroparesis
is rare in the general population, with a prevalence of approximately
0.2%, and is idiopathic in approximately half of all cases [47]. How-
ever, in people with types 1 and 2 diabetes, rates of gastroparesis
overall are estimated to be approximately 5% and 1%, respectively, and
are reported to be 40% and 10–20%, respectively, at tertiary care
medical centers, where reported rates are likely to be elevated [33,48].
Formal prevalence studies of gastroparesis have not been performed in
patients with PD, but reports involving small patient samples have
provided frequency estimates from 35 to 100% [25,49,50]. Prevalence
estimates have varied according to the criteria used in studies, because
not all patients with DGE experience GI symptoms [25]. Delayed onset
of levodopa effect may also be a symptom of DGE. Approximately
25–45% of patients with PD report abdominal symptoms such as nausea
or bloating, which may indicate gastroparesis, while scintigraphically
measured DGE has been reported in 70–100% of PD study populations
[25]. Other variables in measurement of gastric emptying are described
in the following section.
The pathophysiology of gastroparesis is yet to be fully elucidated.
Normal digestion in the stomach and gastric emptying are mediated by
multiple hormones, including gastrin, leptin, motilin, ghrelin, and
others, and by neural networks via the vagal and splanchnic pathways,
and the ENS, which is comprised of the ganglionated submucosal
(Meissner's) plexus and the myenteric (Auerbach's) plexus [51,52].
Through its connection with the myenteric plexus, the vagal nerve plays
a key role in mediating gastric emptying [51]. Pathogenic mechanisms
of gastroparesis may involve autonomic and intrinsic neuropathies of
excitatory and inhibitory systems in the gut, including damage to the
vagal nerve and impairment of the interstitial cells of Cajal, which
regulate smooth muscle cell contractility [53,54]. Impairment of gastric
accommodation (relaxation and compliance of the stomach following
meals to aid ingestion), failure of the pyloric sphincter to relax, an-
troduodenal dysmotility and dyscoordination, weak antrum pump,
fundic tone abnormalities, and abnormal duodenal feedback are other
possible mechanisms [5,53,55].
In patients with PD, treatment with oral levodopa itself, as well as
anticholinergic medications, may also contribute to the inhibition of
gastric emptying, in a dose-dependent manner [25,56–59]. Oral levo-
dopa treatment has been shown to delay gastric emptying in healthy
volunteers [60]. A study in 51 patients with mild (n = 22) and mod-
erate (n = 29) PD found that gastric emptying was faster in levodopa-
untreated patients (n = 28; 59 ± 30.6 min) than in levodopa-treated
patients with no motor fluctuations (n = 10; 73.6 ± 16.2 min) [31].
However, levodopa-treated patients with motor fluctuations had much
faster gastric emptying when tested during ON-time than either of the
other groups (49.3 ± 16.2 min). Investigators hypothesized that pa-
tients with motor fluctuations had more advanced PD and longer ex-
posure to levodopa than patients without motor fluctuations, and that
extended levodopa treatment might enhance activity of dopaminergic
cells of the dorsal motor vagal nucleus, resulting in faster gastric
emptying in the ON state [31]. As for other potential factors involved in
65
Parkinsonism and Related Disorders 76 (2020) 63–71
DGE assessed in this study, no difference in gastric emptying was ob-
served according to clinical status/severity of PD [31]. Another study,
in 80 patients with PD, found that gastroparesis was associated with
severity of Unified Parkinson's Disease Rating Scale (UPDRS)-rated
motor impairment, particularly action tremor and rigidity (UPDRS
items 21 and 22) (P < 0.0001), but not with other demographic or
disease characteristics [46].
A recent study identified an interspecies pathway that also meta-
bolizes levodopa in the gut. Enterococcus faecalis can decarboxylate le-
vodopa to produce dopamine and Eggerthella lenta dehydroxylates do-
pamine to m-tyramine. These two species have been shown to
metabolize levodopa in in vitro cocultures and in fecal suspensions from
PD patients ex vivo. Carbidopa was found to be largely ineffective in
inhibiting levodopa decarboxylation in E. faecalis. This highlights the
role that the gut microbiota may have in influencing levodopa ab-
sorption, and in particular emphasizes the role that the gut microbiota
may have in limiting oral levodopa efficacy and accounting for inter-
patient variability responsiveness to oral levodopa [61].
