The relationship between manometric subtype and symptom details in achalasia.

BACKGROUND: Although dysphagia and chest pain are the two most common symptoms in patients with achalasia, the mechanism of evoking symptoms is still unknown. The aim of this study was to reveal the relationship between symptoms and the subtypes of achalasia defined by the Chicago classification. METHODS: A total of 71consecutive patients with newly diagnosed achalasia were enrolled between March 2009 and December 2017. Esophageal motility was assessed by high-resolution manometry (HRM) with the Chicago classification v 3.0. and esophagograms. Their symptoms were evaluated with structured self-reported questionnaires focused on dysphagia and chest pain. Symptom profiles and radiographic findings according to the manometric subtypes were investigated. RESULTS: Among the total 71 patients, 69 patients (97%) had dysphagia and 39 patients (54%) had chest pain. Regarding dysphagia, type II patients reported dysphagia in the throat the most, while types I and III patients mostly felt it in the epigastrium. Type II patients often felt dysphagia at the time of swallowing (41%), but this was reported in only 8.7% of Type I and 33% of Type III patients (p = 0.02). Concerning chest pain, Type I patients rarely had pain during meals (14%), but more often while sleeping (43%) and in early morning (43%), while type III patients often had pain during meals (67%). Type III patients reported that solid food caused pain more often than other types (I/II/III 0/10/33%, p = 0.09). CONCLUSIONS: Detailed symptoms of achalasia, such as its site and timing, varied by subtypes. The status of the esophageal body might induce those differences in symptoms.

Impact of improvement of sleep disturbance on symptoms and quality of life in patients with functional dyspepsia.

BACKGROUND/AIMS: Functional dyspepsia (FD) is often comorbid with sleep disturbance. However, it is not fully understood how sleep disturbance affects the pathophysiology of FD. We aimed to investigate the relationship between FD and sleep disturbance. METHODS: We prospectively enrolled 20 FD patients with sleep disturbance between December 2018 and July 2019. Patients took sleep aids for 4 weeks and filled out questionnaires before and after taking sleep aids. Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Athens Insomnia Scale (AIS) were used to evaluate the severity of their sleep disturbance. Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (mFSSG), Gastrointestinal Symptom Rating Scale (GSRS), and the Japanese version of Patient Assessment of Constipation Quality of Life (JPAC-QOL) were used to evaluate the severity of GI symptoms. Short-Form 36-Item Health Survey (SF-36) was used to evaluate QOL. Pre- and post-sleep medication values of questionnaires were compared. RESULTS: Among 20 enrolled patients, 16 completed the study protocol. Zolpidem, eszopiclone, and suvorexant were administered to six, nine, and one patient, respectively. Each median total score of questionnaires (pre-/post-sleep medication, respectively) was as follows: PSQI, 10.0/8.5; ESS, 12.5/5.0; AIS, 10.0/4.0; mFSSG, 21.0/16.0; GSRS, 44.0/31.0 (Pain in GSRS, 11.0/5.0); JPAC-QOL, 26.0/15.5; SF-36, 63.9/71.9. All of these results showed statistically significant differences between pre- and post-sleep medication (p < 0.05). CONCLUSIONS: Improvement of sleep disturbance by administration of sleep aids resulted in improvement of GI symptoms and QOL in patients with FD. This effect may be related to pain modification.

Efficacy of Vonoprazan, a Novel Potassium-Competitive Acid Blocker, in Patients with Proton Pump Inhibitor-Refractory Acid Reflux.

