Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients

Adjunction of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) to levodopa/carbidopa (LD/CD) improves motor symptoms in patients with Parkinson disease (PD) by a prolonged elimination of LD. But it is not known whether EN addition influences gastric emptying and thus LD pharmacokinetics and pharmacodynamics. Objectives were to simultaneously determine plasma LD elimination, gastric emptying, and clinical response after a single intake of the same LD dosage as LD/CD--or as (LD/CD/EN) formulation on 2 consecutive days. In both groups, PD patients with delayed gastric emptying had significant lower LD plasma concentrations. Addition of EN did not influence gastric emptying but significantly improved motor response, which was not different for patients with delayed gastric emptying. However, with and without EN adjunction gastric emptying distinctly contributes to the variability of plasma LD bioavailability. This may impact LD delivery to the brain and thus motor response in PD patients. Therefore, fine tuning of LD application, which considers gastric emptying, becomes more and more essential in advanced PD stages with a reduced striatal neuronal dopamine capacity, which is responsible for maintenance of motor response in early PD patients.     

Predictors of gastric emptying in Parkinson''s disease

Predictors of gastric emptying (GE) in patients with idiopathic Parkinson's disease (PD) of a solid and liquid meal are not well defined. For measurement of GE 80 patients with PD were randomly assigned to receive either a solid meal (250 kcal) containing 13C-octanoate (n = 40) or a liquid meal (315 kcal) with 13C-acetate (n = 40). All patient groups were off medication affecting motility and were matched for age, gender, body mass index, disease duration and severity, using Unified Parkinson's Disease Rating Scale (UPDRS). Gastric emptying was compared with a healthy control group (n = 40). Multiple regression analysis was used to determine predictors of gastric emptying. Exactly 88% and 38% of PD patients had delayed GE of solids and liquids respectively. Solid and liquid emptying was similar in women and men. There were no differences in GE in PD patients < 65 years of age when compared with patients > or = 65 years. Multiple regression analysis showed that motor handicaps such as rigour and action tremor are independent predictors of solid GE (r = 0.68, P < 0.001). The severity of motor impairment, but not any other neurological symptom, as assessed by UPDRS is associated with gastroparesis in PD and solid emptying is more likely to be delayed.     

Is there a difference in gastric emptying between Parkinson’s disease patients under long-term <Emphasis Type="SmallCaps">l</Emphasis>-dopa therapy with and without motor fluctuations? An analysis using the <Superscript>13</Superscript>C-acetate breath test

The mechanism underlying the motor fluctuations that develop after long-term l-dopa therapy is not fully known. It has been speculated that malabsorption of l-dopa from the small intestine occurs. It was reported that gastric retention in Parkinson’s disease (PD) patients with motor fluctuations is increased as compared with that in PD without fluctuations. Because l-dopa therapy may worsen the symptoms of delayed gastric emptying (GE), it was not clear whether the delayed GE of PD patients with motor fluctuation was affected by l-dopa therapy. We assessed GE in PD patients with and without motor fluctuations. We investigated GE in 40 patients with PD under long-term l-dopa therapy, 20 fluctuators with “delayed-on” and “no-on” phenomena, 20 nonfluctuators, and 20 healthy volunteers. GE was examined by the ¹³C-acetate breath test (¹³C-ABT) [the half emptying time (HET), the peak time of the ¹³C-%-dose-excess curve (T _max)], with expirations collected for 4 h after a test meal and analyzed for ¹³CO₂ using an infrared (IR) spectrophotometer. The T _max of GE as assessed using the ¹³C-ABT was significantly delayed in all PD patients as compared with controls (P = 0.002). The HET was significantly delayed in all PD patients as compared with controls (P < 0.001). The T _max and HET were not significantly delayed in PD patients with motor fluctuations as compared with PD patients without motor fluctuations. These results demonstrated that GE is commonly delayed in PD patients with long-term l-dopa therapy. Delayed GE does not differ between PD patients with and without motor fluctuations. This finding demonstrated that the motor fluctuation in PD may not be influenced by GE.     