6. Measurement of gastric emptying in PD patients
A threshold commonly used to identify abnormal gastric emptying
is a half-life (T1/2) > 61 min, the upper limit for a control group in one
study [31]. The mean T1/2 for gastric emptying in various studies of
patients with PD and DGE typically is 60–90 min, although widely
ranging, versus ~45 min in controls [25]. Tests of DGE also depend on
the food used (liquid or solid). Studies have reported that the most
significant differences in gastric emptying between patients with PD
and controls, and the highest rates of DGE, are with solid food [46,62].
Expert consensus recommendations for evaluation of scintigraphic
gastric emptying values are shown in Table 1 [63].
A 2018 systematic review found that studies of gastric emptying
using gastric scintigraphy (n = 6) overall reported significant DGE in
patients with PD versus normal controls (standardized mean difference
[SMD] 0.59) after one outlier study was removed [64]. In one study, for
example, gastric emptying T1/2 was ~90 min in 12 patients with PD
versus ~46 min in 12 age-matched healthy controls (P < 0.0001, two-
way analysis of variance) [65]. The systematic review also found that 9
studies using 13C-octonoate breath tests to measure gastric emptying
collectively showed an even greater significant difference (SMD 1.70),
although the reliability of these findings is unclear. Breath tests are
indirect assessments of gastric emptying and are dependent on addi-
tional factors such as intestinal absorption and liver metabolism in
addition to mechanical gastric emptying and, therefore, may not be
entirely comparable to the scintigraphic results. Therefore, the actual
prevalence of DGE, especially in early PD, is still not entirely clear and
more accurate and reliable testing modalities are needed. Other tests
Table 1
Normal values for gastric emptying scintigraphy following consumption of a
low-fat egg-white meal: consensus recommendations of the American
Neurogastroenterology and Motility Society and the Society of Nuclear
Medicine.a
Time point, Lower normal limit for gastric Upper normal limit for gastric
hours retention (% food)b retention (% food)c
0.5 70 –
1 30 90
2 – 60
3 – 30
4 – 10
a
Values are the 95th percentile confidence interval, based on available
clinical study data.
b
Lower values at each time point suggest rapid gastric emptying.
c
Greater values at each time point (eg, > 10% food retained at 4 h) suggest
delayed gastric emptying. Adapted from T.L. Abell et al. J Nucl Med Technol. 36
(1) (2008) 44–54 [63].
R.F. Pfeiffer, et al.
used to measure gastric emptying include ultrasonography, electro-
gastrography, and magnetic resonance imaging [25,66]. An alternative
to these methods is the wireless motility capsule (WMC), or “smart pill,”
orally ingested by the patient to record digestive activity [67]. The
WMC is approved by the United States Food and Drug Administration
(FDA) for measurement of GI motility and appears to be concordant
with scintigraphy, although further comparative studies are needed
[68,69].
7. Effects of gastroparesis on oral levodopa absorption
Levodopa passes through the stomach and is not absorbed until it
reaches the proximal small intestine; it is then extensively metabolized
in the colon by DOPA decarboxylase (DDC) and O-methylation by ca-
techol-O-methyltransferase [30]. Transit time of levodopa in the small
intestine is ~3 h and its elimination half-life is short, only 90 min [30].
Thus, gastric emptying through the pyloric sphincter is the rate-limiting
step in levodopa absorption [30,51]. Prolonged exposure of levodopa in
the stomach and small intestine increases its breakdown by DDC and by
catechol-O-methyltransferase, decreasing availability for absorption
[70].
In this context, DGE is a key complication that may further impede
levodopa gastrointestinal absorption, hence lowering its plasma con-
centration and thereby contributing to motor fluctuations [24,70,71].
Multiple factors contribute to oral levodopa absorption, which has been
shown to vary considerably among individuals (Fig. 2) [72]. An oft-
cited 1996 study found that the rate of gastric emptying > 60 min was
significantly higher in 15 PD patients experiencing motor fluctuations
following long-term oral levodopa therapy, compared with 15 patients
with PD without motor fluctuations (77.4 vs 64.0%; P < 0.05) [73].