BACKGROUND/AIM: We evaluated the efficacy of vonoprazan (VPZ), a novel potassium-competitive acid blocker, in patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD), exhibiting continued pathological esophageal acid exposure (EAE). METHODS: Despite ≥8 weeks of appropriate PPI therapy, patients with -persistent reflux symptoms and pathological EAE times (EAETs ≥4%) were invited to switch to VPZ treatment. After an 8-week-course of once-daily VPZ (20 mg), multichannel intraluminal impedance-pH (MII-pH) monitoring was repeated to compare gastric acid exposure times (GAETs), EAETs, and other reflux parameters relative to the baseline values. Before each MII-pH study, reflux symptom severities were scored using the Gastrointestinal Symptom Rating Scale; erosive esophagitis and fasting plasma gastrin levels were also assessed. RESULTS: From among the 124 patients undergoing MII-pH monitoring, 13 patients (median age, 69 years; females, 64%) were monitored at baseline (while on PPI therapy) and after VPZ therapy. The median GAET associated with VPZ treatment (23.8%) was less than that for PPI treatment (41.1%; p = 0.01), including both daytime and nighttime measurements. VPZ therapy resulted in better median EAET values (4.5%) than did PPI therapy (10.6%) during the 24-h monitoring period (p = 0.055). EAE normalization was achieved in 46% of VPZ-treated patients and was associated with complete gastric acid suppression (p = 0.005). After switching to VPZ, reflux symptoms (p < 0.01) and erosive esophagitis (p = 0.01) improved. CONCLUSION: In patients with PPI-refractory GERD, VPZ provides more potent gastric acid suppression, more effective EAE control, enhanced symptom improvement, and better esophagitis healing than PPIs.

Elevated serum uric acid level was a notable adverse event during combination therapy with sofosbuvir and ribavirin.

AIM: Combination therapy with sofosbuvir and ribavirin (SOF/RBV) has been recently available for chronic hepatitis C patients with genotype 2 (CHG2) in Japan. The domestic phase III clinical trial showed a high antiviral effect with a relatively safe adverse event (AE) profile. Our aim was to report an important AE detected during treatment. METHODS: A prospective multi-institutional study of 12-week combination therapy with SOF/RBV for CHG2 was carried out to evaluate efficacy and safety. RESULTS: The eligible subjects included 142 patients. Out of 50 assessable patients, 16% of the patients were diagnosed with hyperuricemia. The proportions of subjects with grade 1, grade 3, and grade 4 hyperuricemia were 12, 2, and 2%, respectively. Serum uric acid (UA) levels at week 1 of the therapy (W1) were numerically the highest during therapy in patients with hyperuricemia, and the ratio of W1/baseline serum UA levels was significantly higher than that of post-treatment week 4 or 8/baseline serum UA levels in assessable patients. Serum UA levels at W1 were significantly correlated with body mass index. The difference between serum UA levels at W1 and baseline serum UA levels was significantly correlated with the difference between serum creatinine levels at W1 and baseline serum creatinine levels. CONCLUSIONS: Elevated serum UA level was a notable AE associated with SOF/RBV therapy for CHG2. However, because of the small number of subjects, the exact frequency of AEs should be re-evaluated with larger cohorts. We need to remember that elevated serum UA level might develop during the therapy, especially at W1.

Therapy of gastroesophageal reflux disease and functional dyspepsia overlaps with symptoms after usual-dose proton pump inhibitor: Acotiamide plus usual-dose proton pump inhibitor versus double-dose proton pump inhibitor.

BACKGROUND AND AIM: Gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) often coexist or overlap. In this study, the efficacy of acotiamide in combination with a standard dose of rabeprazole for GERD and FD was compared with that of a double dose of rabeprazole. METHODS: Patients with overlap between GERD and FD experiencing heartburn and epigastric fullness symptoms after standard-dose proton pump inhibitor (PPI) for ≥ 8 weeks were randomized into two groups and received either acotiamide 300 mg/day + rabeprazole 10 mg/day or rabeprazole 20 mg/day for 4 weeks. Efficacy was assessed by reductions in symptom scores using the Izumo scale questionnaire and modified F-scale questionnaire. RESULTS: As the primary endpoint, three upper gastrointestinal symptoms (heartburn, epigastralgia, and epigastric fullness) were reduced by ≥ 50% in 40.8% and 46.9% of patients in the combination and PPI double-dose groups, respectively, with no significant difference between the two groups. Essentially similar results were obtained for the modified F-scale questionnaire. No serious adverse events were noted. CONCLUSIONS: Acotiamide 300 mg/day in combination with rabeprazole 10 mg/day or rabeprazole 20 mg/day relieved symptoms in patients with overlap between GERD and FD experiencing heartburn and epigastric fullness symptoms after standard-dose PPI for ≥ 8 weeks, and the efficacies did not differ between the two treatments. The combination therapy may be an alternative option for persistent symptoms in these patients.