Clinical implications of gastric complications on levodopa treatment in Parkinson's disease

Disorders of the gastrointestinal (GI) tract are common and distressing nonmotor symptoms of Parkinson's disease (PD) that can adversely affect levodopa absorption and lead to OFF periods, also known as motor fluctuations. Gastroparesis, which is primarily defined as delayed gastric emptying (DGE), and Helicobacter pylori infection, which is present with increased frequency in PD, are among the most common and important GI disorders reported in PD that may impair oral levodopa absorption and increase OFF time. Symptoms of gastroparesis include nausea, vomiting, postprandial bloating, fullness, early satiety, abdominal pain, and weight 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.     

Delayed gastric emptying in Parkinson's disease

Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long‐term l ‐dopa therapy. Neurohormonal aspects of the brain‐gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric‐derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD. © 2013 International Parkinson and Movement Disorder Society     

Delayed gastric emptying and enteric nervous system dysfunction in the rotenone model of Parkinson's disease

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility in PD include early satiety and weight loss from delayed gastric emptying and constipation from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the parkinsonian neurotoxin and mitochondrial complex I inhibitor rotenone causes delayed gastric emptying and enteric neuronal dysfunction when administered chronically to rats in the absence of major motor dysfunction or CNS pathology. When examined 22-28 days after initiation of rotenone infusion by osmotic minipump (3 mg/kg/day), 45% of rotenone-treated rats had a profound delay in gastric emptying. Electrophysiological recording of neurally-mediated muscle contraction in isolated colon from rotenone-treated animals confirmed an enteric inhibitory defect associated with rotenone treatment. Rotenone also induced a transient decrease in stool frequency that was associated with weight loss and decreased food and water intake. Pathologically, no alterations in enteric neuron numbers or morphology were apparent in rotenone-treated animals. These results suggest that enteric inhibitory neurons may be particularly vulnerable to the effects of mitochondrial inhibition by parkinsonian neurotoxins and provide evidence that parkinsonian gastrointestinal abnormalities can be modeled in rodents.     

Gastric emptying after semi–solid food in multiple system atrophy and Parkinson disease

Background Gastrointestinal symptoms such as nausea, abdominal pain, and bloating are frequent complaints in patients with Parkinson disease (PD) and in patients with multiple system atrophy (MSA), and may be associated with delayed gastric emptying (GE). Although several GE studies in patients with PD have been performed, scant data exist in patients with MSA. Methods We assessed GE half–times (T50) in 12 patients with MSA and compared them with those of 12 patients with PD and 12 age–matched healthy controls.GE was estimated scintigraphically using the left anterior oblique method after ingestion of a ^99mTc colloid–labeled balanced semi–solid meal (yogurt). GE data were obtained every 15 minutes until there was complete emptying of the stomach. Blood pressure, heart rate, plasma glucose and glucosylated hemoglobin were regularly determined. Results Reproducibility of the GE technique was excellent (Bland–Altman analysis, limits of agreement: –2.3 to 2.8). T50 was longer in MSA (82 ± 3.4 min) and in PD (90.6 ± 3.9 min) patients compared with controls (46.2 ± 0.7) (two–way ANOVA, p <0.0001). T50 did not differ between patients with MSA and those with PD. No correlation existed between T50 and age, duration of the disease, magnitude of postprandial hypotension, levels of plasma glucose and glucosylated hemoglobin (Kendall’s tau, p > 0.05). Conclusions Our results suggest that patients with MSA have GE rates similar to those of patients with PD, but slower than healthy agematched individuals. It remains to be investigated whether gastrointestinal dysfunction in MSA is related to both brain and peripheral pathology, as is presumed for PD.     

Evaluation of gastric antral motor performance in patients with dysmotility-like dyspepsia using real-time high-resolution ultrasound