Another study in 31 patients being treated with oral levodopa found
that peak-time gastric emptying (Tmax) > 60 min was more common in
patients with plasma levodopa peak at 2 h (69%) than in patients with
plasma levodopa peak at 1 h (22%; P < 0.05), thus illustrating that
DGE may be correlated with delayed ON-time [74]. However, other
studies report more equivocal findings indicating that DGE is one of
multiple factors that may affect oral levodopa pharmacokinetics, in-
cluding PD stage, influence of levodopa itself on gastric function/
emptying, and timing of levodopa administration (ie, during ON or OFF
periods) [31,75–77]. Nonetheless, DGE is believed to be a key risk
factor for motor fluctuations [30,70].
Fig. 2. Individual plasma levodopa concentrations following a single ingested
dose of oral carbidopa/levodopa (25mg/100 mg) in 17 subjects with
Parkinson's disease. From Safirstein B et al. Clin Ther. 2020 [72].
66
Parkinsonism and Related Disorders 76 (2020) 63–71
7.1. Helicobacter pylori
A gastric disorder that is seen with increased frequency in PD and
that can contribute to impairment of oral levodopa absorption is H.
pylori infection, which also is associated with ulcers, gastritis, and
gastric cancer [78]. H. pylori may be diagnosed noninvasively with a
urea breath test, stool antigen test, or serological tests, of which the
most accurate and widely used is an enzyme-linked immunosorbent
assay, or invasively with histologic analysis of endoscopic biopsy
samples or rapid urease testing of biopsy specimens [79]. Studies and
meta-analysis data, collectively involving > 40,000 patients, have
found that H. pylori infection is associated with an estimated two-to
three-fold higher incidence of PD versus matched controls without in-
fection [78,80–82]. Prevalence of H. pylori in patients with PD appears
to be ~32–70% [78].
Conversely, eradication of H. pylori with antibiotic therapy (amox-
icillin, clarithromycin, metronidazole) was found to reduce PD risk in a
large Danish general population study (n = 26,900) that retro-
spectively compared patients with PD (n = 4484) with controls
(n = 22,416) [83]. However, a study of health insurance data in
Taiwan (n = 18,210) found that although persons with H. pylori in-
fection had a higher risk of PD versus controls, eradication therapy had
no effect on PD risk [82]. Further studies have shown that among pa-
tients with PD, H. pylori-positive patients have worse motor function
and UPDRS scores than H. pylori-negative patients [84,85], and H. pylori
eradication improved motor function and UPDRS scores [86–90].
7.2. H. pylori and oral levodopa absorption
Other clinical studies examining the relationship between H. pylori
and levodopa absorption showed that PD patients with H. pylori infec-
tion have decreased motor responses to oral levodopa treatment as
determined by UPDRS Part III (motor) scores, compared with patients
whose H. pylori was eradicated, or noninfected controls [91,92]. It is
hypothesized that H. pylori impairs GI levodopa absorption and phar-
macokinetics, although evidence of this potential mechanism needs
confirmation [93]. Conversely, eradication of H. pylori in patients with
PD has been associated in several studies with improvement of oral
levodopa absorption and clinical PD outcomes [89,90,92,94]. For ex-
ample, a study in 82 patients with PD found that approximately one-
third (32.9%) were positive for H. pylori infection; these patients had
significantly poorer total scores on the UPDRS (P = 0.005) and Par-
kinson's Disease Questionnaire-39 scale (P < 0.0001) [90]. Ad-
ditionally, after 12 weeks of open-label three-drug oral antibiotic
therapy, eradication of H. pylori resulted in significantly shortened OFF
time (14-min decrease; P = 0.01) and increased ON-time at week 6 (56-
min increase; P = 0.04), as well as improved UPDRS scores. In another
study in which 34 H. pylori-infected PD patients were treated in a
double-blind fashion with either antibiotic (n = 17) or generic anti-
oxidant therapy (n = 17), reduced clinical disability, increased ON-
time, and increased levodopa absorption were documented [94]. Al-
though further, more definitive, research is still needed, H. pylori ap-
pears to be an important external risk factor for occurrence of PD, worse
PD outcomes, and poor response to oral levodopa treatment [78].
7.3. Therapeutic strategies to avoid gastric complications
A variety of treatments and therapeutic strategies have been con-
sidered or developed to increase levodopa bioavailability and reduce
motor fluctuations either by circumventing the GI tract with non-oral
therapies and/or improving gastric emptying [30,95–97]. The fol-
lowing summarizes treatments/approaches to avoid gastric complica-
tions that are supported by published data, and includes effects on le-
vodopa and/or ON/OFF periods.