Efficacy and Safety Profile of Z-215 (Azeloprazole Sodium), a Proton Pump Inhibitor, Compared with Rabeprazole Sodium in Patients with Reflux Esophagitis: A Phase II, Multicenter, Randomized, Double-Blind, Comparative Study.

BACKGROUND: The metabolism of many proton pump inhibitors is influenced by CYP2C19 genotype, which is a limitation of their use. OBJECTIVES: To determine the efficacy and safety profile of Z-215 (azeloprazole sodium) as initial treatment for reflux esophagitis (RE), dose response, and optimal dose compared with rabeprazole sodium (RPZ). METHODS: We conducted an exploratory, multicenter, randomized, double-blind, parallel-group study in Japan. Patients with RE aged ≥20 years were enrolled and randomly assigned to receive 10, 20, or 40 mg Z-215 or 10 mg RPZ (1:1:1:1), and orally administered the respective drug for 8 weeks. The primary efficacy end point was the endoscopic healing rate after 8 weeks of treatment (at Week 8). We also assessed the effects of CYP2C19 genotype. Safety end points were the incidence of adverse events and adverse drug reactions. RESULTS: Five hundred three patients received the study drugs (10 mg Z-215: 125 patients, 20 mg Z-215: 126 patients, 40 mg Z-215: 126 patients, and 10 mg RPZ: 126 patients). The endoscopic healing rate at Week 8 was above 95% in all groups (10 mg Z-215: 95.2%, 20 mg Z-215: 96.8%, 40 mg Z-215: 95.2%, and 10 mg RPZ: 96.8%). The endoscopic healing rate and serum gastrin levels of the Z-215 groups were not influenced by CYP2C19 genotype. In patients with Grade C/D, the endoscopic healing rate at Week 4 was slightly higher in the 40-mg Z-215 group compared with the other groups. Incidences of adverse events/adverse drug reactions did not markedly differ between the Z-215 and 10-mg RPZ groups. CONCLUSIONS: Z-215 was as effective and well tolerated as 10 mg RPZ in the treatment of RE in this selected population. CYP2C19 genotype status may not influence the efficacy and safety of Z-215. There were no clear dose-response effects between Z-215 doses in the endoscopic healing of RE. These findings suggest that Z-215 may be 1 option for the initial treatment of RE. ClinicalTrials.gov identifier: NCT 02463643.

Higher frequency of upper gastrointestinal symptoms in healthy young Japanese females compared to males and older generations.

BACKGROUND: The aim of this study was to evaluate the differences in upper gastrointestinal symptoms between generations and genders in relatively healthy Japanese subjects. METHODS: Altogether, 4086 healthy Japanese male and female (M/F) adults (M/F: 2244/1842) were analyzed. Among them, 3505 subjects (M/F: 1922/1583) were underwent a routine medical checkup at one of five hospitals in Saga, Japan from January 2013 to December 2013. The others were 581 (M/F: 322/259) healthy young volunteers at the Saga Medical School from April 2007 to March 2013. The participants were asked to complete the frequency scale for the symptoms of gastroesophageal reflex disease (FSSG) questionnaire, undergo upper gastrointestinal endoscopy, and submit to a rapid urease test to diagnose Helicobacter pylori infection. Among the 4086 subjects, the 2414 who had no H. pylori infection and no positive endoscopic findings were enrolled in the study. RESULTS: Subjects' average age was 46.9 ± 12.2 years, with males' and females' ages being almost equivalent. The total FSSG score were high in females compared to males (P < 0.01) and decreased significantly with aging (P < 0.05). Among the generations, FSSG scores were the highest for those 20-29 years old, and they were significantly decreased with ageing in both males and females (P < 0.05). CONCLUSION: The FSSG score was significantly higher in healthy Japanese females than in males, and the scores decreased with aging.

Spontaneous remission of hepatitis B virus reactivation during direct-acting antiviral agent-based therapy for chronic hepatitis C.

