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DA-9701 on gastric motility in patients with Parkinson's disease: A randomized controlled trial
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
DA-9701 on gastric motility in patients with Parkinson's disease: A randomized controlled trial Cheol Min Shina, Yoon Jin Leeb, Jong-Min Kimc,∗, Jee Young Leed, Kyung-Joon Kimc, Yoon Jin Choia, Nayoung Kima, Dong Ho Leea a
Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea c Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea d Department of Neurology, Seoul National University-Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea b
A R T I C LE I N FO
A B S T R A C T
Keywords: Parkinson's disease DA-9701 Domperidone Gastric emptying Clinical trial
Introduction: To evaluate the effect of DA-9701, a novel prokinetic drug, on gastric motility evaluated by magnetic resonance imaging in patients with Parkinson's disease (PD). Methods: Forty PD patients were randomly allocated to receive either domperidone or DA-9701. Their gastric functions were evaluated using magnetic resonance imaging before and after 4-week treatment period. Information on levodopa daily dose, disease duration, and Unified PD Rating Scale scores was collected. In 18 patients (domperidone: 9, DA-9701: 9), plasma levodopa concentrations were determined. Primary outcome was assessed by a one-sided 95% confidence interval to show non-inferiority of DA-9701 vs. domperidone with a predetermined non-inferiority margin of -10%. Results: Thirty-eight participants (19 men and 19 women; mean age, 67.1 years) completed the study protocol (domperidone: DA-9701 = 19:19). Gastric emptying rate at 120 min (2-hr GER) was comparable between the 2 groups; it was not correlated with levodopa daily dose or disease duration or Unified PD Rating Scale scores (all p > 0.05). DA-9701 was not inferior to domperidone in changes of 2-hr GERs before and after the treatment (absolute difference, 4.0 %; one-sided 95% confidence interval, – 3.7 to infinity). However, a significant increase in 2-hr GER was observed only in DA-9701 group (54.5% and 61.8%, before and after treatment, respectively, p < 0.05). Plasma levodopa concentration showed an insignificant but increasing trend in DA-9701 group. There were neither adverse reactions nor deteriorations of parkinsonian symptoms observed in the study participants. Conclusion: DA-9701 can be used for the patients with PD to enhance gastric motility without aggravating PD symptoms (ClinicalTrials.gov number: NCT03022201).
1. Introduction Patients with Parkinson's disease (PD) have impaired gastric function which can cause unpredictable absorption profiles of oral dopaminergic drugs and predispose suboptimal responses among these patients [1]. Prokinetic drugs are commonly prescribed to PD patients to prevent nausea and vomiting induced by anti-parkinsonian drugs and to reduce response fluctuations. Among prokinetic drugs, metoclopramide, a dopaminergic 2 (D2)receptor antagonist, is known to increase gastrointestinal (GI) motility and accelerate gastric emptying [2]. Metoclopramide accelerates GI
absorption, shortens time to onset of action, and increases blood concentrations of concomitantly administered medications [3]. However, metoclopramide can pass through the blood brain barrier (BBB) and induce extrapyramidal symptoms. Domperidone also increases gastric emptying. Since it rarely passes through BBB, it is regarded as a safe drug in drug-induced Parkinsonism [3]. However, previous studies on domperidone in patients with PD have reported inconsistent results [1,4,5]. Mosapride, a 5-hydroxytryptamine type 4 (5-HT4) agonist, has been reported to increase gastric motility and reduce response fluctuations among PD patients [6]. DA-9701 is a novel drug for functional dyspepsia that has been
∗ Corresponding author. Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do, 463-707, South Korea. E-mail address: [email protected] (J.-M. Kim).
https://doi.org/10.1016/j.parkreldis.2018.04.018 Received 23 November 2017; Received in revised form 7 March 2018; Accepted 17 April 2018 1353-8020/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Shin, C.M., Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.04.018
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marketed in South Korea since 2011 [7]. DA-9701 is formulated as 50% ethanol extract from Corydalis Tuber and Pharbitidis Semen, used in oriental traditional medicine for treatment of GI disorders. In a recent phase III trial, DA-9701 has shown non-inferior efficacy to itopride in patients with FD [8]. DA-9701 has prokinetic effects and improves gastric accommodation and visceral hypersensitivity. A recent study using magnetic resonance imaging (MRI) has shown that DA-9701 can enhance both gastric accommodation and gastric emptying among healthy volunteers [9]. As oral administration of DA-9701 at effective dose in humans did not lead to sufficient brain concentrations to exert central D2 receptor antagonism, this drug has potential to be used for PD patients safely [10]. From this background, we evaluated the effect of DA-9701 on gastric motility based on MRI and parkinsonian symptoms among PD patients.
domperidone group received domperidone plus placebo DA-9701 tablet three times per day 30 min before meal for 4 weeks. Following a 2-week screening period, study participants in each group were given study drugs for 4 weeks. All patients (n = 38) underwent MRI examinations before the treatment, but one patient in DA9701 group refused to undergo follow-up MRI. All study paticipants filled gastrointestinal symptom diary before and during the treatment period. Additionally, they submitted Patient's Global Assessment (PGA) for dyspeptic symptoms at the end of the treatment period. To evaluate any deterioration in PD, Unified Parkinson's Disease Rating Scale (UPDRS) parts III and IV score was assessed before and after the treatment. Blood levodopa concentrations 30 min after L-dopa dose administration were also measured in 18 patients before and after treatment. Concomitant anti-PD medications were allowed without any modification during the trial.
2. Materials and methods
2.3. MRI protocol
2.1. Study subjects
We modified MRI technique reported previously [9,12]. Gastric MRI was performed in supine position. Study participants underwent overnight fasting (6–8 h). After ingestion of 400 cc fluid meal (Nucare®, carbohydrate: protein: fat = 57:15:27; Daesang, Seoul, Korea), postmeal MRI was performed at 5, 10, 15, 30, 60, 90, and 120 min after completing test meal which was defined as time 0 min. Gastric volume was measured with axial 3D T1 mDixon, covering stomach, slice thickness of 4 mm, slice interval of 2 mm, and acquisition time of 16 s (one breath hold).