R.F. Pfeiffer, et al.
8. Non-oral therapies for PD symptoms
8.1. Transdermal
Transdermal administration of levodopa is considered a potential
option for more continuous and controlled drug delivery than oral ad-
ministration provides [98]. However, levodopa has limited dermal
permeability and is poorly soluble in most solvents used pharmaceuti-
cally [98]; current efforts to develop novel transdermal formulations of
levodopa to overcome these barriers are in early, experimental stages
[98,99]. Transdermal rotigotine, a dopamine agonist, has been shown
in phase 3 randomized, controlled trials to significantly reduce OFF
time in patients with advanced PD, versus placebo [100].
8.2. Subcutaneous
Early-morning OFF occurs in ~60% of patients with PD and causes
disability with substantial adverse impacts on QoL [101]. Among the 88
patients in the full analysis set of the phase 4 IMPAKT trial, levodopa-
treated patients with PD suffering from delayed ON-related morning
akinesia (n = 127, safety population; n = 88, full analysis set) showed
that apomorphine injection reduced mean time to ON by ~37 min
(60.9 min at baseline vs 23.7 min at end of treatment period;
P < 0.0001) [102]. Apomorphine injection is approved for treatment
of OFF symptoms in patients with PD in the US and European Union
[103]. In addition, the phase 3, multicenter TOLEDO trial randomized
107 levodopa-treated patients with PD and poorly controlled motor
fluctuations to double-blind treatment with apomorphine infusion
using a small ambulatory minipump (n = 53) or placebo (saline infu-
sion; n = 53) [104]. After 12 weeks, apomorphine infusion had sig-
nificantly reduced OFF time hours per day overall (based on patient's
diary) versus placebo (−2.47 h per day vs −0.58 h per day; −1.89 h
per day difference in favor of apomorphine; P = 0.0025).
Among other novel subcutaneous therapies, ND0612 is a solution of
carbidopa/levodopa administered by a pump-patch device in develop-
ment for continuous nonsurgical subcutaneous infusion, which aims to
produce smoother plasma levodopa levels than oral therapy and im-
prove OFF time. Good tolerability and safety have been reported in a
phase 1 study in 54 healthy volunteers; other studies are in progress
[105,106]. ABBV-951 is another carbidopa/levodopa prodrug designed
for minimally invasive subcutaneous continuous infusion [107]. A
phase 1 study of ABBV-951 in 6 healthy older adults (aged 45–75 years)
found that its pharmacokinetics over the first 16 h were similar to those
of levodopa-carbidopa intestinal gel (LCIG) in a comparable phase 1
study [108].
8.3. Sublingual
A sublingually administered formulation of apomorphine (APL-
130277) designed to reduce OFF time is in development and was
evaluated in a phase 3, randomized, placebo-controlled study.
Preliminary data for 76 patients who completed the open-label dose-
titration stage of the phase 3 trial showed that 83% of patients turned
fully ON with APL-130277 (median dose 20 mg) with onset of clinical
benefit between 5 and 12 min; 38% of patients were fully on by 15 min,
and 78% by 30 min [109]. Improvements of 22 and 16 points were also
observed in UPDRS at 30 and 90 min, respectively [110].
8.4. Intrajejunal
LCIG is a well-established and approved therapy designed for con-
tinuous infusion into the proximal jejunum via percutaneous endo-
scopic gastrojejunostomy tube connected to a portable infusion pump
[111,112]. Because of its invasive delivery system and associated risks
(eg, pain, tube detachment, weight loss), LCIG is indicated for patients
with motor fluctuations who have not benefited from other adjunctive
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Parkinsonism and Related Disorders 76 (2020) 63–71
treatments [111]. A systematic review of eight controlled clinical trials
showed that LCIG treatment in patients with PD significantly reduced
OFF time and related dyskinesias, although it posed a risk of surgical
and device-related adverse events [112].
8.5. Pulmonary
An orally inhaled levodopa powder (CVT-301) with pulmonary
delivery was developed to reduce OFF symptoms by circumventing the
GI tract. CVT-301 is approved in the US for treatment of OFF episodes
in patients who are already on an oral DDC inhibitor/levodopa re-
gimen. The inhaled levodopa quickly reaches the epithelium lining the
alveoli capillary network, leading to rapid absorption and onset of ac-
tion [71,72,97,113–115].