The administration of direct-acting antiviral agents (DAAs) to treat hepatitis C virus (HCV) infection has been reported to cause hepatitis B virus (HBV) reactivation. However, the actual conditions of HBV reactivation and the ideal timing of medical intervention have not been fully evaluated. We report the cases of two female patients dually infected with HBV and HCV. Both patients were inactive HBV carriers. Although the serum HCV RNA levels promptly decreased after the initiation of DAA-based therapy, the serum HBV DNA levels gradually increased during DAA-based therapy, with the peak serum HBV DNA levels observed at 16 weeks after the initiation of DAA-based therapy in both cases. Subsequently, we checked the serum HBV DNA levels closely every week several times. Fortunately, the serum HBV DNA levels gradually decreased without medical intervention. Neither case developed an alanine aminotransferase flare-up. The HCV genotypes were 2a and 1b, and the DAA-based therapies of Cases 1 and 2 were 12 weeks of sofosbuvir/ribavirin and ombitasvir/paritaprevir/ritonavir, respectively. The significance of our case reports is the demonstration of the existence of spontaneous remission of HBV reactivation that developed during DAA-based therapy, the avoidance of intervention of nucleot(s)ide analogs by frequent monitoring of serum HBV DNA levels, and development of HBV reactivation regardless of the viral genotype or class of DAA. In conclusion, the close monitoring of serum HBV DNA levels during and after DAA-based therapy is essential and medical intervention for HBV reactivation should be carefully considered on an individual basis.

Clinical and virological features of acute hepatitis E in Gunma prefecture, Japan between 2004 and 2015.

AIM: To evaluate the clinical and virological features of acute hepatitis E (AH-E) in Gunma prefecture and focus on the hepatitis E virus (HEV) infection in immunocompromised patients. METHODS: A total of 30 patients with AH-E diagnosed at our Gunma University Hospital, and located in 3-39-15 Showa-machi, Maebashi, Gunma 371-8511 Japan, and its affiliated hospitals from 2004 to 2015, were studied. We evaluated the detailed medical histories, laboratory examinations and virological features of these participants. RESULTS: Of the 30 patients, 21 patients were men, with a median age of 61 years. Three of these patients had a history of recent oversea travel. A total of 14 patients had eaten raw or undercooked meat/viscera from animals, and two patients had contracted transfusion-transmitted AH-E. Eight patients were immunocompromised, including those with hematological disease, cancer receiving systemic chemotherapy and kidney transplant or connective tissue disease undergoing immunosuppressive medications. The alanine aminotransferase and total bilirubin levels were more significantly reduced in these immunocompromised patients than in the non-immunocompromised patients. Severe thrombocytopenia, an extra-hepatic manifestation of AH-E, occurred in one case. Among the 22 HEV strains whose subgenotype was determined, two were imported strains (1a and 1f), and 11 strains formed four distinct phylogenetic clusters within subgenotype 3b. The remaining nine strains differed from each other by 9.8-22.4%, and were classified into four subgenotypes (3a, 3b, 3e and 3f). CONCLUSION: Markedly divergent HEV strains (3a, 3b, 3e and 3f) were found to circulate in Gunma. Although immunosuppression appears to play a crucial role in establishing chronic sequels, AH-E in eight immunocompromised patients, including transfusion-transmitted HEV infection in two patients, did not become chronic.

Combination Therapy with Ombitasvir/Paritaprevir/Ritonavir for Dialysis Patients Infected with Hepatitis C Virus: A Prospective Multi-Institutional Study.

Hepatitis C virus (HCV) infection is common in dialysis patients worldwide and nosocomial HCV spread within dialysis facilities continues to develop. Combination therapy with daclatasvir and asunaprevir (DCV/ASV) that has proven efficacy for dialysis patients infected with genotype 1b HCV (HCV/1b) has several concerns in Japan. The recently available combination therapy with ombitasvir, paritaprevir, and ritonavir (OBV/PTV/r) is not contraindicated in patients with chronic renal failure and has more safety profile and shorter treatment period than that with DCV/ASV. We evaluated the effects of combination therapy with OBV/PTV/r in four dialysis patients infected with HCV/1b, who were eligible for our study. On-treatment assessments included standard laboratory testing, serum HCV RNA and symptom-directed physical examinations. Three patients had a sustained virological response at 12 weeks after treatment, but one remaining patient had viral breakthrough. Notably, the patient with viral breakthrough had been coinfected with HCV/1b and HCV/2b; namely, HCV/2b with resistance-associated variations was not eradicated by the combination therapy. Among the three patients responsive to the combination therapy, one patient complained of appetite loss and itching, while in another patient the therapy was discontinued due to itching, exacerbation of wamble, and a falling tendency probably due to interaction with valsartan. These AEs were ameliorated or disappeared after the completion of the therapy. The significance of our study is persuasive virological evaluation associated to the combination therapy and reasonable interpretation of AEs. In conclusion, combination therapy with OBV/PTV/r may have promise as an efficacious therapy, but caution regarding AEs should be practiced.

