Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: A randomized clinical trial (the DREAM study).

BACKGROUND: Functional dyspepsia (FD), a heterogeneous disorder, involves multiple pathogenetic mechanisms. Developing treatments for FD has been challenging. We performed a randomized, placebo-controlled, double-blind clinical trial to determine the efficacy of rikkunshito, a Japanese herbal medicine, in FD patients. METHODS: FD patients (n = 192) who met the Rome III criteria without Helicobacter pylori infection, predominant heartburn, and depression were enrolled at 56 hospitals in Japan. After 2 weeks of single-blind placebo treatment, 128 patients with continuous symptoms were randomly assigned to 8 weeks of rikkunshito (n = 64) or placebo (n = 61). The primary efficacy endpoint was global assessment of overall treatment efficacy (OTE). The secondary efficacy endpoints were improvements in upper gastrointestinal symptoms evaluated by the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), the Global Overall Symptom scale (GOS), and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (m-FSSG), and psychological symptoms evaluated by the Hospital Anxiety and Depression Scale (HADS). KEY RESULTS: Rikkunshito increased OTE compared to placebo at 8 weeks (P = .019). Rikkunshito improved upper gastrointestinal symptoms (PAGI-SYM, GOS, and m-FSSG) at 8 weeks, especially postprandial fullness/early satiety (P = .015 and P = .001) and bloating (P = .007 and P = .002) of the PAGI-SYM subscales at 4 weeks and 8 weeks. Improvement of HADS at 8 weeks (P = .027) correlated with those of PAGI-SYM (r = .302, P = .001), GOS (r = .186, P = .044), and m-FSSG (r = .462, P < .001), postprandial fullness/early satiety (r = .226, P = .014), dyspepsia (r = .215, P = .019), and PDS (r = .221, P = .016). CONCLUSION & INFERENCES: Rikkunshito may be beneficial for FD patients to simultaneously treat gastrointestinal and psychological symptoms.

Severely impaired gastric accommodation is a hallmark of post-Nissen functional dyspepsia symptoms.

BACKGROUND: Laparoscopic Nissen fundoplication is a commonly performed antireflux surgery, after which reflux symptoms are well controlled, however, complications such as inability to belch or dyspeptic symptoms (mimicking those of functional dyspepsia [FD]) might occur. The aim of the study was to prospectively evaluate symptom pattern and underlying pathophysiological mechanisms in patients with post-Nissen dyspepsia. METHODS: Twenty-four patients (12 f, mean age 44.5±2.8 years) with post-Nissen dyspepsia symptoms, five patients (3 f, mean age 38.8±3.2 years) with post-Nissen dysphagia symptoms and 14 pre-fundoplication patients (3 f, mean age 42.1±2.5 years) were evaluated. Patients filled out a Rome II-based dyspepsia symptom severity score, performed a gastric emptying test, and a gastric barostat study was used to evaluate the function of the proximal stomach. KEY RESULTS: Upper abdominal bloating scores were higher in post-Nissen dyspepsia patients (P=.016) and symptoms of postprandial distress syndrome (PDS) were more present in post-Nissen dyspepsia patients compared to the other two groups (P=.07). Weight loss was significantly higher in the post-Nissen groups compared to the pre-fundoplication (P=.02). Gastric emptying rates were similar in the three groups. Gastric accommodation (GA) was significantly impaired in the post-Nissen dyspepsia group (dyspepsia -30[-86-83] vs dysphagia 163[148-203] vs pre-fundoplication 147[75-174] mL, P=.004) and the prevalence of patients with impaired GA was higher in the post-Nissen group (P=.007). Postprandial fullness was more prevalent in patients with impaired GA compared to those with normal GA (P=.01). CONCLUSIONS AND INTERFERENCES: Patients with post-Nissen dyspepsia show a symptom pattern similar to that in FD patients with PDS, and the main underlying mechanism seems to be impaired gastric accommodation to a meal.

Randomised clinical trial: the safety and efficacy of AST-120 in non-constipating irritable bowel syndrome - a double-blind, placebo-controlled study.