PD patients between 20 and 80 years old were eligible for this study. They were recruited from Seoul National University Bungdang Hospital between May 2013 and May 2016. Inclusion criteria were (1) subjects who were diagnosed with parkinsonism using the United Kingdom Parkinson's Disease Society Brain Bank criteria; (2) subjects who could explain symptoms they experienced and complete relevant assessment and examinations including questionnaires; (3) subjects who could understand the purpose and protocols of this study and agreed to participate in the study. Although some patients reported a predictable, minimal, or mild fluctuation, significant motor fluctuation was not present. Exclusion criteria were (1) subjects who experienced psychiatric disorders or cognitive impairment; (2) subjects who were on prokinetics which they could not cease; (3) subjects who had neurological or gastrointestinal disorders which could affect gastrointestinal motility; (4) subjects with a history of gastrectomy or colectomy; (5) subjects diagnosed with Parkinson plus syndrome; (6) subjects who were unable to receive or complete the course of medication due to other comorbidities; (7) subjects who were unable to undergo MRI scan for safety reasons due to claustrophobia or certain devices such as cardiac pacemakers or aneurysm clips. A recent Korean study have reported that standard deviation of gastric emptying rate at 120 min (2-hr GER) in healthy individuals were 10% [9], so non-inferiority limit was pre-determined to be - 10%. A priori power analysis determined that, if there is no difference between domperidone and DA-9701 treatment, 36 patients (18 per each group) are required to be 90% sure that the lower limit of a one-sided 95% confidence interval (CI) (or equivalently a 90% two-sided CI) will be above the non-inferiority limit of - 10% [11]. This study protocol was conducted in accordance with the Declaration of Helsinki. It was approved by the Institutional Review Board at Seoul National University Bundang Hospital (IRB No. B-1210/173-006). All subjects provided written informed consent before inclusion. The study was registered at ClinicalTrials.gov (NCT03022201).
2.4. Laboratory tests For all study participants, blood was drawn by venipuncture at baseline and at the 4-week follow-up to determine serum levels of liver enzymes [alanine transaminase (ALT)/aspartate transaminase (AST)], blood urea nitrogen (BUN), creatinine, and fasting glucose. In addition, 12-lead electrocardiogram was obtained for each patient before and after the treatment period. 2.5. Outcomes Primary outcome was changes in 2-hr GER evaluated by MRI from baseline to 4 weeks after the treatment period in the 2 groups. GER was calculated as follows: (gastric contents volume [GCV] at 5 min after the test meal – GCV at 10, 15, 30, 60, 90, 120 min after the test meal)/(GCV at 5 min after the test meal) × 100 (%). Percentage of gastric retention is calculated as 100 – GER (%). Secondary outcomes were changes of patient's symptoms of dyspepsia and constipation assessed by patient's diary. In addition, PGA for dyspeptic symptoms at the end of the treatment period was compared between the 2 groups. Other outcomes included changes in plasma levodopa concentration 30 min after L-dopa administration and changes in UPDRS part III score before and after treatment in the 2 groups. 2.6. Safety assessments
2.2. Study protocol
Safety was evaluated based on full clinical and laboratory assessment at every visit. Adverse events were checked during the treatment period, Dates of onset and resolution, severity, relationship with the study drug, and outcomes were recorded.
This study was a randomized, double-blind, and non-inferiority clinical trial. The study flow chart is summarized in Fig. 1. Eligible subjects were randomly allocated 1:1 using a blocked randomization method (block size = 4) to receive either DA-9701 (experimental drug) or domperidone (active comparator drug). A third party generated permuted-block allocation table. Allocation number and medicine containing both active drugs and placebo were provided to research nurses and pharmacist, respectively. Participants in DA-9701 group received DA-9701 30 mg plus placebo domperidone 10 mg three times per day 30 min before meal for 4 weeks while participants in
2.7. Statistical analyses Data are expressed as means ± SD or numbers and percentages. Characteristics of the study population were compared using Student's t-test or χ2 test. This study was designed to test DA-9701 in terms of 2hr GER with a non-inferiority margin of -10%. DA-9701 was determined to be non-inferior to domperidone when the lower limit of 2
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Fig. 1. Details of the study protocol. PD, Parkinson's disease; Mx, management; GI, gastrointestinal; Sx, symptom; MRI, magnetic resonance imaging; UPDRS, Unified Parkinson's Disease Rating Scale.
3.2. Effects of treatment on gastric emptying rate and gastrointestinal symptoms
one-sided 95% CI of the absolute difference in 2-hr GER was higher than -10%. Paired t-test was used to analyze paired samples. A general linear model was used to compare changes in UPDRS III score and plasma levodopa concentration from baseline to 4-weeks post-treatment between the 2 groups. All statistical analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). Statistical tests other than the primary outcome analysis were two-sided, and p-values of less than 0.05 were considered statistically significant.
After 4-week treatment, the changes of 2-hr GER in DA-9701 and domperidone groups were 7.3 ± 14.7% and 3.3 ± 12.9%, respectively. The absolute treatment difference was 4.0% (a one-sided 95% CI, -3.7 to infinity). The lower limit of the CI for the absolute difference (-3.7) was higher than the - 10% margin specified in the protocol. Then, 2-hr GERs were compared before and after the treatment for each group. Significant increase in GER after the treatment was observed in DA-9701 group (2-hr GER: 54.5% and 61.8% at before and after treatment, respectively, p < 0.05 by paired t-test, Fig. 2A), but not in domperidone group (Fig. 2B). The presence or absence of dyspeptic symptoms did not affect the outcomes (Supplementary Fig. S3). Among dyspeptic patients (n = 28), no significant improvement in dyspepsia was observed in either group (Supplementary Fig. S4). No differences in PGA for dyspepsia or frequencies of SCBMs were observed in either group (Table 2).
3. Results 3.1. Baseline characteristics Thirty-eight participants completed the study protocol (domperidone: DA-9701 = 19:19). There were no significant differences in demographic characteristics between the 2 groups (Table 1). Both UPDRS and Korean version of Non-Motor Symptoms Scale scores were not different between the 2 groups (all p-values > 0.05). Duration with L-dopa and L-dopa equivalent daily dose (LEDD) for domperidone group were longer (p = 0.056) and higher (p = 0.086) than those for DA-9701 group, respectively. Proportions of functional constipation and dyspeptic symptoms were not significantly different between the 2 groups. Frequencies of spontaneous complete bowel movements (SCBMs) per week were also comparable between the 2 groups (p > 0.05). As for laboratory findings, there were no significant differences between the 2 groups except for serum creatinine levels which were higher in DA-9701 group than in domperidone group (p = 0.031). Baseline gastric MRI showed no significant differences between the 2 groups (p > 0.05, Supplementary Fig. S1). However, GERs were significantly decreased in patients with dyspeptic symptoms (n = 28) compared with those in patients without dyspepsia (n = 10, Supplementary Fig. S2A). The decrease was most prominent among patients with both meal-related symptoms (early satiation or postprandial fullness) and epigastric pain/burning (Supplementary Fig. S2D). On the other hand, 2-hr GER was not correlated with LEDD, duration of PD, or UPDRS scores (Supplementary Table S1).
