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The purpose of medicines is to improve patients’ lives. Stakeholders involved in the development and lifecycle management of medicines agree that more effective patient involvement is needed to ensure that patient needs and priorities are identified and met. Despite the increasing number and scope of patient involvement initiatives, there is no accepted master framework for systematic patient involvement in industry-led medicines research and development, regulatory review, or market access decisions. Patient engagement is very productive in some indications, but inconsistent and fragmentary on a broader level. This often results in inefficient drug development, increasing evidence requirements, lack of patient-centered outcomes that address unmet medical needs and facilitate adherence, and consequently, lack of required therapeutic options and high costs to society and involved parties. Improved patient involvement can drive the development of innovative medicines that deliver more relevant and impactful patient outcomes and make medicine development faster, more efficient, and more productive. It can lead to better prioritization of early research; improved resource allocation; improved trial protocol designs that better reflect patient needs; and, by addressing potential barriers to patient participation, enhanced recruitment and retention. It may also improve trial conduct and lead to more focused, economically viable clinical trials. At launch and beyond, systematic patient involvement can also improve the ongoing benefit-risk assessment, ensure that public funds prioritize medicines of value to patients, and further the development of the medicine. Progress toward a universal framework for patient involvement requires a joint, precompetitive, and international approach by all stakeholders, working in true partnership to consolidate outputs from existing initiatives, identify gaps, and develop a comprehensive framework. It is essential that all stakeholders participate to drive adoption and implementation of the framework and to ensure that patients and their needs are embedded at the heart of medicines development and lifecycle management.

The purpose of medicines is to improve patients' lives. Stakeholders involved in the development and lifecycle management of medicines agree that more effective patient involvement is needed to ensure that patient needs and priorities are identified and met. Despite the increasing number and scope of patient involvement initiatives, there is no accepted master framework for systematic patient involvement in industry-led medicines research and development, regulatory review, or market access decisions. Patient engagement is very productive in some indications, but inconsistent and fragmentary on a broader level. This often results in inefficient drug development, increasing evidence requirements, lack of patient-centered outcomes that address unmet medical needs and facilitate adherence, and consequently, lack of required therapeutic options and high costs to society and involved parties. Improved patient involvement can drive the development of innovative medicines that deliver more relevant and impactful patient outcomes and make medicine development faster, more efficient, and more productive. It can lead to better prioritization of early research; improved resource allocation; improved trial protocol designs that better reflect patient needs; and, by addressing potential barriers to patient participation, enhanced recruitment and retention. It may also improve trial conduct and lead to more focused, economically viable clinical trials. At launch and beyond, systematic patient involvement can also improve the ongoing benefit-risk assessment, ensure that public funds prioritize medicines of value to patients, and further the development of the medicine. Progress toward a universal framework for patient involvement requires a joint, precompetitive, and international approach by all stakeholders, working in true partnership to consolidate outputs from existing initiatives, identify gaps, and develop a comprehensive framework. It is essential that all stakeholders participate to drive adoption and implementation of the framework and to ensure that patients and their needs are embedded at the heart of medicines development and lifecycle management.

The BioLogue International Symposium on Adaptive Clinical Trials was held October 10, 2006, in Copenhagen, Denmark. This symposium brought together clinical trialists and trial experts from academia, industry, and regulatory agencies to initiate a dialogue on opportunities, scope, and challenges regarding adaptive clinical trials.

The diagnosis of irritable bowel syndrome (IBS) is arbitrary, being based on criteria defined by consensus rather than specific biologic markers. IBS is merely a consortium of symptoms and as presently defined is no more a disease than dyspnea or fatigue are diseases. In this context, it is therefore not surprising that defining the nature of pain has proven elusive. It is often etiologically assumed that the origins of the pain seen in IBS patients are mechanistically distinct from those of some of the other symptoms of IBS such as diarrhea and constipation. In addition pain is assumed to be part of a continuum ranging from complete absence of any pain to varying degrees of discomfort to severe pain. Both of these assumptions should be challenged: there are no data to support the notion that discomfort and pain experienced in IBS are mediated through different pathways than symptoms such as bloating or that they are not merely the consequence of the physiological perturbations associated with altered bowel function. Similarly one can easily argue that visceral pain may actually be the cause rather than the effect of the altered gut function seen in IBS. Abdominal discomfort could then be the consequence of the latter and be only indirectly related to pain. It is likely that central (such as stress) and peripheral factors (such as intestinal infection) will produce similar symptoms but via markedly different pathways. It may be time to deconstruct IBS as a concept and to approach the clinical picture from a mechanistic rather than a phenomenological perspective, particularly if we are interested in understanding the basis of the symptoms and develop effective therapeutic modalities. Our patients deserve no less.

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 P300evoked 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.