Abstract Although manometric antral hypomotility and delayed gastric emptying have been reported separately in patients with dyspepsia, relationships between symptoms, antral contractility and emptying rate have not been sought. The present study therefore aimed to evaluate, simultaneously, gastric antral excursion characteristics and emptying in a sub-group of patients with severe functional dyspepsia using high-resolution real-time ultrasound. The circumference of the relaxed and contracted antrum was measured at 15-min intervals after ingestion of a 360 mL mixed nutrient meal in 36 chronic dyspepsia patients with symptoms of post-prandial bloating and epigastric distension, and in 25 healthy volunteers. Antral emptying (measured as the rate of decrease in circumference of the relaxed antrum) was slower in patients than normals (P = 0.02). In both groups, the average values for antral excursion were similar but the range of excursion in patients was significantly wider than in controls (F < 0.001), with 11 patients showing values above, and 8 showing values below the normal range. There was no relationship between antral emptying and antral excursion in either patients or volunteers. In conclusion, patients with severe functional dyspepsia show a wide range of antral performance characteristics, suggesting not only that the mechanisms responsible for the control of antral motor function are disturbed but also that the cause of the symptoms and the disturbed antral motor function are probably not directly related.     

A randomized controlled trial of etilevodopa in patients with Parkinson disease who have motor fluctuations

BACKGROUND: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. OBJECTIVE: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. DESIGN: A double-blind, randomized, comparative clinical trial. SETTING: Forty-four sites in the United States and Canada. PATIENTS: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. INTERVENTION: Treatment with either etilevodopa-carbidopa or levodopa-carbidopa for 18 weeks. MAIN OUTCOME MEASURE: Change from baseline in total daily TTON as measured using home diaries. RESULTS: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily "off" time improved in the etilevodopa-carbidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. CONCLUSION: Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.     

Gastrointestinal barriers to levodopa transport and absorption in Parkinson's disease

Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, ‘delayed on’ or ‘no on’ phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.     

Gastric emptying and the organization of antro-duodenal pressures in the critically ill.

The motor dysfunctions underlying delayed gastric emptying (GE) in critical illness are poorly defined. Our aim was to characterize the relationship between antro-duodenal (AD) motility and GE in critically ill patients. AD pressures were recorded in 15 mechanically ventilated patients and 10 healthy volunteers for 2 h (i) during fasting, (ii) following an intragastric nutrient bolus with concurrent assessment of GE using the (13)C-octanoate breath test and (iii) during duodenal nutrient infusion. Propagated waves were characterized by length and direction of migration. Critical illness was associated with: (i) slower GE (GEC: 3.47 +/- 0.1 vs 2.99 +/- 0.2; P = 0.046), (ii) fewer antegrade (duodenal: 44%vs 83%, AD: 16%vs 83%; P < 0.001) and more retrograde (duodenal: 46%vs 12%, AD: 38%vs 4%; P < 0.001) waves, (iii) shorter wave propagation (duodenal: 4.7 +/- 0.3 vs 6.0 +/- 0.4 cm; AD: 7.7 +/- 0.6 vs 10.9 +/- 0.9 cm; P = 0.004) and (iv) a close correlation between GE with the percentage of propagated phase 3 waves that were antegrade (r = 0.914, P = 0.03) and retrograde (r = -0.95, P = 0.014). In critical illness, the organization of AD pressure waves is abnormal and associated with slow GE.     

Effects of clonidine and sumatriptan on postprandial gastric volume response, antral contraction waves and emptying: an MRI study

Abstract Gastric emptying (GE) may be driven by tonic contraction of the stomach (‘pressure pump’) or antral contraction waves (ACW) (‘peristaltic pump’). The mechanism underlying GE was studied by contrasting the effects of clonidine (α₂‐adrenergic agonist) and sumatriptan (5‐HT₁ agonist) on gastric function. Magnetic resonance imaging provided non‐invasive assessment of gastric volume responses, ACW and GE in nine healthy volunteers. Investigations were performed in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) under placebo [0.9% NaCl intravenous (IV) and subcutaneous (SC)], clonidine [0.01 mg min^?1 IV, max 0.1 mg (placebo SC)] or sumatriptan [6 mg SC (placebo IV)]. Total gastric volume (TGV) and gastric content volume (GCV) were assessed every 5 min for 90 min, interspersed with dynamic scan sequences to measure ACW activity. During gastric filling, TGV increased with GCV indicating that meal volume dictates initial relaxation. Gastric contents volume continued to increase over the early postprandial period due to gastric secretion surpassing initial gastric emptying. Clonidine diminished this early increase in GCV, reduced gastric relaxation, decreased ACW frequency compared with placebo. Gastric emptying (GE) rate increased. Sumatriptan had no effect on initial GCV, but prolonged gastric relaxation and disrupted ACW activity. Gastric emptying was delayed. There was a negative correlation between gastric relaxation and GE rate (r² = 49%, P < 0.001), whereas the association between ACW frequency and GE rate was inconsistent and weak (r² = 15%, P = 0.05). These findings support the hypothesis that nutrient liquid emptying is primarily driven by the ‘pressure pump’ mechanism.     