An open-label study in 24 patients with PD who experienced ≥2 h
of OFF time daily found that CVT-301 (25 or 50 mg) treatment during
an OFF episode occurring ≥4 h after the patient's morning dose of oral
carbidopa/levodopa produced a more rapid increase in levodopa
plasma concentration than oral carbidopa/levodopa [71]. Significant
improvements with CVT-301 (primarily at the 50 mg dose) versus
placebo were also observed in several motor function parameters. In a
12-week phase 3 study, 339 patients on a standard oral carbidopa/le-
vodopa regimen received CVT-301 60 mg, 84 mg, or placebo to be used
as an intermittent, adjunct treatment for the relief of OFF symptoms as
required [113]. The CVT-301 treatment was well tolerated and resulted
in significantly greater improvement in UPDRS Part III scores 30 min
after inhalation versus placebo; patients experienced a symptomatic
treatment effect as soon as 10 min following administration. Two ran-
domized, placebo-controlled, double-blind studies (total n = 110) also
found that CVT-301 did not appear to cause acute airflow obstruction in
this population [116]. A phase 3, open-label, long-term study in 408
patients with PD also found that those randomized to CVT-301
(n = 278) for 12 months showed no adverse effects on pulmonary
function, compared with controls (n = 130); reduction in total daily
OFF time (1.3–1.4 h) was consistent over the 52-week trial [117].
8.6. Subthalamic deep brain stimulation
Subthalamic nucleus deep brain stimulation (STN-DBS) has proven
to be very effective in ameliorating motor fluctuations in individuals
with PD, with reductions of up to 50–70% in dyskinesia, OFF time, and
levodopa-equivalent dosage [118]. Improvement has also been re-
ported in some nonmotor symptoms [119]. A study investigated the
effects of STN-DBS on gastroparesis in 16 patients with PD and de-
monstrated that STN-DBS stimulation improved gastric emptying,
whereas patients' usual DDC inhibitor/levodopa had no significant ef-
fect [119]. This study compared the gastric emptying time to maximum
emptying time (Tmax) as measured by the 13CO2 excretion breath test
before the STN-DBS surgery both with and without DDC inhibitor/le-
vodopa treatment, and the same DGE test procedures three months
post-surgery (levodopa treatment was withheld during STN-DBS testing
and for ≥12 h before the study days). Mean Tmax values for gastric
emptying demonstrated a significant reduction when STN-DBS stimu-
lation was switched on at three months post-surgery versus when the
stimulation was off (44.0 min versus 30.0 min; P < 0.001). This
contrasted with the pre-surgery values of 45.6 min and 42.5 min for
when the patient was ON (after DDC/levodopa administration) and OFF
respectively.
9. Therapies to improve gastric emptying
9.1. Prokinetic agents
Prokinetic agents such as dopamine receptor antagonists have long
been used as treatments for gastroparesis, regardless of etiology, based
on their ability to counteract dopamine- or levodopa-induced DGE
R.F. Pfeiffer, et al.
[120]. Although metoclopramide is the only dopamine receptor an-
tagonist FDA-approved for gastroparesis treatment, it may aggravate
PD motor symptoms and thus is not recommended for use in PD pa-
tients [120,121]. Domperidone is a dopamine receptor antagonist that
does not cross the blood–brain barrier and does not exacerbate motor
dysfunction in PD patients. Efficacy has been demonstrated in the
management of gastroparesis [33], including in patients with PD [122],
and domperidone co-administered with levodopa prevents levodopa-
induced DGE and increases levodopa plasma levels and bioavailability
[123–125]. Concerns regarding cardiac safety have been raised, but do
not preclude judicious use of domperidone [126]. However, it is neither
FDA-approved nor available in the US [120]. Mosapride, a 5-hydro-
xytryptamine type 4 (5HT4) agonist, is a benzamine derivative that is
used as a prokinetic agent in some Asian countries [127]. An open-label
study in 5 patients with PD and motor fluctuations found that mosa-
pride treatment significantly reduced gastric emptying T1/2 and motor
fluctuations, and improved motor function in all patients [128]. Pru-
calopride, another 5HT4 agonist, is approved for treatment of con-
stipation in the European Union and US and was also evaluated in a
small open-label study in patients with PD (n = 10) [129]. In this
study, prucalopride (n = 5) also significantly reduced mean gastric
emptying T1/2 versus baseline and compared (baseline-adjusted) with
domperidone (n = 5) but did not improve percent ON-time or UPDRS
motor function versus either comparator.