The aim of this study was to determine the prevalence of upper gastrointestinal symptoms (UGIS) in a general population and quantify the relationship of those symptoms to health-care utilization and quality of life. In-person interviews were conducted with 2056 United States and Canadian residents selected at random. Subjects reported frequency and severity for 11 symptoms, prescription and over-the-counter medication use, primary care and specialty physician visits in prior three months, and completed the Psychological General Well-Being Scale. For analyses, subjects were classified into four mutually exclusive symptom groups: gastroesophageal reflux disease (GERD) -like, GERD plus motility-like (GERD+), ulcerlike, and motility-like. Of the total sample, 51.4% reported the occurrence of at least one UGIS in the prior three months. Subjects in the GERD+ and ulcer groups used more prescription medications and were more likely to see a physician about the symptoms (P< 0.001). Subjects with symptoms demonstrated poorer quality of life compared to subjects with no symptoms. The prevalence of UGIS in the general population is high and symptoms are associated with significant health-care utilization and poorer quality of life.

Research into the causes of gastroesophageal reflux disease continues to cover a broad base. It ranges from the roles of transient relaxations of the lower esophageal sphincter, neural control mechanisms, nitric oxide, and impairment of the crural diaphragm in the production of reflux, to the roles of mucosal bicarbonate secretion, mucosal blood flow, and epithelial cell acid handling in the protection of the esophageal mucosa. Impaired esophageal acid clearance is also likely to be a major factor, although current manometric techniques have not been able to identify a clear abnormality in mild to moderate reflux disease. It is still unclear whether episodes of esophageal alkalinization signal the reflux of noxious pancreaticobiliary secretions or whether they indicate the presence of esophageal mucosal and salivary bicarbonate. There is increasing interest in the central and peripheral mechanisms responsible for the genesis of esophageal symptoms and also in the relationship between reflux and respiratory tract symptoms. Esophageal pH monitoring is used widely but there is continuing debate regarding its clinical utility; concomitant monitoring of other modalities, including esophageal motility and electrocardiography, remains a research tool. It is clear that the proton pump inhibitors, omeprazole and lansoprazole, are highly effective therapy for reflux esophagitis but the comparison of healing rates achieved by different medical modalities and by surgery remains thwarted by the absence of a generally accepted classification system for reflux esophagitis. Controlled studies comparing the latest treatment options, including laparoscopic fundoplication and proton pump inhibitors, are needed urgently.

1. The heart and the oesophagus have similar sensory pathways, and sensations originating from the oesophagus are often difficult to differentiate from those of cardiac origin. We hypothesized that oesophageal sensory stimuli could alter neurocardiac function through autonomic reflexes elicited by these oesophageal stimuli. In the present study, we examined the neurocardiac response to oesophageal stimulation and the effects of electrical and mechanical oesophageal stimulation on the power spectrum of beat-to-beat heart rate variability in male volunteers. 2. In 14 healthy volunteers, beat-to-beat heart rate variability was compared at rest and during oesophageal stimulation, using either electrical (200 μs, 16 mA, 0.2 Hz) or mechanical (0.5 s, 14 ml, 0.2 Hz) stimuli. The power spectrum of beat-to-beat heart rate variability was obtained and its low- and high-frequency components were determined. 3. Distal oesophageal stimulation decreased heart rate slightly (both electrical and mechanical) (P < 0.005), and markedly altered heart rate variability (P < 0.001). Both electrical and mechanical oesophageal stimulation increased the absolute and normalized area of the high-frequency band within the power spectrum (P < 0.001), while simultaneously decreasing the low-frequency power (P < 0.005). 4. In humans, oesophageal stimulation, whether electrical or mechanical, appears to amplify respiratory-driven cardiac vagoafferent modulation while decreasing sympathetic modulation. The technique provides access to vagoafferent fibres and thus may yield useful information on the autonomic effects of visceral or oesophageal sensory stimulation.

Six randomized, placebo controlled studies were performed to investigate the effect of electroacupuncture on gastric acid output in 38 healthy males. Electroacupuncture decreased basal acid output when compared to placebo acupuncture [from 3.50±0.59 mmol/hr to 2.54±0.56 mmol/hr (P<0.05)] as well as sham feeding-stimulated acid output [from 18.52±2.25 mmol/hr to 5.38±2.11 mmol/hr (P<0.005)], but had no effect on the pentagastrin stimulated acid output. The inhibitory effect of acupuncture on sham feeding-stimulated acid output was not affected by local anesthesia of the acupoint, but was prevented by a prior intravenous naloxone injection. Acupuncture did not alter plasma gastrin levels (20.7±7.6 µg/liter, vs control 21.2±7.2 µg/liter) but naloxone increased it (26.1±14.5 µg/liter) (P<0.05). We conclude that the antisecretory effects of electroacupuncture do not result from decreased gastrin release or decreased parietal cell sensitivity to gastrin, but are mediated through naloxone-sensitive opioid neural pathways and vagal efferent pathways.