Hyperglycemia impairs antro-pyloric coordination and delays gastric emptying in conscious rats

Delayed gastric emptying has been shown in diabetes. Although it has been proposed that hyperglycemia, and not only autonomic neuropathy, contributes to the pathogenesis of delayed gastric emptying, the inhibitory mechanism of hyperglycemia on gastric emptying remains unclear. We studied the effects of hyperglycemia per se on gastric emptying and postprandial gastric motility in conscious rats. Liquid and solid gastric emptying were compared between saline-infused rats and D-glucose-infused rats. Two strain gauge transducers were implanted on the antrum and pylorus and the postprandial antro-pyloric coordination was compared between euglycemia and hyperglycemia. D-glucose infusion for 30 min increased blood glucose level from 5.4 +/- 0.5 to 13.0 +/- 1.3 mM and significantly delayed gastric emptying. Forty minutes after the feeding, contractions with low frequency (<3 cycles min(-1)) and high amplitude (>15 g) of the antrum were observed. This period reflects the emptying process of the gastric content and the coordination between the antrum and pylorus was frequently observed. D-glucose infusion significantly reduced feeding-induced antral contractions and abolished the number of episodes of antro-pyloric coordination. Sham feeding-induced gastric contractions were also significantly reduced by hyperglycemia. Postprandial antro-pyloric coordination was not observed in vagotomized rats, suggesting a mediation of vagus nerve. It is concluded that hyperglycemia impairs antral contractions and antro-pyloric coordination in rats. The inhibitory effect of hyperglycemia on gastric emptying is mediated, at least in part, via impaired vagal activity.     

Levodopa infusion therapy in Parkinson disease: state of the art in 2004

Orally administered levodopa, in combination with a decarboxylase inhibitor, is the gold standard therapy for Parkinson disease (PD). The problems in management of motor fluctuations in the advanced stages of the disorder are due to the close relationship between plasma levodopa levels and availability of dopamine at striatal receptor sites. The fluctuating levodopa concentrations are mainly explained by the fact that levodopa absorption only occurs in the proximal small intestine. The patient's motor function thus depends on gastric emptying, which is erratic and may even be delayed in PD. Oral therapy with sustained-release formulations and COMT inhibitors have not solved the problems satisfactorily. Therefore, infusions of levodopa by intravenous and enteral (duodenal/jejunal) routes of administration have been studied. In this review of the literature on clinically relevant levodopa infusion studies, it is shown that improvements regarding fluctuations in both plasma levodopa levels and motor performance have been repeatedly reported. The results acquired so far suggest that levodopa infusion is a safe and efficacious therapy. Recent drug delivery development and long-term studies have shown that infusion is a clinically feasible alternative to treat advanced PD.     

Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson's disease? An analysis using the 13C-acetate breath test

During the pre-symptomatic stage of Parkinson's disease (PD), the idiopathic PD related abnormal synuclein immunostaining is confined to the medulla oblongata and olfactory bulb, according to Braak. In the study of the enteric nervous system of PD, it has reported that Lewy bodies were found in the Auerbach's and Meissner's plexuses. These lesions may cause dysfunction of the gastrointestinal tract (GI) as pre-clinical symptoms of PD. However, because L: -dopa therapy itself may worsen the symptoms of the digestive tract function, it is needed to evaluate the gastrointestinal tract function in patients with early-stage, untreated (de novo) PD. In the present study, using the (13)C-acetate breath test ((13)C-ABT), we investigated gastric emptying in 20 untreated, early-stage PD patients and 40 treated, advanced-stage PD patients, and 20 healthy volunteers. Gastric emptying was examined by the (13)C-ABT [the half emptying time (HET), the peak time of the (13)C% dose-excess curve (T (max))]. The T (max) and HET of gastric emptying as assessed using the (13)C-ABT was significantly delayed in untreated, early-stage PD patients as compared to the controls (P < 0.001). The T (max) and HET of gastric emptying were not significantly delayed in untreated, early-stage PD patients as compared to treated, advanced-stage PD patients. The results demonstrated that delay in gastric emptying did not differ between untreated, early-stage and treated, advanced-stage PD patients. Gastric emptying of untreated, early-stage PD is already delayed. Delayed gastric emptying may be one of markers of the pre-clinical stage of PD.     