BACKGROUND: There is a need for safe and effective treatment options for irritable bowel syndrome (IBS). AST-120 (spherical carbon adsorbent) is a non-absorbed, carbon-based adsorbent with extensive adsorbing capability for histamine, serotonin and other substances implicated in IBS pathogenesis. AIM: To evaluate the efficacy and safety of AST-120 in non-constipating forms of IBS. METHODS: This randomised, double-blind, placebo-controlled trial conducted in the US and Belgium enrolled 115 male and female patients fulfilling Rome III criteria for IBS; individuals with predominantly constipation symptoms were excluded. Subjects were randomised to AST-120 2 g tds or placebo for an 8-week double-blind treatment period, followed by a 2-week single-blind placebo washout and 8-week single-blind active treatment. The primary efficacy endpoint was the proportion of subjects achieving at least a 50% reduction in the number of days with abdominal pain compared with baseline. RESULTS: At Week 4, 26.8% of subjects treated with AST-120 responded on the primary endpoint vs. 10.2% in the placebo arm (P=0.029); at Week 8 response rates were 32.1 and 25.4% respectively (NS). More AST-120 treated subjects experienced improvement in bloating and stool consistency. These benefits abated when AST-120 was replaced by placebo, and resumed once AST-120 was restarted. The frequency of adverse events with AST-120 were less than or equal to placebo. CONCLUSIONS: AST-120 is safe and well-tolerated and reduces pain and bloating in non-constipating IBS, although beneficial effects may be limited in duration. AST-120 represents a locally acting, non-absorbed, novel treatment for IBS and warrants further studies.

Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting.

BACKGROUND: Despite the relatively high prevalence of gastroparesis and functional dyspepsia, the aetiology and pathophysiology of these disorders remain incompletely understood. Similarly, the diagnostic and treatment options for these two disorders are relatively limited despite recent advances in our understanding of both disorders. PURPOSE: This manuscript reviews the advances in the understanding of the epidemiology, pathophysiology, diagnosis, and treatment of gastroparesis and functional dyspepsia as discussed at a recent conference sponsored by the American Gastroenterological Association (AGA) and the American Neurogastroenterology and Motility Society (ANMS). Particular focus is placed on discussing unmet needs and areas for future research.

Actions of 5-hydroxytryptamine on myenteric neurons in guinea pig gastric antrum.

Intracellular recording methods were used to study the actions of 5-hydroxytryptamine (5-HT) on 257 myenteric neurons in the guinea pig gastric antrum. Application of 5-HT caused three types of postsynaptic responses. A fast-activating depolarizing response was accompanied by a decreased input resistance and desensitized quickly to repeated applications. It was mediated by a 5-HT3 receptor. A slowly activating depolarization, accompanied by an increase in the input resistance and enhancement of the excitability, was mainly observed in after hyperpolarizing/type 2 neurons. It was suppressed by the prokinetic benzamide compound renzapride, while classical 5-HT1-4 receptor antagonists had no effect, suggesting the involvement of a 5-HT1p receptor as described in small intestinal neurons. A long-lasting hyperpolarizing response, accompanied by a decreased input resistance, was observed in a small subset of neurons. This response seemed to be mediated by a 5-HT1a receptor. Superfusion of 5-HT caused a dose-dependent inhibition of the stimulus-evoked nicotinic cholinergic fast excitatory postsynaptic potential (EPSP), which was mediated by a presynaptic 5-HT1a receptor. 5-HT also presynaptically inhibited the slow EPSP.

Actions of noradrenaline on myenteric neurons in the guinea pig gastric antrum.

We used intracellular electrophysiological recording to study the actions of noradrenaline on myenteric neurons in the guinea pig gastric antrum. Noradrenaline caused a dose-dependent inhibition of the stimulus-evoked cholinergic fast excitatory postsynaptic potentials (EPSPs). Noradrenaline had no effect on the postsynaptic response to acetylcholine, suggesting a presynaptic site of action. The slow EPSP was also presynaptically inhibited by noradrenaline. In only 5% of the neurons, noradrenaline caused a postsynaptic depolarization, accompanied by increased input resistance and enhanced excitability. Studies with adrenergic antagonists and agonists revealed that the presynaptic inhibitory effect was mediated by an alpha 2-receptor, while the postsynaptic excitatory effect seemed to be mediated by an alpha 1 receptor. We conclude that noradrenaline inhibits neurotransmitter release from cholinergic and non-cholinergic nerve terminals in the myenteric plexus of the antrum and that it excites a subpopulation of antral neurons. Both mechanisms may contribute to the neurally mediated inhibitory action of noradrenaline on gastric contractility.

Electrical behaviour of myenteric neurones in the gastric antrum of the guinea-pig.