3.3. Effects of treatment on parkinsonian symptoms DA-9701 group had significantly higher proportion of patients with improved UPDRS part III score than domperidone group (42.1% and 73.7% in domperidone and DA-9701 group, respectively, p = 0.049 by χ2-test, Table 2). The duration of “on” time or dyskinesia evaluated by UPDRS IV did not change in any patient during the treatment (Supplementary Table S2). 3.4. Effects of treatment on plasma levodopa concentration Eighteen patients (domperidone: DA-9701 = 9:9) had data on plasma levodopa concentrations 30 min after dose administration before and after the treatment. The median of their daily L-dopa dose at the time of enrollment was 540 mg (interquartile range, 312.5–656.3 mg). L-Dopa doses in these patients were not changed during the study period. Plasma levodopa concentration showed an increase in DA-9701 group only (Δ L-dopa concentration: −17.2 ± 688.3 ng/mL and 256.3 ± 814.8 ng/mL in domperidone and DA-9701 groups, respectively), which was not statistically significant. 3
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Table 1 Baseline characteristics of the study participants.
Male (%) Age (y) BMI (kg/m2) Comorbidities Chronic renal diseases (%) Diabetes (%) Hypertension (%) UPDRS score Part I Part II Part III Part IV NMSS-K total score Duration with L-dopa (months) L-dopa equivalent daily dose (LEDD, mg/day) Daily L-dopa doses (mg/day) Functional constipation (ROME III) Lumpy or hard stools Straining Sensation of incomplete evacuation Sensation of anorectal obstruction/blockage Manual maneuvers to facilitate defecations Fewer than 3 defecations per week Dyspeptic symptoms present (%) Epigastric pain/burning (%) Early satiation/postprandial fullness (%) SCBM per week Laboratory findings AST (IU/L) ALT (IU/L) Alkaline phophatase (IU/L) Bilirubin, total (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Prolactin (ng/mL)
Domperidone
DA-9701
P-value
(n = 19)
(n = 19)
9 (47.4) 65.2 ± 7.8 23.1 ± 3.3
10 (55.6) 68.5 ± 6.0 23.2 ± 2.6
0.618 0.302 0.945
0 (0.0) 3 (15.8) 3 (15.8)
1 (5.3) 3 (15.8) 4 (21.1)
1.000 1.000 1.000
10.0 ± 6.2 13.4 ± 4.9 22.7 ± 10.0 4.4 ± 2.8 50.2 ± 22.9 60.6 ± 49.8 743.2 ± 499.9
9.1 ± 4.7 12.7 ± 4.4 21.8 ± 8.3 3.2 ± 2.3 42.0 ± 14.1 33.9 ± 31.6 522.7 ± 235.4
0.621 0.617 0.772 0.153 0.195 0.056 0.086
441.7 ± 393.7 11 (57.9) 10 (52.6) 11 (57.9) 9 (47.4)
361.1 ± 179.9 14 (73.7) 11 (57.9) 13 (68.4) 9 (47.4)
0.584 0.305 0.744 0.501 1.000
10 (52.6)
14 (73.7)
0.179
1 (5.3)
1 (5.3)
1.000
6 (31.6)
6 (31.6)
1.000
16 (84.2) 7 (36.8) 15 (78.9)
12 (63.2) 6 (31.6) 10 (52.6)
0.269 0.732 0.087
6.6 ± 4.4
4.8 ± 2.8
0.152
24.2 ± 7.0 18.2 ± 8.3 74.5 ± 20.0 0.7 ± 0.2 9.0 ± 0.4 3.6 ± 0.6 14.9 ± 3.8 0.7 ± 0.2 5.0 ± 10.4
22.9 ± 8.2 24.6 ± 23.3 61.0 ± 22.8 0.7 ± 0.2 9.1 ± 0.2 0.3 ± 0.5 17.1 ± 4.5 0.9 ± 0.2 5.4 ± 9.0
0.612 0.265 0.059 0.498 0.154 0.239 0.118 0.031 0.895
Fig. 2. Gastric emptying after administration of test meal (400 cc, 200 kcal) before and after the treatment in DA-9701 (A) and domperidone (B) groups. Significant difference in 2-hr GER was observed in DA-9701 group only (2-hr GER; 54.5% and 61.8%, before and after treatment, respectively.) Data were presented as mean ± standard error. 2-hr GER, gastric emptying rate at 2 h. *p < 0.05.
p-values were calculated using either Student's t-test (for continuous variables) or χ2-test (for categorical variables). BMI, body mass index; UPDRS, Unified Parkinson's Disease Rating Scale; NMSS-K, Korean version of Non-Motor Symptoms Scale; SCBM, spontaneous complete bowel movement; AST, aspartate transaminase; ALT, alanine transaminase. Bold style indicates statistical significance (p < 0.05).
4. Discussion This study evaluated gastric motor function using MRI, a well-validated means in assessing gastric motor functions [13–15]. Concomitant anti-PD medications were allowed, but any modifications to these medications were not allowed during the study period. We observed that patients with PD had decreased gastric function compared to non-PD individuals. A recent Korean study has evaluated GER using similar MRI technique and shown that 2-hr GERs were ∼80% among healthy volunteers [9], significantly higher than those of patients with PD in this study (∼60%). This is consistent with previous studies indicating that gastroparesis is very common among individuals with PD [16]. In addition, we found that PD patients with dyspeptic symptoms had even more impaired gastric function than those without dyspepsia (Supplementary Fig. S2). Meal-related symptoms were associated with delayed gastric emptying more than epigastric pain/burning symptoms. Overlap of these two dyspeptic symptoms could decrease gastric function even more. The pathogenesis of delayed gastric emptying is known to be complicated, involving abnormalities of both enteric and central nervous
3.5. Assessments for compliance and safety Compliances of domperidone and DA-9701 were 88.0% and 87.8%, respectively. The incidences of adverse reactions were minimal in both groups (Table 2 and Supplementary Tables S2 and S3). No subjects had any adverse reactions that might have resulted in their dropping out from the study. There were no deteriorations of parkinsonian symptoms in either group. In laboratory test, serum prolactin level was increased in domperidone group (p = 0.012), but not in DA-9701 group (p > 0.05, Supplementary Table S3). Serum liver enzymes, BUN, creatinine, alkaline phosphatase, calcium, and phosphate levels did not differ between before and after the treatment in either group. No serious electrocardiographic alternations occurred during the study period in either group. There were no significant changes in corrected QT intervals before and after the treatment in either group.