Ghrelin is an endogenous protein produced in the stomach and
exerts prokinetic effects in the GI tract, including appetite stimulation
[24]. Clinical studies in healthy subjects showed that exogenously ad-
ministered ghrelin treatment increased the tone of the proximal sto-
mach [130] and rate of gastric emptying [131]. Administration of
ghrelin [132] and ghrelin receptor agonists, including relamorelin
[133,134], also significantly increased the rate of gastric emptying in
patients with diabetes types 1 and 2 and gastroparesis. In fasted rats,
oral and intraperitoneally injected ghrelin significantly decreased gas-
tric emptying time, neutralized the inhibitory action of levodopa on
gastric emptying, and increased levodopa and dopamine plasma levels
[135].
9.2. Dietary considerations
Consumption of protein-rich meals may interfere with levodopa
absorption and contribute to motor complications, primarily through
competition of large neutral amino acids (eg, phenylalanine, tyrosine,
and tryptophan) with levodopa for specific active-transport systems in
the small intestine and at the blood–brain barrier [136–139]. Timing of
meals with respect to oral levodopa dosing may also significantly im-
pact levodopa absorption [140]. Dietary modification studies evalu-
ating restriction of protein intake to evening hours (the day's last meal)
and/or overall reduced protein consumption, in patients with PD and
motor complications, have demonstrated decreased motor fluctuations
in 30–90% of patients [137,141–145] and increased levodopa bioa-
vailability [138]. It is important to remember, however, that protein
restriction potentially magnifies the risk of weight loss, malnutrition,
and sarcopenia in PD patients [146] and the proportion of patients with
PD who benefit from dietary modification, and/or are compliant with
low-protein diets, remains unclear [137].
10. Conclusions
Gastroparesis is a complication of PD and H. pylori infection appears
with increased frequency in PD. Either may delay and reduce levodopa
absorption and efficacy, leading to prolonged OFF episodes. Treatment
of DGE and H. pylori may help improve levodopa absorption. Non-oral
routes of medication delivery may be used when GI dysmotility impairs
levodopa absorption. Clinically available treatments include trans-
dermal rotigotine patch, subcutaneous apomorphine, pulmonary levo-
dopa inhalation powder, and intrajejunal LCIG. Preliminary evidence
68
Parkinsonism and Related Disorders 76 (2020) 63–71
also suggest that STN-DBS may be effective.
Funding source
Editorial support was funded by Acorda Therapeutics, Inc.
Author contributions
The research, drafting, and revision of this review for important
intellectual content, as well as the final approval of the version to be
submitted, were carried out by all the authors equally.
Declaration of competing interest
RFP reports consulting honoraria from Acadia and Acorda; lecture
honoraria from Acadia; a research grant from Acorda; book royalties
from CRC Press and Humana Press.
SHI reports honoraria for CME, consultant, research grants, and/or
promotional speaker on behalf of AbbVie, Acadia, Acorda, Adamas
Pharmaceuticals, Addex, Allergan, Amarantus, Auspex, Avid, Axovant,
AZ Therapies, Biogen, Biotie, Britannia, Cynapsus, Eisai, Eli Lilly, GE
Healthcare, Impax, Intec Pharma, Ipsen, Kyowa, Lundbeck, Medtronics,
Merz, The Michael J. Fox Foundation, Neurocrine, Neuroderm, NINDS/
NIH, Parkinson Study Group, Pfizer, Pharma2B, Prothena, Roche,
Sanofi, Shire, Sunovion, Teva, UCB, US WorldMeds, and XenoPort.
RP reports compensation for advisory services or consulting, re-
search grant support, or speaker honoraria from the following: Abbott,
AbbVie, Acadia, Acorda, Adamas, Biogen, Boston Scientific,
CalaHealth, Cavion, Global Kinetics, Intec, Kyowa, Lilly, Lundbeck,
Neurocrine, NIH/NINDS, Parkinson Foundation, Photopharmics,
Prilenia, Sunovion, Teva Neuroscience, Theranexus, Theravance, US
WorldMeds, Voyager.
Acknowledgments
Editorial assistance was provided by Larry Deblinger and Robin
Smith, PhD of The Curry Rockefeller Group, LLC, which was funded by
Acorda Therapeutics, Inc.
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