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.     

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.     

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     

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.     

39Gastrointestinal electrical stimulation in post-surgical gastroparesis improves symptoms independently while gastric emptying response is dependent on baseline emptying

Introduction:  Temporary GES (tempGES) can improve both gastric emptying and symptoms in post-surgical gastroparesis (PS-GP). (SSAT 2004). Long-term effects on GI symptoms and gastric emptying are unknown. Since many PS-GP patients have non-delayed emptying, the long-term effect on baseline normal or rapid emptying is also unknown.
Patients:  36 pts (6 M, 30 F, mean age 42 years) with post-surgical: Bilroth I ( n  = 11), Bilroth II ( n  = 4), other gastric surgery ( n  = 21) disordered gastric emptying were evaluated.
Methods:  GI symptoms (vomiting = V, Total = TSS), and solid meal gastric emptying (GET) at 1 and 4 h, were compared at baseline (Base), after temporary (tempGES) and permanent (permGES) gastric electrical stimulation as previously described (NGM, 2004; 16: 635.) Long-term follow-up for permanent GES ranged from 6 month to 10 years. Results were compared by t-tests, and are reported as means ± SEM.
Results:  29 of the 36 patients were able to tolerate food for baseline quantitative gastric emptying testing. 20 patients had delayed and 9 patients had non-delayed gastric emptying, with 7/9 being rapid. With both tempGES and permGES, GI symptoms improved (p < 0.05). Both tempGES and permGES showed accelerated GET for delayed patients and generally slowed GET for non-delayed (p < 0.05 for 1 h values). See tables below.
Conclusions:  In a large group of post-surgical GP patients, temporary and permanent gastrointestinal electrical stimulation improved GI symptoms independent of gastric emptying and for a prolonged time. GES improves symptoms independent of baseline gastric emptying, and improves GET dependent on the baseline gastric emptying.
 

     

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.     

A ghrelin agonist fails to show benefit in patients with diabetic gastroparesis: let's not throw the baby out with the bath water

Ghrelin is the endogenous ligand for the growth hormone secretagogue‐1a receptor and is a potential target for treatment of gastroparesis. This viewpoint assesses the potential role of ghrelin agonists in the treatment of gastroparesis through a review of the early phase, randomized, controlled trials of ghrelin agonists in patients with diabetes and, either, delayed gastric emptying at the time of the trial or symptoms at the time of the trial, and prior documentation of delayed gastric emptying of solids. Whereas recent experience with ghrelin agonists that have a macrocycle structure (TZP‐101, TZP‐102) has not confirmed earlier promising results, there is little evidence that ghrelin receptors downregulate with repeated treatment, in contrast to motilin receptors. Phase IIa clinical trials performed with a different agent (RM‐131, which is a small molecule ghrelin agonist) suggest that, as a class, ghrelin agonists may be efficacious in stimulating gastric emptying. It is premature to dismiss ghrelin agonists as potential therapies for gastroparesis.     

Gastrointestinal hormonal dysfunction in gastroparesis and functional dyspepsia

Background Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients. Purpose This article will discuss the hypersensitivity to enteral fat and endogenous (nutrient‐stimulated) and exogenous cholecystokinin (CCK) in patients with FD, and the elevation in both fasting and postprandial CCK levels evident in this group. It will review the use of pharmacological agonists of motilin and ghrelin, which accelerate gastric emptying, in the management of gastroparesis and FD. The frequent finding of markedly delayed gastric emptying in the critically ill will be examined; this is associated with elevated plasma CCK and peptide YY in both the fasted and postprandial states, which may account for the increase in small intestinal nutrient inhibitory feedback on gastric motility in this group. The concepts that the rate of gastric emptying is a major determinant of postprandial glycemic excursions in diabetes, and that modulation of gastric emptying may improve glycemic control, will be addressed; in type 1 and insulin‐treated type 2 diabetic patients, co‐ordination of insulin administration with nutrient delivery and absorption should be optimized, while type 2 patients who are not on insulin are likely to respond to dietary and/or pharmacological interventions which slow gastric emptying.     

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction 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 prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.     

