Functional dyspepsia, delayed gastric emptying, and impaired quality of life

BACKGROUND: It remains controversial as to whether delayed gastric emptying in functional dyspepsia is associated with a specific symptom pattern, and it is unknown if gastric emptying in functional dyspepsia is a driver of impaired health related quality of life (HRQOL). We aimed to evaluate the relationship between functional dyspepsia symptoms, gastric emptying, and HRQOL. METHODS: US patients (n=864; mean age 44 years (range 18-82); 74% female) with functional dyspepsia, as defined by Rome II criteria, were enrolled into one of four clinical trials. All patients had a baseline scintigraphic assessment of gastric emptying of an egg substitute meal, and the trials were stratified on this assessment. Delayed gastric emptying was defined as having at least 6.3% residual volume at four hours. A total of 290 (34%) patients had delayed gastric emptying. HRQOL was assessed by the SF 36 and Nepean dyspepsia index (NDI). RESULTS: Postprandial fullness was independently associated with delayed gastric emptying but the association was weak (odds ratio (OR) 1.98 (95% confidence interval (CI) 1.02, 3.86); p=0.04). No independent association was seen with epigastric pain, early satiety, nausea, or bloating. Mean SF 36 physical composite score (PCS) was 42.3 (95% CI 41.6, 43.0) and the mean SF 36 mental composite score (MCS) was 46.8 (95% CI 46.0, 47.5); both mean scores were significantly lower than age and sex adjusted national norms of 50 (p<.0001). Female sex, increasing age, and higher symptom scores for fullness, epigastric pain, and nausea were each independently associated with decreased PCS scores (all p<0.05). Higher baseline nausea symptom score, lower gastric emptying rates at one hour, and lower body mass index were associated with decreased MCS (all p<0.05). Female sex, epigastric pain, and nausea, but not gastric emptying, were associated with an impaired score on the NDI. However, the magnitude of the significant associations were all small. CONCLUSIONS: In patients with functional dyspepsia selected for a clinical trial programme, gastric emptying did not usefully stratify them symptomatically. Quality of life of patients with functional dyspepsia enrolled in this clinical trial programme was significantly impaired but this was not explained by delayed gastric emptying.     

The cerebral response to electrical stimuli in the oesophagus is altered by increasing stimulus frequencies

Recording of cerebral evoked responses (EP) allows the assessment of visceral afferent pathways and gut–brain communication, but the optimal stimulation parameters remain to be established. The present study determined the optimal stimulation frequency of electrical stimulation of the oesophagus to elicit EP responses. In 13 healthy male volunteers (24.1 ± 5.9 years), a 5 mm stainless-steel electrode was placed in the distal oesophagus for electrical stimulation (ES). EP were recorded from 21 scalp electrodes placed according to the 10/20 International system. ES (15 mA, 200 μs) were delivered in repeated series of 24 stimuli. Stimulus frequency was randomly altered in different series using a pseudologarithmic range (0.1, 0.2, 0.3, 0.5, and 1 Hz). Two series of stimuli were applied using each stimulation frequency. Two-dimensional topographic brain maps were created using interpolation techniques at each stimulation frequency. With increasing stimulus frequency, a significant and progressive decrease of EP amplitudes was observed between frequencies of 0.1 Hz and 1.0 Hz (P1/N2: 7.6 ± 1.2 vs 1.4 ± 0.3* μV, N2/P2: 17.2 ± 1.7 vs 4.6 ± 0.4* μV, P2/N3: 6.9 ± 0.7 vs 4.2 ± 0.5* μV; * = P < 0.05). In addition, there was a significant shortening of the mean peak latency of the intercalated P2 peak (P < 0.0005), with a similar trend for the P3 peak (P < 0.06), with increasing stimulus frequency from 0.1–1.0 Hz. Topographic brain maps localized the maximal early peaks (N1,P1,N2) in the paracentral cortical region (C3, Cz, C4), whereas the later peaks (P2 to P3) were symmetrically spread over the centro-parietal and temporal regions (Cz, Pz, T5, T4). There was no difference in the cortical location of maximal EP amplitudes with increasing stimulus frequency. In conclusion, there is a clear relationship between stimulus frequency and amplitude of EP, suggesting rapid attenuation of the cerebral autonomic neural responses with increased electrical stimulation frequency. The effect of increased frequency on peak latencies suggests an alteration of stimulus processing in the thalamocortical region due to an altered perception of stimuli. Early EP peaks originate from basal structures of primarily the dominant hemisphere, while later peaks are localized in centroparietal cortical regions.     