1. Intracellular microelectrodes were used to study the electrical behaviour of ganglion cells in the myenteric plexus of the antrum of the guinea-pig stomach. In the absence of any information on antral myenteric neurones, the aim was to characterize the electrical behaviour and identify biophysical properties of the neurones that could be related to specialized organization of the neural microcircuits in this physiologically important division of the stomach. 2. Myenteric neurones in the gastric antrum were classified into four subtypes based on electrophysiological properties. These were gastric I, II, III and AH/type 2 neurones. Gastric I neurones were characterized by repetitive spike discharge during intraneuronal injection of depolarizing current, by higher input resistances and by lower resting membrane potentials than the other cell types. Gastric II neurones did not discharge repetitively. They discharged one or two spikes only at the beginning of depolarizing current pulses. Gastric III neurones did not discharge action potentials in response to depolarizing pulses. These neurones had higher membrane potentials and lower input resistances than the other types. A fourth type of neurone discharged one or more spikes during depolarizing current pulses and had long-lasting hyperpolarizing after-potentials associated with the spikes. The behaviour of these neurones was like AH/type 2 neurones found elsewhere in the enteric nervous system. 3. Action potentials in gastric I and II neurones were abolished by tetrodotoxin. Spikes of the AH/type 2 cells were not abolished by tetrodotoxin due to a calcium component of the inward current. Application of tetraethylammonium broadened the spikes. This was reversed by removal of Ca2+ from the bathing medium. 4. The hyperpolarizing after-potentials of AH/type 2 neurones were suppressed by removal of Ca2+ from the bathing medium. Treatment with 4-aminopyridine decreased the amplitude and duration of the after-hyperpolarization, whereas tetraethylammonium increased the duration and amplitude of the after-potentials. The hyperpolarizing after-potentials were unaffected by apamin. 5. Elevation of cyclic 3',5'-adenosine monophosphate by forskolin resulted in excitation of all AH/type 2 neurones and some of the gastric III cells. Gastric I and II neurones were unaffected. 6. The electrophysiological behaviour of myenteric neurones in the antrum was similar in some respects and different in others from neurones in the gastric corpus and the small and large intestine of the same animal. The differences may reflect distinct organization of the microcircuits for the specialized neural control of the effector functions which characterize the gastric antrum.

Synaptic behaviour in the myenteric plexus of the guinea-pig gastric antrum.

1. Intracellular recording methods were used to study the synaptic behaviour of neurones in the myenteric plexus of the guinea-pig gastric antrum. Synaptic potentials occurred spontaneously or were evoked by focal electrical stimulation of interganglionic fibre tracts. Synaptic events consisted of fast and slow excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs). 2. Fast EPSPs with durations less than 20 ms were evoked in every antral neurone in a population sample of 370 cells. Most of the ganglion cells received multiple inputs from axons entering the individual ganglia in several different interganglionic fibre tracts. Many of the neurones also received input from multiple axons projecting in individual fibre tracts. The fast EPSPs behaved like nicotinic cholinergic EPSPs. They were evoked at stimulus frequencies up to 60 Hz without evidence of the run-down characteristic of fast EPSPs in the intestine. 3. Slow EPSPs were evoked by repetitive stimulation of the interganglionic connectives. They consisted of a slowly activating depolarization which persisted for several seconds after termination of the stimulus. The depolarizing responses were associated with an increase in the input resistance, with enhanced excitability and with suppression of hyperpolarizing after-potentials in AH/type 2 neurones. They were observed in 14.4% of the neurones of which 89% were AH/type 2 neurones. AH/type 2 neurones, unlike other myenteric neurones, were identified by action potentials with long lasting after-hyperpolarization. 4. IPSPs were hyperpolarizing potentials evoked by repetitive stimulation of interganglionic fibre tracts. The hyperpolarizing responses were associated with decreased input resistance. They occurred in 1.4% of the antral neurones. 5. Application of acetylcholine (ACh) by micro-ejection mimicked the fast EPSPs in all neurones. This fast nicotinic response to ACh was followed by a slowly activating, long-lasting muscarinic depolarization in 32% of the neurones. The slow muscarinic response was associated with increased input resistance, suppression of hyperpolarizing after-potentials and enhanced excitability. 6. Fast EPSPs were not suppressed by accumulation of ACh at presynaptic transmitter release sites. Unlike the intestine, presynaptic muscarinic autoreceptors appeared to be absent from the microcircuits in the antrum. 7. Synaptic behaviour in the local circuits of the gastric antrum differed from the gastric corpus. This may be a reflection of specialization of the circuits for organization of the distinctive patterns of digestive behaviour found in this region of the stomach.