Increase of transient lower esophageal sphincter relaxation associated with cascade stomach.

We previously reported that cascade stomach was associated with reflux symptoms and esophagitis. Delayed gastric emptying has been believed to initiate transient lower esophageal sphincter relaxation (TLESR). We hypothesized that cascade stomach may be associated with frequent TLESR with delayed gastric emptying. Eleven subjects with cascade stomach and 11 subjects without cascade stomach were enrolled. Postprandial gastroesophageal manometry and gastric emptying using a continuous 13C breath system were measured simultaneously after a liquid test meal. TLESR events were counted in early period (0-60 min), late period (60-120 min), and total monitoring period. Three parameters of gastric emptying were calculated: the half emptying time, lag time, and gastric emptying coefficient. The median frequency of TLESR events in the cascade stomach and non-cascade stomach groups was 6.0 (median), 4.6 (interquartile range) vs 5.0, 3.0 in the early period, 5.0, 3.2 vs 3.0, 1.8 in the late period, and 10.0, 6.2 vs 8.0, 5.0 in the total monitoring period. TLESR events were significantly more frequent in the cascade stomach group during the late and total monitoring periods. In contrast, gastric emptying parameters showed no significant differences between the two groups. We concluded that TLESR events were significantly more frequent in persons with cascade stomach without delayed gastric emptying.

Higher Frequency of Reflux Symptoms and Acid-Related Dyspepsia in Women than Men Regardless of Endoscopic Esophagitis: Analysis of 3,505 Japanese Subjects Undergoing Medical Health Checkups.

BACKGROUND/AIMS: This study aimed at (i) clarifying the factors associated with high scores on the modified frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) among 3,505 relatively healthy subjects undergoing routine medical health checkups with gastrointestinal endoscopy and (ii) comparing risk factors for high FSSG scores between subjects with and without reflux esophagitis. METHODS: In total, 3,505 subjects (male/female: 1,922/1,583) who underwent upper gastrointestinal endoscopy during health medical checkups at 5 hospitals in Saga, Japan from January 2013 to December 2013 were enrolled. All subjects completed a modified FSSG questionnaire, which comprised 7 questions regarding reflux symptoms and 7 questions regarding acid-related dyspepsia. Each question was assigned a score based on the frequency of symptoms. RESULTS: Younger age, female gender, hiatal herniation, and endoscopic reflux esophagitis were risk factors for a FSSG score with a high total. Subjects with high scores but without esophagitis were women, and hiatal herniation and Barrett's esophagus were frequently seen in patients with reflux esophagitis. CONCLUSION: Younger age, female gender, hiatal hernia, and endoscopic esophagitis were risk factors for a high FSSG score, and women tended to complain of upper gastrointestinal symptoms more frequently than did men among subjects without endoscopic esophagitis.

24-hour esophageal multichannel intraluminal impedance and pH monitoring.

Monitoring of esophageal impedance is a technique for determining the physical characteris- tics (liquid, gas, or mixed) of refluxate, while impedance monitoring combined with pH recording makes it possible to assess the acidity of reflux(acid or non-acid). Assessment is usually performed by the total acid exposure time (%time pH< 4) and symptom-reflux asso- ciations including acidic and non-acidic reflux. This monitoring is quite useful for evaluation of proton pump inhibitor-resistant gastroesophageal reflux disease or non-erosive reflux disease. When normal acid exposure time and significant symptom-reflux associations are observed, a patient should be diagnosed as having hypersensitive esophagus. When normal acid exposure time and no significant symptom-reflux associations are observed, a patient should be diagnosed as having functional heartburn. Therefore, the result makes it possible to decide treatment strategy.