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Dopaminergic agents are essential to treat motor symptoms of PD. However, they are likely to exacerbate gastroparesis. Anti-dopaminergic agents such as metoclopramide or itopride are contraindicated because they can exacerbate motor symptoms. Domperidone does not cross the BBB. However, domperidone has potential risk of causing cardiac arrhythmia [24]. Mosapride might be a good option for some PD patients. However, there is little evidence to support its benefit [6]. Deep brain stimulation might improve gastric emptying in some PD patients [25]. Endoscopic pyloric botulinum injections or gastric electrical stimulation might be an option. However, these only have limited evidence in PD patients [26,27]. DA-9701 can be used in PD patients safely. As this study was a short-term follow-up study, large-scale longterm follow-up studies are necessary to confirm these findings. Our study has several limitations. First,this study was not designed to show the superiority of DA-9701 to domperidone, thus, the positive results in DA-9701 group should be confirmed by a pre-planned superiority design study. Second, patients with PD were included in this study regardless of the presence or absence of dyspeptic symptoms. Thus, analyses for effects of the study drug on dyspeptic symptoms were limited. Previous studies on the prevalence of dyspepsia in PD patients were limited. Nevertheless, in this study, we found that dyspeptic PD patients, especially those who had postprandial distress, had more delayed gastric emptying. Thus, prokinetic drugs might improve dyspepsia in these patients. A large prospective study regarding the effect of long-term administration of DA-9701 on dyspeptic symptoms among the dyspeptic PD patients is warranted to clarify this issue. Third, there were only 18 patients who had blood samples available for plasma levodopa concentration analyses. Lastly, in this study, gastric MRI was performed in the supine position. However, it has been reported that gastric motor function or intragastric meal distribution is not significantly different between upright and supine positions [12,28]. In conclusion, DA-9701 was not inferior to domperidone in terms of the improvement of gastric function in patients with PD. DA-9701 showed a potential to enhance gastric motility without aggravating parkinsonian symptoms. Thus, DA-9701 can be used as an option for these patients safely. Further studies are warranted to clarify the clinical efficacy of DA-9701 in patients with PD.
Table 2 Comparison of Unified Parkinson's Disease Rating Scale part III scores, dyspeptic symptoms, and plasma levodopa concentration between the 2 groups after the 4-week treatment. Domperidone
DA-9701
(n = 19)
(n = 19)
Δ UPDRS III score 0.39 ± 3.37 UPDRS III score improved (%) 8 (42.1) Patient's global assessment for dyspeptic symptoms Markedly improved (≥75%) 0 (0.0) Moderately improved (50–74%) 4 (21.1) Mildly improved (25–49%) 11 (57.9) No improvement (0–25%) 4 (21.1) Symptoms aggravated 0 (0.0) Δ plasma levodopa concentration −17.2 ± 688.3 (ng/mL, n = 18)
P-value
−1.29 ± 4.37 14 (73.7)
0.192 0.049
0 (0.0) 6 (31.6) 10 (52.6) 3 (15.8) 0 (0.0) 256.3 ± 814.8
0.744
0.531
P-values were calculated using general linear model (for the comparison between the 2 groups in the changes of UPDRS III score and plasma levodopa concentration before and after the treatment) or χ2-test (for categorical variables). UPDRS III, Unified Parkinson's Disease Rating Scale part III. Bold style indicates statistical significance (p < 0.05).
systems. L-Dopa medication also causes delayed gastric emptying [2]. Several studies have reported that delayed gastric emptying could lead to increased unpredictability of motor fluctuation due to the possibility that delayed gastric emptying could lead to delayed delivery and decreased absorption of L-dopa which is mainly absorbed in the small intestine [17–19]. In this study, GERs did not correlate with LEDD, disease duration, or UPDRS scores (Supplementary Table S1). Previous studies on this issue have shown inconsistent results [20–22]. Delayed gastric emptying might occur from an early stage of PD. DA-9701 has antagonistic effect on D2 receptor and agonistic effects on 5-HT1A, 5-HT4 and adrenergic α2 receptors. DA-9701 can enhance gastric emptying by D2 antagonistic effect and 5-HT4 agonistic effect [7]. Tetrahydroberberine isolated from Corydalis Tuber has an affinity to both D2 and 5-HT1A receptors. It is associated with enhancement of gastric emptying and restoration of delayed gastric emptying [23]. The results of changes in 2-hr GERs after 4-week treatment showed that DA-9701 was not inferior to domperidone (Fig. 2). Nevertheless, DA-9701 group, but not domperidone group, showed significant improvement in 2-hr GER after the treatment (Fig. 2). Levodopa blood concentrations also increased in DA-9701 group, although it did not reach statistical significance probably due to small sample size (Table 2). Further studies are necessary to confirm whether DA-9701 can improve the levodopa pharmacokinetics. After the treatment, more patients in DA-9701 group showed an improvement in UPDRS part III score than those in domperidone group (Table 2). Improvements in delayed gastric emptying followed by improved pharmacokinetics of L-dopa might be related to favorable outcomes. Non-motor symptoms evaluated by UPDRS part IV were not changed after treatment in either group (Supplementary Table S3). For example, there were no changes in the duration of “off” time. However, study participants were not asked to keep a diary about their parkinsonian symptoms. More studies are needed to determine whether DA9701 could improve the “on” time duration among PD patients. On the other hand, there were no significant improvements in dyspeptic symptoms observed after treatment in either group (Supplementary Fig. S4). Sample size was not large enough to yield significant results. In fact, the objective of this study was not to determine the effect of prokinetics on relieving dyspeptic symptoms in PD patients. In terms of adverse effects, DA-9701 also showed favorable outcomes. Especially, domperidone caused prolactinemia whereas DA9701 did not (Supplementary Table S3). Currently, we have only limited options to control gastric dysfunction in patients with PD.
Author contributions CMS designed the entire study protocol, performed the data analyses, and wrote the first draft. YJL performed gastric MRI analyses, and review and criticized the 1st draft. JMK conceptualized the study design, enrolled all study subjects, and reviewed the 1st draft. JYL conceptualized the study design, and review and criticized the 1st draft. KJL performed part of the data analyses and reviewed the 1st draft. YJC designed the study protocol and reviewed the 1st draft. NK supervised the protocol and criticized the 1st draft. DHL conceptualized the study protocol and review the 1st draft.
Financial disclosure/Conflict of interest Dong-A ST was funded by the Ministry of Knowledge Economy for the drug. No author has any conflict of interest or financial arrangement that could potentially influence the presented research.
Funding sources for study This work was supported by the Global Leading Technology Program of the Office of Strategic R&D Planning (OSP), funded by the Ministry of Knowledge Economy, Republic of Korea (10039303). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 5
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Acknowledgement [13]
The authors are indebted to Professor Yang Won Min and Professor Poong-Lyul Rhee, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, for their advice regarding gastric MRI protocol.
[14]
Appendix A. Supplementary data
[15]
Supplementary data related to this article can be found at http://dx. doi.org/10.1016/j.parkreldis.2018.04.018.