33Effect of afferent vagal stimulation through oral exposure to a sour or a salty taste on gastric myoelectrical activity evaluated by means of multi-channel electrogastrography

Introduction: Rapid gastric emptying has been described not only in patients with nausea and vomiting and gastroparesis but also in obesity and dyspepsia. We investigated the use of three measures of rapid gastric emptying in a large group of patients with gastroparesis as compared to normal controls. Patients: From a pool of 214 consecutive patients with the symptoms of gastroparesis we reviewed the results of standardized solid gastric emptying tests and compared the results to a group of normal controls as previously described (AJG 95: 1456‐14622000). Patients were 39 males, 175 females mean age 42 years, with diagnosis of 42 Diabetes Mellitus, 26 Post Surgical and 146 Idiopathic diseases. Methods: Gastric emptying was compared by three models: Area under the emptying curve (AUC, rapid < 0.257), total gastric emptying (TGE: the sum of 1, 2 and 4 hours; rapid < 47), and percentage remaining at 1 hour (<37%) for rapid and/or at 4 hours (>10%) for delayed emptying, using data and techniques previously described (AGJ2004; 99: S45 and NGM 2005; 17: 470). Results: Measurable gastric emptying could be determined for 4 hours emptying in 146 patients; 87 patients had complete 1, 2 and 4 hours emptying. 44 patients had delayed emptying by 4 hour% >10%, seven patients (8%) had rapid gastric emptying by AUC and eight pts (9%) had rapid emptying by the TGE values; and 16 (18%) pts had rapid emptying by the 1 hour value alone. Conclusion: Rapid gastric emptying of a solid meal is not uncommon in patients with the symptoms of gastroparesis. The AUC and TGE models identified approximately the same number of patients with rapid emptying, while the 1‐hour model identified approximately twice as many patients. Using the three techniques described to determine rapid gastric emptying awaits prospective use in other patients, including dyspepsia and obesity. Standardized measure for rapid gastric emptying may be useful in evaluating therapeutic outcomes for these disorders.     

Measurement of gastric emptying by radiopaque markers in patients with diabetes: correlation with scintigraphy and upper gastrointestinal symptoms

Background Scintigraphy, the gold standard to measure gastric emptying, is expensive and not widely available. Therefore, we compared emptying of radiopaque markers (ROM) from the stomach, by use of fluoroscopy, with scintigraphy in patients with insulin‐treated diabetes. Methods On the same day we measured gastric emptying of 20 ROM using fluoroscopy and scintigraphic emptying of a standard solid meal. The subjects also completed a validated gastrointestinal (GI) symptom questionnaire. Key Results We included 115 patients with insulin‐treated diabetes (median age 53, range 21–69 years; 59 women). A moderately strong correlation was demonstrated between scintigraphic (% retained at 2 h) and ROM emptying (markers retained at 6 h) (r = 0.47; P < 0.0001). Eighty‐three patients had delayed gastric emptying with scintigraphy, whereas only 29 patients had delayed emptying of ROM. Of the 29 patients with delayed emptying of ROM, 28 also had delayed scintigraphic emptying. The sensitivity and specificity of the ROM test was 34% and 97%, respectively. Significant correlations were only noted between scintigraphic gastric emptying and GI symptom severity, with the strongest correlations for fullness/early satiety (r = 0.34; P < 0.001) and nausea/vomiting (r = 0.30; P < 0.001). Conclusions & Inferences A gastric emptying test with ROM is a widely available screening method to detect delayed gastric emptying in patients with diabetes, where a positive result seems reliable. However, a normal ROM test does not exclude delayed gastric emptying, and if the clinical suspicion of gastroparesis remains, scintigraphy should be performed. Results from scintigraphy also correlate with GI symptom severity, which ROM test did not.     

Gastric emptying time and gastric motility in patients with Parkinson's disease.

Gastrointestinal symptoms such as nausea, abdominal pain, and bloating are frequent complaints of patients with Parkinson's disease (PD). It has been postulated that impaired gastrointestinal function may contribute to the development of motor fluctuations such as delay on and no on in patients with PD. Gastrointestinal impaired function and symptoms may be associated with the disease itself or secondary to levodopa treatment. Thus, we assessed gastric emptying (GE) and gastric motility in PD patients to examine the association between clinical status and gastric function. GE and antral contraction (frequency and amplitude) were evaluated by scintigraphy in 29 patients with mild PD (Hoehn and Yahr [H&Y] stage 1.0-2.0); 22 patients with moderate PD (H&Y stage 2.5-3.0); and 22 healthy volunteers, following the ingestion of a labeled standard meal. Gastric emptying (mean +/- SD of T(1/2)) and antral contraction were not significantly different between patients with mild PD (63.4 +/- 28.8 minutes) and moderate PD (54.7 +/- 25.5 minutes). In the control group, GE was 43.4 +/- 10.8 minutes (range 29.0 - 61.0 minutes). The prevalence of delayed emptying (>61 minutes) was not significantly different in patients with mild disease (48.3%) as compared with patients with moderate disease (36.4%). Antral contraction, both frequency and amplitude, were not significantly different between patients with mild and moderate PD throughout the entire 100 minutes of the study. Untreated patients (n = 28) had mean GE T(1/2) of 59 +/- 30.6 minutes. Patients with smooth response to levodopa showed slower GE (n = 10; 73.6 +/- 25.3 minutes), while treated patients with motor response fluctuations when tested at the on state (n = 13), had much faster GE (49.3 +/- 16.2 minutes). This shortened GE in the on state was similar to the GE of normal volunteers. We conclude that gastric emptying time in patients with PD was delayed compared with control volunteers. It was even slower in patients treated with levodopa. This effect of levodopa treatment was reversed to pseudonormalization (normal GE) at the advanced stages of the disease, when patients developed motor response fluctuation. Other clinical features of PD were not associated with delayed gastric emptying.     