A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia.

OBJECTIVES: The aim of this study was to assess the long-term prognosis, efficacy, and safety of combination therapy using ursodeoxycholic acid (UDCA) and bezafibrate (BF) for primary biliary cirrhosis (PBC) patients exhibiting dyslipidemia. METHODS: We performed a prospective, randomized, controlled, multicenter study to compare the long-term clinical results between combination therapy and UDCA monotherapy for patients refractory to UDCA monotherapy. Twenty-seven consecutive PBC patients were enrolled. RESULTS: The median treatment period in the UDCA and UDCA+BF groups was 107 and 110 months, respectively. The serum alkaline phosphatase (ALP) levels and the Mayo risk score in the combination therapy group (mean 290 IU/l and 0.91, respectively) were significantly lower than those in the UDCA monotherapy group (mean 461 IU/l and 1.42, respectively) at 8 years after the beginning of the study (P<0.05). The serum creatinine levels in the combination therapy group (mean 0.94 mg/dl) were significantly higher than those in the UDCA monotherapy group (mean 0.56 mg/dl) at 8 years after the beginning of the study (P<0.05). However, the survival rate was not significantly different between the groups. We observed dose reduction or discontinuation of the administration of BF, but not UDCA, due to renal dysfunction or muscle pain. CONCLUSIONS: Long-term combination therapy significantly improved the serum ALP levels and the Mayo risk score. However, the survival rate was not significantly different between the groups. In addition, long-term combination therapy significantly increased the serum creatinine levels. We should pay close attention to adverse events during this long-term combination therapy.

A prospective randomized controlled study of endoscopic sphincterotomy with the Endocut mode or conventional blended cut mode.

BACKGROUND: Although the potential advantages of the Endocut mode (E-mode) of endoscopic sphincterotomy (EST) over the conventional blended cut mode (C-mode) have been reported, the problems, including the small sample size and retrospective analysis, that occurred in previous studies make it difficult to conclude the advantage of the E-mode regarding the safety and efficacy. We performed a prospective randomized controlled study to compare these modes. METHODS: A total of 360 patients with choledocholithiasis or stenosis of the bile duct were randomly assigned to one of the modes. To avoid the technical bias due to multiple operators or institutions, the main operator and the institution were restricted to only one experienced doctor and 3 institutions at his place of employment, respectively. We defined pancreatitis, bleeding, and perforation as complications of EST. Besides, bleeding includes endoscopically evident bleeding that was defined as visible during the procedure of sphincterotomy and temporary slight oozing. RESULTS: The complications occurred in 20 (11.2%) patients from the E-mode group: pancreatitis in 6 (3.4%) and endoscopically evident bleeding in 14 (7.8%). In contrast, the complications occurred in 25 (13.8%) patients from the C-mode group: pancreatitis in 7 (3.9%) and endoscopically evident bleeding in 18 (9.9%), although these findings were not statistically significant. Overall, there were no severe complications. There were no significant differences in completion ratio of EST and the time taken for the sphincterotomy between both groups. CONCLUSIONS: The E-mode could not surpass the C-mode in safety and efficacy under the operation by a single endoscopist.

Evaluation of proton pump inhibitor-resistant nonerosive reflux disease by esophageal manometry and 24-hour esophageal impedance and pH monitoring.