[16]
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
DA-9701 on gastric motility in patients with Parkinson's disease: A randomized controlled trial Cheol Min Shina, Yoon Jin Leeb, Jong-Min Kimc,∗, Jee Young Leed, Kyung-Joon Kimc, Yoon Jin Choia, Nayoung Kima, Dong Ho Leea a
Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea c Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea d Department of Neurology, Seoul National University-Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea b
A R T I C LE I N FO
A B S T R A C T
Keywords: Parkinson's disease DA-9701 Domperidone Gastric emptying Clinical trial
Introduction: To evaluate the effect of DA-9701, a novel prokinetic drug, on gastric motility evaluated by magnetic resonance imaging in patients with Parkinson's disease (PD). Methods: Forty PD patients were randomly allocated to receive either domperidone or DA-9701. Their gastric functions were evaluated using magnetic resonance imaging before and after 4-week treatment period. Information on levodopa daily dose, disease duration, and Unified PD Rating Scale scores was collected. In 18 patients (domperidone: 9, DA-9701: 9), plasma levodopa concentrations were determined. Primary outcome was assessed by a one-sided 95% confidence interval to show non-inferiority of DA-9701 vs. domperidone with a predetermined non-inferiority margin of -10%. Results: Thirty-eight participants (19 men and 19 women; mean age, 67.1 years) completed the study protocol (domperidone: DA-9701 = 19:19). Gastric emptying rate at 120 min (2-hr GER) was comparable between the 2 groups; it was not correlated with levodopa daily dose or disease duration or Unified PD Rating Scale scores (all p > 0.05). DA-9701 was not inferior to domperidone in changes of 2-hr GERs before and after the treatment (absolute difference, 4.0 %; one-sided 95% confidence interval, – 3.7 to infinity). However, a significant increase in 2-hr GER was observed only in DA-9701 group (54.5% and 61.8%, before and after treatment, respectively, p < 0.05). Plasma levodopa concentration showed an insignificant but increasing trend in DA-9701 group. There were neither adverse reactions nor deteriorations of parkinsonian symptoms observed in the study participants. Conclusion: DA-9701 can be used for the patients with PD to enhance gastric motility without aggravating PD symptoms (ClinicalTrials.gov number: NCT03022201).
1. Introduction Patients with Parkinson's disease (PD) have impaired gastric function which can cause unpredictable absorption profiles of oral dopaminergic drugs and predispose suboptimal responses among these patients [1]. Prokinetic drugs are commonly prescribed to PD patients to prevent nausea and vomiting induced by anti-parkinsonian drugs and to reduce response fluctuations. Among prokinetic drugs, metoclopramide, a dopaminergic 2 (D2)receptor antagonist, is known to increase gastrointestinal (GI) motility and accelerate gastric emptying [2]. Metoclopramide accelerates GI
absorption, shortens time to onset of action, and increases blood concentrations of concomitantly administered medications [3]. However, metoclopramide can pass through the blood brain barrier (BBB) and induce extrapyramidal symptoms. Domperidone also increases gastric emptying. Since it rarely passes through BBB, it is regarded as a safe drug in drug-induced Parkinsonism [3]. However, previous studies on domperidone in patients with PD have reported inconsistent results [1,4,5]. Mosapride, a 5-hydroxytryptamine type 4 (5-HT4) agonist, has been reported to increase gastric motility and reduce response fluctuations among PD patients [6]. DA-9701 is a novel drug for functional dyspepsia that has been
∗ Corresponding author. Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do, 463-707, South Korea. E-mail address: [email protected] (J.-M. Kim).
https://doi.org/10.1016/j.parkreldis.2018.04.018 Received 23 November 2017; Received in revised form 7 March 2018; Accepted 17 April 2018 1353-8020/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Shin, C.M., Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.04.018
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marketed in South Korea since 2011 [7]. DA-9701 is formulated as 50% ethanol extract from Corydalis Tuber and Pharbitidis Semen, used in oriental traditional medicine for treatment of GI disorders. In a recent phase III trial, DA-9701 has shown non-inferior efficacy to itopride in patients with FD [8]. DA-9701 has prokinetic effects and improves gastric accommodation and visceral hypersensitivity. A recent study using magnetic resonance imaging (MRI) has shown that DA-9701 can enhance both gastric accommodation and gastric emptying among healthy volunteers [9]. As oral administration of DA-9701 at effective dose in humans did not lead to sufficient brain concentrations to exert central D2 receptor antagonism, this drug has potential to be used for PD patients safely [10]. From this background, we evaluated the effect of DA-9701 on gastric motility based on MRI and parkinsonian symptoms among PD patients.
domperidone group received domperidone plus placebo DA-9701 tablet three times per day 30 min before meal for 4 weeks. Following a 2-week screening period, study participants in each group were given study drugs for 4 weeks. All patients (n = 38) underwent MRI examinations before the treatment, but one patient in DA9701 group refused to undergo follow-up MRI. All study paticipants filled gastrointestinal symptom diary before and during the treatment period. Additionally, they submitted Patient's Global Assessment (PGA) for dyspeptic symptoms at the end of the treatment period. To evaluate any deterioration in PD, Unified Parkinson's Disease Rating Scale (UPDRS) parts III and IV score was assessed before and after the treatment. Blood levodopa concentrations 30 min after L-dopa dose administration were also measured in 18 patients before and after treatment. Concomitant anti-PD medications were allowed without any modification during the trial.
2. Materials and methods
2.3. MRI protocol
2.1. Study subjects
We modified MRI technique reported previously [9,12]. Gastric MRI was performed in supine position. Study participants underwent overnight fasting (6–8 h). After ingestion of 400 cc fluid meal (Nucare®, carbohydrate: protein: fat = 57:15:27; Daesang, Seoul, Korea), postmeal MRI was performed at 5, 10, 15, 30, 60, 90, and 120 min after completing test meal which was defined as time 0 min. Gastric volume was measured with axial 3D T1 mDixon, covering stomach, slice thickness of 4 mm, slice interval of 2 mm, and acquisition time of 16 s (one breath hold).