Increased gastric motility during 5-HT4 agonist therapy reduces response fluctuations in Parkinson's disease

We investigated the clinical efficacy and tolerability of 45 mg/day mosapride, a selective 5-hydroxytryptamine type 4 (5-HT₄) agonist, in an open-label study involving five patients with Parkinson's disease (PD) who had response fluctuations (RFs). ‘On’ time and motor function scores were determined, and gastric motility was measured by a radionuclide gastric emptying (GE) test, the most reliable quantitative method available. We found that mosapride therapy significantly shortened GE half-time, reduced RFs, and improved motor functions in all patients. There were no adverse reactions. We conclude that selective 5-HT₄ agonist therapy is beneficial for patients with PD who have RFs.     

Rapid intravenous loading of levodopa for human research: clinical results

Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2,169 and 1,200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612+/-187 ng/ml, mean+/-S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P<0.0005).     

Involvement of NO in gastric emptying of semi-solid meal in conscious pigs

The influence of non-selective nitric oxide synthase (NOS) inhibition on gastric emptying of a semi-solid meal was studied in conscious pigs. Antroduodenal motility and fundic compliance were also assessed to evaluate the mechanisms at the origin of potential alteration in gastric emptying pattern. N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg kg(-1) i.v.) delayed gastric emptying (half-emptying time of 128.98 +/- 16.86 min vs 73.74 +/- 7.73 min after saline, P < 0.05, n = 6) as a result of decreased proximal gastric emptying. No changes were observed for distal gastric emptying as a result of unchanged antral motility. Similarly, no changes were noted on duodenal motor patterns either in the fasted or in the fed state. L-NAME decreased fundic compliance in fasted state (49 +/- 11 mL mmHg(-1) vs 118 +/- 15 mL mmHg(-1) after saline, P < 0.05, n = 6). As this phenomenon is expected to increase emptying rate, the gastroparesis induced by NOS inhibition is thus likely to originate from distal resistive forces. It is concluded that NO positively modulates gastric emptying.     

Is there a difference in gastric emptying between myotonic dystrophy type 1 patients with and without gastrointestinal symptoms?

Gastrointestinal symptoms are frequent complaints in patients with myotonic dystrophy type 1 (MyD1) and may be associated with reduced gastrointestinal motility caused by smooth muscle dysfunction. Although previous studies have found delayed gastric emptying (GE) in MyD1 patients, the relationship between GE and symptoms has been unclear. We investigated GE in 23 MyD1 patients and 20 healthy volunteers using the ¹³C-acetate breath test. The MyD1 patients were divided into two groups: those with gastrointestinal symptoms (n = 9) and those without gastrointestinal symptoms (n = 14). The GE function was estimated using the ¹³C-acetate breath test as half-emptying time (HET) and peak time of the ¹³C-%-dose-excess curve (T _max). GE (HET and T _max) was more significantly delayed in patients with MyD1 than in the controls. The GE in MyD1 patients with gastrointestinal symptoms was significantly delayed compared to those without gastrointestinal symptoms. The GE in MyD1 patients with gastrointestinal symptoms was more significantly delayed than in the controls. The GE was significantly delayed in MyD1 patients with gastrointestinal symptoms for >5 years as compared to those with the disease for <5 years, while GE of MyD1 patients without gastrointestinal symptoms did not correlate with the duration of the disease. The GE in MyD1 patients did not correlate with the muscular disability rating scale. These findings suggest that impairment of GE evolves over time and that the progression of delayed GE and skeletal muscle impairment are independent. Smooth muscle impairment may be affected at an earlier stage in MyD1.     

High-dose treatment with pergolide in Parkinson's disease patients with motor fluctuations and dyskinesias

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.