Variable abnormal physiological motility in the proximal upper gastrointestinal tract in gastroparesis

Background Traditional testing for gastroparesis with gastric emptying scintigraphy (GES) likely misses a subset of patients because of the heterogeneous nature of the disease. The primary aim of this study is to determine the prevalence of simultaneously measured transit and pressure abnormalities in patients with gastroparesis. The secondary aim is to assess diagnostic gain realized by measuring antroduodenal pressure and gastric transit with wireless motility capsule (WMC) compared to gastric transit measured by GES. Identification of abnormalities beyond gastric transit delay in gastroparesis may yield novel targets for pharmacological therapies. Methods Forty‐three subjects with symptoms of gastroparesis and previous abnormal GES within 2 years were enrolled in the study. Subjects underwent simultaneous GES and WMC to assess gastric transit. Gastric and small bowel pressure profiles were measured by WMC to determine the contribution of pressure to diagnostic gain realized with WMC. Key Results Fifty‐one percent of subjects had abnormal GES while 70% of subjects had either abnormal gastric emptying time (GET) or antroduodenal pressure. Gastric emptying time was abnormal in 60% of subjects while gastric or small bowel pressure was abnormal in 47% of subjects. The overall diagnostic gain of WMC compared to GES was 19% (P = 0.04). Seven percent of subjects had abnormal small bowel pressure profiles when both GES and GET were normal. Conclusions & Inferences (i) Gastroparesis is a heterogeneous disorder and testing only solid food emptying by scintigraphy may miss a significant amount of pathology. (ii) Measuring complementary aspects of gastric and small bowel function simultaneously results in greater detection of physiologic abnormalities that may underlie patient symptoms.     

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.     

Electrogastrography as a diagnostic tool for delayed gastric emptying in functional dyspepsia and irritable bowel syndrome

Several pathophysiological mechanisms have been proposed in functional gastrointestinal (GI) disorders, e.g. altered GI motility and sensitivity. The aim of this study was to investigate gastric electrical activity (GEA) in patients with functional dyspepsia (FD) or irritable bowel syndrome (IBS) compared with healthy controls (HC), and to assess if abdominal symptoms and delayed gastric emptying are associated with alterations in GEA, as determined by electrogastrography (EGG). Forty patients with FD, IBS or both were compared with 22 HC. EGG was performed before and after a standard meal. Frequencies and amplitudes pre- and post-prandially were analysed. Furthermore, gastric emptying and symptom scores were assessed. Eight of 40 patients (20%; three FD, three IBS, two FD and IBS) had delayed gastric emptying. Disturbed gastric emptying and lack of a postprandial increase in the EGG amplitude were significantly correlated (r = 0.8; P < 0.005). No differences between controls and patients were observed in the distribution of EGG frequencies. Treatment with the prokinetically active macrolide erythromycin improved gastric emptying, GEA and symptoms (n = 4). The data suggest that EGG could be useful as a diagnostic tool in patients with FD and IBS to identify a subgroup of patients with delayed gastric emptying.     

Helicobacter pylori infection and gastric emptying of solids in humans

Helicobacter pylori has been implicated in a number of upper gastrointestinal illnesses. In a controlled study, we have investigated the relationship between H. pylori infection and gastric emptying of solids in two groups of patients with chronic symptoms of dyspepsia. In the first group, 19 patients with non-ulcer dyspepsia and H. pylori infection underwent a standard test of gastric emptying after ingestion of 500 μCi of Tc-labelled chicken liver. The results were compared to a control group of 16 uninfected volunteers. We also studied a second group of 20 patients with previously diagnosed idiopathic gastroparesis for the prevalence of H. pylori infection and its relationship to symptom severity and rates of gastric emptying. In the first group of patients, the half-time of gastric emptying was significantly less among the infected patients compared to the uninfected volunteers (108 ± 9 vs. 142 ± 14 min, P < 0.05). In the second group of patients with gastroparesis, the prevalence of H. pylori was not significantly different among these patients than among 21 age and sex matched controls (20% vs. 38%, P = 0.32). Gastric emptying was markedly slow in all 20 patients in the second group but less so among the four with H. pylori infection. Symptom scores were no different between infected and uninfected patients. We conclude that H. pylori infection is not associated with abnormally slow gastric emptying. On the contrary, gastric H. pylori infection appears to be associated with mildly accelerated emptying of solids compared to normal controls. Idiopathic gastroparesis and dyspepsia related H. pylori infection are separate but sometimes overlapping disorders.     