PD patients between 20 and 80 years old were eligible for this study. They were recruited from Seoul National University Bungdang Hospital between May 2013 and May 2016. Inclusion criteria were (1) subjects who were diagnosed with parkinsonism using the United Kingdom Parkinson's Disease Society Brain Bank criteria; (2) subjects who could explain symptoms they experienced and complete relevant assessment and examinations including questionnaires; (3) subjects who could understand the purpose and protocols of this study and agreed to participate in the study. Although some patients reported a predictable, minimal, or mild fluctuation, significant motor fluctuation was not present. Exclusion criteria were (1) subjects who experienced psychiatric disorders or cognitive impairment; (2) subjects who were on prokinetics which they could not cease; (3) subjects who had neurological or gastrointestinal disorders which could affect gastrointestinal motility; (4) subjects with a history of gastrectomy or colectomy; (5) subjects diagnosed with Parkinson plus syndrome; (6) subjects who were unable to receive or complete the course of medication due to other comorbidities; (7) subjects who were unable to undergo MRI scan for safety reasons due to claustrophobia or certain devices such as cardiac pacemakers or aneurysm clips. A recent Korean study have reported that standard deviation of gastric emptying rate at 120 min (2-hr GER) in healthy individuals were 10% [9], so non-inferiority limit was pre-determined to be - 10%. A priori power analysis determined that, if there is no difference between domperidone and DA-9701 treatment, 36 patients (18 per each group) are required to be 90% sure that the lower limit of a one-sided 95% confidence interval (CI) (or equivalently a 90% two-sided CI) will be above the non-inferiority limit of - 10% [11]. This study protocol was conducted in accordance with the Declaration of Helsinki. It was approved by the Institutional Review Board at Seoul National University Bundang Hospital (IRB No. B-1210/173-006). All subjects provided written informed consent before inclusion. The study was registered at ClinicalTrials.gov (NCT03022201).
2.4. Laboratory tests For all study participants, blood was drawn by venipuncture at baseline and at the 4-week follow-up to determine serum levels of liver enzymes [alanine transaminase (ALT)/aspartate transaminase (AST)], blood urea nitrogen (BUN), creatinine, and fasting glucose. In addition, 12-lead electrocardiogram was obtained for each patient before and after the treatment period. 2.5. Outcomes Primary outcome was changes in 2-hr GER evaluated by MRI from baseline to 4 weeks after the treatment period in the 2 groups. GER was calculated as follows: (gastric contents volume [GCV] at 5 min after the test meal – GCV at 10, 15, 30, 60, 90, 120 min after the test meal)/(GCV at 5 min after the test meal) × 100 (%). Percentage of gastric retention is calculated as 100 – GER (%). Secondary outcomes were changes of patient's symptoms of dyspepsia and constipation assessed by patient's diary. In addition, PGA for dyspeptic symptoms at the end of the treatment period was compared between the 2 groups. Other outcomes included changes in plasma levodopa concentration 30 min after L-dopa administration and changes in UPDRS part III score before and after treatment in the 2 groups. 2.6. Safety assessments
2.2. Study protocol
Safety was evaluated based on full clinical and laboratory assessment at every visit. Adverse events were checked during the treatment period, Dates of onset and resolution, severity, relationship with the study drug, and outcomes were recorded.
This study was a randomized, double-blind, and non-inferiority clinical trial. The study flow chart is summarized in Fig. 1. Eligible subjects were randomly allocated 1:1 using a blocked randomization method (block size = 4) to receive either DA-9701 (experimental drug) or domperidone (active comparator drug). A third party generated permuted-block allocation table. Allocation number and medicine containing both active drugs and placebo were provided to research nurses and pharmacist, respectively. Participants in DA-9701 group received DA-9701 30 mg plus placebo domperidone 10 mg three times per day 30 min before meal for 4 weeks while participants in
2.7. Statistical analyses Data are expressed as means ± SD or numbers and percentages. Characteristics of the study population were compared using Student's t-test or χ2 test. This study was designed to test DA-9701 in terms of 2hr GER with a non-inferiority margin of -10%. DA-9701 was determined to be non-inferior to domperidone when the lower limit of 2
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Fig. 1. Details of the study protocol. PD, Parkinson's disease; Mx, management; GI, gastrointestinal; Sx, symptom; MRI, magnetic resonance imaging; UPDRS, Unified Parkinson's Disease Rating Scale.
3.2. Effects of treatment on gastric emptying rate and gastrointestinal symptoms
one-sided 95% CI of the absolute difference in 2-hr GER was higher than -10%. Paired t-test was used to analyze paired samples. A general linear model was used to compare changes in UPDRS III score and plasma levodopa concentration from baseline to 4-weeks post-treatment between the 2 groups. All statistical analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). Statistical tests other than the primary outcome analysis were two-sided, and p-values of less than 0.05 were considered statistically significant.
After 4-week treatment, the changes of 2-hr GER in DA-9701 and domperidone groups were 7.3 ± 14.7% and 3.3 ± 12.9%, respectively. The absolute treatment difference was 4.0% (a one-sided 95% CI, -3.7 to infinity). The lower limit of the CI for the absolute difference (-3.7) was higher than the - 10% margin specified in the protocol. Then, 2-hr GERs were compared before and after the treatment for each group. Significant increase in GER after the treatment was observed in DA-9701 group (2-hr GER: 54.5% and 61.8% at before and after treatment, respectively, p < 0.05 by paired t-test, Fig. 2A), but not in domperidone group (Fig. 2B). The presence or absence of dyspeptic symptoms did not affect the outcomes (Supplementary Fig. S3). Among dyspeptic patients (n = 28), no significant improvement in dyspepsia was observed in either group (Supplementary Fig. S4). No differences in PGA for dyspepsia or frequencies of SCBMs were observed in either group (Table 2).
3. Results 3.1. Baseline characteristics Thirty-eight participants completed the study protocol (domperidone: DA-9701 = 19:19). There were no significant differences in demographic characteristics between the 2 groups (Table 1). Both UPDRS and Korean version of Non-Motor Symptoms Scale scores were not different between the 2 groups (all p-values > 0.05). Duration with L-dopa and L-dopa equivalent daily dose (LEDD) for domperidone group were longer (p = 0.056) and higher (p = 0.086) than those for DA-9701 group, respectively. Proportions of functional constipation and dyspeptic symptoms were not significantly different between the 2 groups. Frequencies of spontaneous complete bowel movements (SCBMs) per week were also comparable between the 2 groups (p > 0.05). As for laboratory findings, there were no significant differences between the 2 groups except for serum creatinine levels which were higher in DA-9701 group than in domperidone group (p = 0.031). Baseline gastric MRI showed no significant differences between the 2 groups (p > 0.05, Supplementary Fig. S1). However, GERs were significantly decreased in patients with dyspeptic symptoms (n = 28) compared with those in patients without dyspepsia (n = 10, Supplementary Fig. S2A). The decrease was most prominent among patients with both meal-related symptoms (early satiation or postprandial fullness) and epigastric pain/burning (Supplementary Fig. S2D). On the other hand, 2-hr GER was not correlated with LEDD, duration of PD, or UPDRS scores (Supplementary Table S1).