Assessment of the afferent vagal nerve in patients with gastroesophageal reflux

Background: The objective of this study was to assess the integrity of the vagal nerve afferent pathways in patients with gastroesophageal reflux disease (GERD). Methods: Seven GERD patients (4 males and 3 females, mean age 39 ± 8 years) were studied. Twelve healthy volunteers (11 males and 1 female, mean age 32 ± 8 years) were used as the control group. Cortical evoked potentials were measured. Electrical stimulation of the esophageal mucosa was performed through a custom-built device. Latencies and N2/P2 amplitude were measured. Results: Reproducible cortical evoked potentials were obtained from all subjects. The stimulation threshold for GERD patients to electrical esophageal stimulation was 5.1 ± 1.5 mA compared to 7.8 ± 2.0 mA in healthy volunteers (p <0.05). There was no difference in peak latencies or N2/P2 amplitude between GERD patients and controls. Conclusions: GERD patients have a normal vagal nerve function, but they exhibit a decreased threshold for esophageal perception. The mechanism responsible for increased esophageal sensitivity observed in GERD patients is still undetermined and warrants further study.     

Afferent vagal modulation. Clinical studies of visceral sensory input

The frequency composition of a continuous time series of R-R intervals may be viewed as the phasic output of a central processing system intimately dependent on sensory input from a variety of afferent sources. While different measures of heart rate variability permit a glimpse into the autonomic efferent limb of this complex system, direct access of afferent fibers in humans has remained elusive. Using a specially designed esophageal catheter/manometer probe, we have been able to gain access to vagal afferent fibers in the distal esophagus. Our studies on the effect of vagal afferent electrostimulation on both cerebral evoked potentials (EvP) and the power spectrum of heart rate variability have yielded the following observations: 1. Stimulation of esophageal vagal afferents dramatically and reproducibly increases the high frequency (HF) vagal power and reduces the low frequency (LF) power of the heart rate autospectrum. 2. This effect is constant across stimulation frequencies from 0.1 to 1.0 Hz and across stimulation intensities from 2.5 to 20 mA. 3. Regardless of the stimulation parameters, there are only minimal changes in heart rate (2-6 bpm) and no change in respiratory frequency. 4. There is a linear correlation between electrical stimulation intensity and the amplitude of cerebral evoked potentials, whereas there is a non-linear relationship with all short-term power spectral indices. 5. While cerebral evoked potentials are only elicited at stimulation intensities above perception threshold, there is already a significant shift to increased vagal efferent modulation well below perception threshold. CONCLUSION: These studies support the concept that power spectral indices of heart rate variability represent phasic output responses to tonic afferent viscerosensory signals in humans. These studies also demonstrate the feasibility of accessing vagal afferents in humans.     

Nitrergic and cholinergic vagal pathways involved in the regulation of canine proximal gastric tone: an in vivo study

To better understand the relationship between cholinergic and nitrergic (NO) innervation in the regulation of proximal gastric (fundic) tone in vivo, the effects of nitric oxide synthase blockade on fundic tone were studied in conscious dogs using vagal cooling and an electronic barostat. Vagal cooling, atropine (0.05 mg kg-1 i. v. bolus) and hexamethonium (1 mg kg-1 i.v. bolus) all markedly decreased fundic tone as reflected by increased intragastric volume, indicating a significant contribution of vagal and enteric cholinergic pathways to the maintenance of canine fundic tone. Administration of L-NNA (10 mg kg-1 i.v. bolus) increased fundic tone and the effects of L-NNA were completely prevented by prior vagal cooling or atropine administration, but not by pretreatment with hexamethonium. The relaxation effects of neurally derived NO appear primarily related to inhibition of ongoing vagal cholinergic activity. The data are consistent with the primary site of action of nitrergic mechanisms on gastric fundic tone in conscious dogs being at a presynaptic site on vagal cholinergic efferent nerves.     

功能性消化不良、胃排空延迟和生活质量下降

功能性消化不良（FD）是一种临床上最常见的综合征，表现为慢性反复性中上腹疼痛或不适，传统的诊断检测方法不能检测出病因。许多FD患者诉说症状与饮食有关，但病理生理情况不明。25％～50％的FD患者发生胃排空延迟症状，这与胃窦部动力降低有关。其他FD的异常表现包括胃底容受性限制、胃扩张过度敏感和幽门螺杆菌（H．pylori）感染。     

Cardiac autonomic function and oesophageal acid sensitivity in patients with non-cardiac chest pain