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.     

Association between changes in symptoms and gastric emptying in gastroparetic patients treated with gastric electrical stimulation

Abstract  To investigate whether there is an association between gastric emptying rate and symptom improvement in gastroparetic patients treated with gastric electrical stimulation (GES), we retrospectively reviewed 63 gastroparetic patients who received GES therapy for at least 1 year. Patient characteristics, seven upper gastrointestinal (GI) symptoms and 4-h standardized gastric emptying test (GET) were evaluated at baseline and at 1 year of GES. All symptoms were significantly reduced ( P  <   0.001). Mean gastric retention was reduced by 7% ( P  =   0.102) for measurement at 4 h. Of the 63 patients, 14 had their GET normalized and 49 remained delayed after 1 year. Normalized GET patients had a similar symptom improvement as those whose GET remained delayed. Of all upper GI symptoms, the improvements in vomiting ( P  =   0.04), nausea ( P  =   0.002) and epigastric pain ( P  =   0.001) were significantly correlated with reduction in 4-h gastric retention between baseline and 12 months of GES therapy for patients with normalized gastric emptying but there were no correlations with any symptoms and change in gastric emptying for those patients who remained delayed. In summary, overall gastric emptying is not significantly accelerated at 4 h after successful symptomatic improvement with GES but nausea, vomiting and epigastric pain can be correlated with normalization of GET in a subset of patients.     

The effects of tegaserod, a 5-HT4 receptor agonist, on gastric emptying in a murine model of diabetes mellitus

The C57BLKS/J db/db transgenic mouse is a model of diabetes mellitus that has been shown to have delayed gastric emptying. We assessed gastric emptying rates in C57BLKS/J mice, and determined the effects of tegaserod, a new selective 5-HT(4) receptor partial agonist, on gastric emptying. METHODS: Gastric emptying rates of a 20% glucose test meal were determined in 12-20-week-old female db/db mice and control littermates. The effects of tegaserod (0.1-2.0 mg kg(-1), i.p.) on gastric transit were tested in a second group of db/db mice. Pretreatment with GR11308, a specific 5-HT(4)antagonist, was used to confirm the mechanism of action of tegaserod on gastric emptying. RESULTS: Gastric emptying of glucose was significantly slower in db/db mice than in control littermates. Tegaserod (0.1 mg kg(-1)) significantly accelerated the gastric emptying rate of glucose in db/db mice, reducing the fraction of the meal remaining in the stomach at 30 min by 80%. GR11308 blocked the gastrokinetic effects of tegaserod. CONCLUSIONS: Gastric emptying was impaired in db/db mice. Low dose tegaserod improved gastric emptying rates in this model of gastroparesis through the activation of 5-HT(4) receptors. These findings suggest that 5-HT(4) receptor agonists may prove useful for improving delayed gastric emptying in gastroparesis.     

Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium

Background Cellular changes associated with diabetic (DG) and idiopathic gastroparesis (IG) have recently been described from patients enrolled in the Gastroparesis Clinical Research Consortium. The association of these cellular changes with gastroparesis symptoms and gastric emptying is unknown. The aim of this study was to relate cellular changes to symptoms and gastric emptying in patients with gastroparesis. Methods Earlier, using full thickness gastric body biopsies from 20 DG, 20 IG, and 20 matched controls, we found decreased interstitial cells of Cajal (ICC) and enteric nerves and an increase in immune cells in both DG and IG. Here, demographic, symptoms [gastroparesis cardinal symptom index score (GCSI)], and gastric emptying were related to cellular alterations using Pearson’s correlation coefficients. Key Results Interstitial cells of Cajal counts inversely correlated with 4 h gastric retention in DG but not in IG (r = ?0.6, P = 0.008, DG, r = 0.2, P = 0.4, IG). There was also a significant correlation between loss of ICC and enteric nerves in DG but not in IG (r = 0.5, P = 0.03 for DG, r = 0.3, P = 0.16, IG). Idiopathic gastroparesis with a myenteric immune infiltrate scored higher on the average GCSI (3.6 ± 0.7 vs 2.7 ± 0.9, P = 0.05) and nausea score (3.8 ± 0.9 vs 2.6 ± 1.0, P = 0.02) as compared to those without an infiltrate. Conclusions & Inferences In DG, loss of ICC is associated with delayed gastric emptying. Interstitial cells of Cajal or enteric nerve loss did not correlate with symptom severity. Overall clinical severity and nausea in IG is associated with a myenteric immune infiltrate. Thus, full thickness gastric biopsies can help define specific cellular abnormalities in gastroparesis, some of which are associated with physiological and clinical characteristics of gastroparesis.