3.3. Effects of treatment on parkinsonian symptoms DA-9701 group had significantly higher proportion of patients with improved UPDRS part III score than domperidone group (42.1% and 73.7% in domperidone and DA-9701 group, respectively, p = 0.049 by χ2-test, Table 2). The duration of “on” time or dyskinesia evaluated by UPDRS IV did not change in any patient during the treatment (Supplementary Table S2). 3.4. Effects of treatment on plasma levodopa concentration Eighteen patients (domperidone: DA-9701 = 9:9) had data on plasma levodopa concentrations 30 min after dose administration before and after the treatment. The median of their daily L-dopa dose at the time of enrollment was 540 mg (interquartile range, 312.5–656.3 mg). L-Dopa doses in these patients were not changed during the study period. Plasma levodopa concentration showed an increase in DA-9701 group only (Δ L-dopa concentration: −17.2 ± 688.3 ng/mL and 256.3 ± 814.8 ng/mL in domperidone and DA-9701 groups, respectively), which was not statistically significant. 3
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Table 1 Baseline characteristics of the study participants.
Male (%) Age (y) BMI (kg/m2) Comorbidities Chronic renal diseases (%) Diabetes (%) Hypertension (%) UPDRS score Part I Part II Part III Part IV NMSS-K total score Duration with L-dopa (months) L-dopa equivalent daily dose (LEDD, mg/day) Daily L-dopa doses (mg/day) Functional constipation (ROME III) Lumpy or hard stools Straining Sensation of incomplete evacuation Sensation of anorectal obstruction/blockage Manual maneuvers to facilitate defecations Fewer than 3 defecations per week Dyspeptic symptoms present (%) Epigastric pain/burning (%) Early satiation/postprandial fullness (%) SCBM per week Laboratory findings AST (IU/L) ALT (IU/L) Alkaline phophatase (IU/L) Bilirubin, total (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Prolactin (ng/mL)
Domperidone
DA-9701
P-value
(n = 19)
(n = 19)
9 (47.4) 65.2 ± 7.8 23.1 ± 3.3
10 (55.6) 68.5 ± 6.0 23.2 ± 2.6
0.618 0.302 0.945
0 (0.0) 3 (15.8) 3 (15.8)
1 (5.3) 3 (15.8) 4 (21.1)
1.000 1.000 1.000
10.0 ± 6.2 13.4 ± 4.9 22.7 ± 10.0 4.4 ± 2.8 50.2 ± 22.9 60.6 ± 49.8 743.2 ± 499.9
9.1 ± 4.7 12.7 ± 4.4 21.8 ± 8.3 3.2 ± 2.3 42.0 ± 14.1 33.9 ± 31.6 522.7 ± 235.4
0.621 0.617 0.772 0.153 0.195 0.056 0.086
441.7 ± 393.7 11 (57.9) 10 (52.6) 11 (57.9) 9 (47.4)
361.1 ± 179.9 14 (73.7) 11 (57.9) 13 (68.4) 9 (47.4)
0.584 0.305 0.744 0.501 1.000
10 (52.6)
14 (73.7)
0.179
1 (5.3)
1 (5.3)
1.000
6 (31.6)
6 (31.6)
1.000
16 (84.2) 7 (36.8) 15 (78.9)
12 (63.2) 6 (31.6) 10 (52.6)
0.269 0.732 0.087
6.6 ± 4.4
4.8 ± 2.8
0.152
24.2 ± 7.0 18.2 ± 8.3 74.5 ± 20.0 0.7 ± 0.2 9.0 ± 0.4 3.6 ± 0.6 14.9 ± 3.8 0.7 ± 0.2 5.0 ± 10.4
22.9 ± 8.2 24.6 ± 23.3 61.0 ± 22.8 0.7 ± 0.2 9.1 ± 0.2 0.3 ± 0.5 17.1 ± 4.5 0.9 ± 0.2 5.4 ± 9.0
0.612 0.265 0.059 0.498 0.154 0.239 0.118 0.031 0.895
Fig. 2. Gastric emptying after administration of test meal (400 cc, 200 kcal) before and after the treatment in DA-9701 (A) and domperidone (B) groups. Significant difference in 2-hr GER was observed in DA-9701 group only (2-hr GER; 54.5% and 61.8%, before and after treatment, respectively.) Data were presented as mean ± standard error. 2-hr GER, gastric emptying rate at 2 h. *p < 0.05.
p-values were calculated using either Student's t-test (for continuous variables) or χ2-test (for categorical variables). BMI, body mass index; UPDRS, Unified Parkinson's Disease Rating Scale; NMSS-K, Korean version of Non-Motor Symptoms Scale; SCBM, spontaneous complete bowel movement; AST, aspartate transaminase; ALT, alanine transaminase. Bold style indicates statistical significance (p < 0.05).
4. Discussion This study evaluated gastric motor function using MRI, a well-validated means in assessing gastric motor functions [13–15]. Concomitant anti-PD medications were allowed, but any modifications to these medications were not allowed during the study period. We observed that patients with PD had decreased gastric function compared to non-PD individuals. A recent Korean study has evaluated GER using similar MRI technique and shown that 2-hr GERs were ∼80% among healthy volunteers [9], significantly higher than those of patients with PD in this study (∼60%). This is consistent with previous studies indicating that gastroparesis is very common among individuals with PD [16]. In addition, we found that PD patients with dyspeptic symptoms had even more impaired gastric function than those without dyspepsia (Supplementary Fig. S2). Meal-related symptoms were associated with delayed gastric emptying more than epigastric pain/burning symptoms. Overlap of these two dyspeptic symptoms could decrease gastric function even more. The pathogenesis of delayed gastric emptying is known to be complicated, involving abnormalities of both enteric and central nervous
3.5. Assessments for compliance and safety Compliances of domperidone and DA-9701 were 88.0% and 87.8%, respectively. The incidences of adverse reactions were minimal in both groups (Table 2 and Supplementary Tables S2 and S3). No subjects had any adverse reactions that might have resulted in their dropping out from the study. There were no deteriorations of parkinsonian symptoms in either group. In laboratory test, serum prolactin level was increased in domperidone group (p = 0.012), but not in DA-9701 group (p > 0.05, Supplementary Table S3). Serum liver enzymes, BUN, creatinine, alkaline phosphatase, calcium, and phosphate levels did not differ between before and after the treatment in either group. No serious electrocardiographic alternations occurred during the study period in either group. There were no significant changes in corrected QT intervals before and after the treatment in either group.