BACKGROUND: Patients with proton pump inhibitor (PPI)-resistant nonerosive reflux disease (NERD) include subgroups that have markedly different pathophysiology. This study aimed to clarify the pathophysiology of NERD by esophageal manometry with 24-hour esophageal impedance and pH monitoring. METHODS: Eighteen consecutive outpatients referred to our expert center for functional gastrointestinal motility with suspected PPI-resistant NERD were enrolled. Manometry was performed to detect esophageal motility disorders. Subsequently, 24-hour esophageal impedance and pH monitoring was done while patients were on PPI therapy. RESULTS: Manometry revealed 1 case of achalasia, 1 case of nutcracker esophagus and 3 cases of diffuse esophageal spasm. Three patients had ineffective esophageal motility, with impedance and pH monitoring being performed in 2 of them. Esophageal acid exposure (%time pH <4) was normal in both, but the symptom index (SI) was positive for nonacidic reflux in 1 patient. One of the 10 patients with normal esophageal motility had abnormal esophageal acid exposure. The SI was positive for weakly acidic and nonacidic reflux in 3 of the remaining 9 patients with normal esophageal acid exposure. Five of the other 6 patients seemed to have functional heartburn. CONCLUSION: A substantial percentage (28%) of patients with suspected PPI-resistant NERD had primary esophageal motility disorders. Both nonacidic reflux and weakly acidic reflux are important contributors to the symptoms of patients with PPI-resistant NERD. Esophageal manometry is required to exclude motility disorders, while 24-hour esophageal impedance and pH monitoring is invaluable for assessing symptom-reflux associations and the indications for fundoplication in patients with suspected PPI-resistant NERD.

Effect of acotiamide on gastric emptying in healthy adult humans.

BACKGROUND: Acotiamide is a first-in-class drug that is used to treat functional dyspepsia (FD). It is considered that acotiamide acts as an antagonist on muscarinic autoreceptors in the enteric nervous system and inhibits acetylcholinesterase activity. We examined the effect of acotiamide on gastric emptying in healthy adult humans. MATERIALS AND METHODS: Twelve healthy adult males were enrolled in this double-blind crossover study. Acotiamide or placebo was administered orally in the 12 subjects 30 min before ingestion of a nutritional liquid meal (400 Kcal/400 mL). Six of the 12 participants took 100 mg of acotiamide or placebo, and six of the 12 participants took 300 mg of acotiamide or placebo in a double-blind crossover fashion. All subjects underwent measurement of gastric emptying by the (13) C breath test. RESULTS: After the meal with placebo was ingested, the %dose/h curve ascended. The %dose/h curve after a meal with 100 or 300 mg of acotiamide ascended in an identical manner compared with the results with placebo. No significant differences were observed at any studied time point, and there were no significant changes in gastric emptying parameters (gastric emptying coefficient, t-1/2ex and t-lag ex). CONCLUSIONS: A single administration of 100 or 300 mg of acotiamide did not affect gastric emptying after a liquid meal in healthy adult humans. Acotiamide has profound effects on restoring delayed gastric emptying and impaired accommodation in patients with FD but may have no effect on gastric emptying in healthy subjects. Such pharmacological actions have not been observed in previous gastroprokinetic studies.

Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito.

BACKGROUND: The incidence and severity of gastroesophageal reflux disease (GERD) in Japan tends to increase in elderly women. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and improves gastric emptying and gastric accommodation. Our previous prospective randomized placebo-controlled study showed that RKT combined with a standard-dose of rabeprazole (RPZ) significantly improved the acid-related dysmotility symptoms (ARD) in elderly patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study aimed to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT. METHODS: Two hundred forty-two patients with PPI-refractory NERD were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) + RKT (7.5 g/t.i.d.) (RKT group) or RPZ + placebo (PL group). Among them, 95 were elderly (≥65 years) with ARD (RKT group: n = 52; PL group: n = 43). We analyzed the changes using the 12 subscale score of frequency scale for the symptoms of GERD (FSSG) and 15 items of the Gastrointestinal Symptom Rating Scale at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups. RESULTS: There were no marked differences in baseline demographic or clinical characteristics in the 2 groups except for rate of current smoking. The FSSG score (mean ± SD at 0, 4, and 8 weeks) in both the RKT (16.0 ± 7.0; 9.9 ± 8.4; 7.0 ± 6.4) and PL (15.1 ± 6.4; 10.9 ± 6.7, 11.1 ± 8.5) groups significantly decreased after treatment. However, the degree of improvement of total and ARD scores of FSSG after the 8-week treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain. CONCLUSIONS: RKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. Thus, RKT was particularly effective for resolving postprandial GERD symptoms (heavy feeling in stomach, sick feeling, and heartburn after meals). TRIAL REGISTRATION: (UMIN000005880).