BACKGROUND: Acid reflux can elicit non-cardiac chest pain (NCCP), possibly through altered visceral sensory or autonomic function. The interactions between symptoms, autonomic function, and acid exposure are poorly understood. AIM: To examine autonomic function in NCCP patients during exposure to oesophageal acid infusion. SUBJECTS AND METHODS: Autonomic activity was assessed using power spectral analysis of heart rate variability (PSHRV), before and during oesophageal acidification (0.1 N HCl), in 28 NCCP patients (40.5 (10) years; 13 females) and in 10 matched healthy controls. Measured PSHRV indices included high frequency (HF) (0.15-0.5 Hz) and low frequency (LF) (0.06-0.15 Hz) power to assess vagal and sympathetic activity, respectively. RESULTS: A total of 19/28 patients had angina-like symptoms elicited by acid. There were no significant manometric changes observed in either acid sensitive or insensitive patients. Acid sensitive patients had a higher baseline heart rate (82.9 (3.1) v 66.7 (3.5) beats/min; p<0.005) and lower baseline vagal activity (HF normalised area: 31.1 (1.9)% v 38.9 (2.3)%; p< 0.03) than acid insensitive patients. During acid infusion, vagal cardiac outflow increased (p<0.03) in acid sensitive but not in acid insensitive patients. CONCLUSIONS: Patients with angina-like pain during acid infusion have decreased resting vagal activity. The symptoms elicited by perception of acid are further associated with a simultaneous increase in vagal activity in keeping with a vagally mediated pseudoaffective response.     

Objective Assessment of Cognitive Factors Involved in Visceral Perception by Using Event-Related Cerebral Evoked Responses to Esophageal Target Stimulation in Man

Evoked potential (EP) studies provide an objective measure of the neural pathways involved with perception of gastrointestinal stimulation. The effects of cognitive factors, such as anticipation or awareness, on EP responses are not known. We compared the EP response to esophageal electrical stimulation with the cortical activity associated with target detection and anticipation of the same stimulus. In 12 healthy men (26.8 ± 6 years old), esophageal electrical stimulation (0.2 Hz, 0.2 msec, 15 mA) was applied, and the EP recorded using scalp electrodes. A computerized model of randomly applied target stimuli (1:5 ratio) was used to separately record the EP associated with stimulation and the event-related cognitive EP associated with a dual task-related or anticipated stimulation approach. A periodic electrical stimulus represented the nontarget stimulus and a second electrical impulse (oddball model) or an omitted stimulus (anticipatory model) the target stimulus. The event-related cognitive EP responses were also compared with standard and anticipatory auditory P₃₀₀ evoked potentials. The esophageal and auditory oddball stimulus approach elicited event-related P₃₀₀EP in all subjects. P₃₀₀EP associated with electrical stimulation had a longer peak latency (P < 0.0001) and smaller amplitude than those obtained with auditory stimulation. Anticipatory evoked potentials could be obtained by electrical skipped stimulation in 8 of 12 subjects. These EP were similar to those obtained with omitted auditory target stimulation, although of significantly smaller amplitude than auditory standard P₃₀₀EP (P < 0.001). In conclusion, the brain response associated with directed effortful processing of discriminate esophageal stimuli consists of a large event-related potential (P₃₀₀EP). Anticipatory stimulation produces a similar event-related cortical response, which is associated with attention to and awareness of the actual stimulus. The P₃₀₀EP to gastrointestinal stimuli may provide an objective and powerful electrophysiological tool for the assessment of the cognitive factors associated with visceral perception.     

Best Practices for Drug Substance Stress and Stability Studies During Early-Stage Development Part II—Conducting Abbreviated Long-Term and Accelerated Stability Testing on the First Clinical Drug Substance Batch to Confirm and Adjust the Drug Substance Retest Period/Powder for Oral Solution Shelf Life

In pursuit of continuous process improvement, the authors streamlined the drug substance (DS) stress and stability testing process from preclinical to the first clinical batch. High temperature/high humidity stress and ICH Q1B confirmatory photostability testing on an early DS batch provide stability data that help quickly assess the new DS stability behavior, extrapolate the initial DS retest period and the initial powder for oral solution (PFOS) shelf life, and evaluate packaging requirements. Then, concurrent stability testing on the first clinical batch (or alternatively a representative nonclinical batch) is conducted under long-term (LT) and accelerated (AC) storage conditions. The LT/AC stability testing is used to verify the solid stress testing results and to adjust the DS retest period and the shelf life of (PFOS), if necessary. This paper describes how to perform abbreviated LT/AC stability testing, compares LT/AC stability results with the solid stress results, shows how to adjust the DS retest period and PFOS shelf life if necessary, and shares our regulatory experiences with this new approach. Our science- and risk-based DS stress and stability process has offered a quick turnaround in obtaining adequate stability information for new DS development, eliminated redundancies, improved efficiency and consistency, achieved an optimal balance between risk and cost for early drug development, and received regulatory acceptances.