4
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Dopaminergic agents are essential to treat motor symptoms of PD. However, they are likely to exacerbate gastroparesis. Anti-dopaminergic agents such as metoclopramide or itopride are contraindicated because they can exacerbate motor symptoms. Domperidone does not cross the BBB. However, domperidone has potential risk of causing cardiac arrhythmia [24]. Mosapride might be a good option for some PD patients. However, there is little evidence to support its benefit [6]. Deep brain stimulation might improve gastric emptying in some PD patients [25]. Endoscopic pyloric botulinum injections or gastric electrical stimulation might be an option. However, these only have limited evidence in PD patients [26,27]. DA-9701 can be used in PD patients safely. As this study was a short-term follow-up study, large-scale longterm follow-up studies are necessary to confirm these findings. Our study has several limitations. First,this study was not designed to show the superiority of DA-9701 to domperidone, thus, the positive results in DA-9701 group should be confirmed by a pre-planned superiority design study. Second, patients with PD were included in this study regardless of the presence or absence of dyspeptic symptoms. Thus, analyses for effects of the study drug on dyspeptic symptoms were limited. Previous studies on the prevalence of dyspepsia in PD patients were limited. Nevertheless, in this study, we found that dyspeptic PD patients, especially those who had postprandial distress, had more delayed gastric emptying. Thus, prokinetic drugs might improve dyspepsia in these patients. A large prospective study regarding the effect of long-term administration of DA-9701 on dyspeptic symptoms among the dyspeptic PD patients is warranted to clarify this issue. Third, there were only 18 patients who had blood samples available for plasma levodopa concentration analyses. Lastly, in this study, gastric MRI was performed in the supine position. However, it has been reported that gastric motor function or intragastric meal distribution is not significantly different between upright and supine positions [12,28]. In conclusion, DA-9701 was not inferior to domperidone in terms of the improvement of gastric function in patients with PD. DA-9701 showed a potential to enhance gastric motility without aggravating parkinsonian symptoms. Thus, DA-9701 can be used as an option for these patients safely. Further studies are warranted to clarify the clinical efficacy of DA-9701 in patients with PD.
Table 2 Comparison of Unified Parkinson's Disease Rating Scale part III scores, dyspeptic symptoms, and plasma levodopa concentration between the 2 groups after the 4-week treatment. Domperidone
DA-9701
(n = 19)
(n = 19)
Δ UPDRS III score 0.39 ± 3.37 UPDRS III score improved (%) 8 (42.1) Patient's global assessment for dyspeptic symptoms Markedly improved (≥75%) 0 (0.0) Moderately improved (50–74%) 4 (21.1) Mildly improved (25–49%) 11 (57.9) No improvement (0–25%) 4 (21.1) Symptoms aggravated 0 (0.0) Δ plasma levodopa concentration −17.2 ± 688.3 (ng/mL, n = 18)
P-value
−1.29 ± 4.37 14 (73.7)
0.192 0.049
0 (0.0) 6 (31.6) 10 (52.6) 3 (15.8) 0 (0.0) 256.3 ± 814.8
0.744
0.531
P-values were calculated using general linear model (for the comparison between the 2 groups in the changes of UPDRS III score and plasma levodopa concentration before and after the treatment) or χ2-test (for categorical variables). UPDRS III, Unified Parkinson's Disease Rating Scale part III. Bold style indicates statistical significance (p < 0.05).
systems. L-Dopa medication also causes delayed gastric emptying [2]. Several studies have reported that delayed gastric emptying could lead to increased unpredictability of motor fluctuation due to the possibility that delayed gastric emptying could lead to delayed delivery and decreased absorption of L-dopa which is mainly absorbed in the small intestine [17–19]. In this study, GERs did not correlate with LEDD, disease duration, or UPDRS scores (Supplementary Table S1). Previous studies on this issue have shown inconsistent results [20–22]. Delayed gastric emptying might occur from an early stage of PD. DA-9701 has antagonistic effect on D2 receptor and agonistic effects on 5-HT1A, 5-HT4 and adrenergic α2 receptors. DA-9701 can enhance gastric emptying by D2 antagonistic effect and 5-HT4 agonistic effect [7]. Tetrahydroberberine isolated from Corydalis Tuber has an affinity to both D2 and 5-HT1A receptors. It is associated with enhancement of gastric emptying and restoration of delayed gastric emptying [23]. The results of changes in 2-hr GERs after 4-week treatment showed that DA-9701 was not inferior to domperidone (Fig. 2). Nevertheless, DA-9701 group, but not domperidone group, showed significant improvement in 2-hr GER after the treatment (Fig. 2). Levodopa blood concentrations also increased in DA-9701 group, although it did not reach statistical significance probably due to small sample size (Table 2). Further studies are necessary to confirm whether DA-9701 can improve the levodopa pharmacokinetics. After the treatment, more patients in DA-9701 group showed an improvement in UPDRS part III score than those in domperidone group (Table 2). Improvements in delayed gastric emptying followed by improved pharmacokinetics of L-dopa might be related to favorable outcomes. Non-motor symptoms evaluated by UPDRS part IV were not changed after treatment in either group (Supplementary Table S3). For example, there were no changes in the duration of “off” time. However, study participants were not asked to keep a diary about their parkinsonian symptoms. More studies are needed to determine whether DA9701 could improve the “on” time duration among PD patients. On the other hand, there were no significant improvements in dyspeptic symptoms observed after treatment in either group (Supplementary Fig. S4). Sample size was not large enough to yield significant results. In fact, the objective of this study was not to determine the effect of prokinetics on relieving dyspeptic symptoms in PD patients. In terms of adverse effects, DA-9701 also showed favorable outcomes. Especially, domperidone caused prolactinemia whereas DA9701 did not (Supplementary Table S3). Currently, we have only limited options to control gastric dysfunction in patients with PD.
Author contributions CMS designed the entire study protocol, performed the data analyses, and wrote the first draft. YJL performed gastric MRI analyses, and review and criticized the 1st draft. JMK conceptualized the study design, enrolled all study subjects, and reviewed the 1st draft. JYL conceptualized the study design, and review and criticized the 1st draft. KJL performed part of the data analyses and reviewed the 1st draft. YJC designed the study protocol and reviewed the 1st draft. NK supervised the protocol and criticized the 1st draft. DHL conceptualized the study protocol and review the 1st draft.
Financial disclosure/Conflict of interest Dong-A ST was funded by the Ministry of Knowledge Economy for the drug. No author has any conflict of interest or financial arrangement that could potentially influence the presented research.
Funding sources for study This work was supported by the Global Leading Technology Program of the Office of Strategic R&D Planning (OSP), funded by the Ministry of Knowledge Economy, Republic of Korea (10039303). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 5
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Acknowledgement [13]
The authors are indebted to Professor Yang Won Min and Professor Poong-Lyul Rhee, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, for their advice regarding gastric MRI protocol.
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Appendix A. Supplementary data
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Supplementary data related to this article can be found at http://dx. doi.org/10.1016/j.parkreldis.2018.04.018.
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