Scintigraphy and real-time ultrasound are valid techniques to measure parameters of gastric emptying. However, scintigraphy involves exposure to ionizing radiation, while the precision of real-time ultrasound has not been previously evaluated. The objectives of the present study were to determine the inter observer and day-to-day variability of liquid gastric emptying rate measured by real-time ultrasonography in healthy volunteers and to compare the gastric emptying rate of males and females. Twenty healthy volunteers had ultrasonographic measurement of gastric emptying rate after ingestion of 300 ml beef broth. Nine subjects had a concurrent assessment by a second observer. Nine subjects had two studies performed on different days by the same sonographer. TheT1/2 for 20 subjects was 24.77±6.84 min with no difference between the half-emptying time for males (25.89±6.99 min) and females (24.02±6.94 min). The Pearson and intraclass correlation coefficients for observations made by two observers were 0.83 and 0.625, with a difference due to observer of 2.37 min±5.26 (NS). The test-retest reliability across successive days was 0.136, representing considerable day-to-day variability within subjects. The variability between subjects was also large, explaining up to 79% of the total variance. We conclude that ultrasound is a useful method to evaluate gastric emptying with good interobserver agreement. Due to substantial day-to-day variability, sample sizes larger than previously suggested are required to demonstrate clinically important changes in gastric emptying rate in clinical trials.

While there is evidence that omeprazole may induce changes in parietal cells, the effect of acid suppression on parietal cells in humans is poorly documented. This study was undertaken to evaluate the effects of omeprazole in human parietal cells over time. The light microscopic morphology of parietal cells in gastric biopsies from 17 patients on omeprazole were compared with those from 13 patients on ranitidine and 20 patients on no acid-lowering medication. Light microscopic and ultrastructural morphology of parietal cells was also evaluated in an additional 14 patients before and after omeprazole administration. Objective measurements of parietal cell height, mass and number were analyzed using analyses of variance. Electron microscopy was used to evaluate parietal cell enlargement. Twenty-five of 31 biopsies from patients on omeprazole, 1 of 13 from patients on ranitidine, and 0 of 20 from patients on neither drug showed parietal cell enlargement. Parietal cell height, mass, and number were increased in omeprazole-treated patients compared with ranitidine-treated patients and those on neither drug, and with the group also evaluated prior to beginning omeprazole treatment. Parietal cell height and mass were increased in patients on omeprazole longer than 12 months compared with biopsies from patients on the drug for less than 12 months. Resin-embedded sections and electron microscopy showed enlarged parietal cells with prominence of cytoplasmic tubulovesicles with sparse secretory canaliculi. Parietal cell hypertrophy and hyperplasia develops in patients on chronic omeprazole therapy; this can be recognized on routine examination of histologic sections. These morphologic changes increase with duration of therapy.

Recording of evoked potential responsesrepresents an objective and quantifiable method to studyvisceral afferent sensory pathways in humans. Weexamined the evoked responses to mechanical distension(balloon) and electrical stimulation of the proximal anddistal esophagus. A standard manometric catheter with alatex balloon and an additional electrode attached toits body was placed in the lower esophagus in 15 healthy young volunteers. Repeatednonpainful balloon distension stimuli above theindividual sensation threshold (0.17 Hz, 12-20 ml) orshort electrical impulses (0.2 Hz, 12-16 mA) weredelivered in an alternate fashion at 23 and 33 cm from thenares. Evoked potential responses (EP) were recordedthrough 22 scalp surface electrodes using the standard10/20 International EEG system of electrode placement. Balloon distension produced a reproducibletriphasic response at both sites. Peak latencies ofthree negative EP peaks were 92 ± 17, 229± 40, and 339 ± 36 msec with proximalstimulation versus 154 ± 24, 275 ± 24, and384 ± 30 msec obtained with distal stimulation (P< 0.001). Electrical stimulation produced a triphasicresponse with significantly shorter peak latencies atboth sites when compared to mechanical stimulation (P <0.001). Peak latencies were 74 ± 12, 137 ±11, and 245 ± 27 msec proximal versus 83 ±12, 148 ± 32, and 247 ± 51 msec withdistal stimulation (P < 0.01). The calculated conduction velocities forboth modes of stimulation (balloon: 1.73 ± 0.9m/sec vs electrical: 10.1 ± 3.4 m/sec) arecompatible with conduction through C fibers and Adeltafibers, respectively. Both modes of stimulation producecharacteristic brain responses that are conveyed throughdifferent types of afferent fibers. The respectivecontributions of both types of fibers to esophageal function and symptomatology can be specificallyaddressed using this approach in both normal andpathologic conditions.

This study examines whether opioid receptors are involved in the mediation of the pyloric motor response to intraduodenal lipid infusion. Antral, pyloric, and duodenal manometry was performed in seven healthy volunteers with a sleeve/multiple side-hole manometric assembly. Triglyceride emulsion and normal saline were infused alternately into the duodenum through the manometric assembly for two 30-minute periods each. Naloxone was then administered as an IV bolus, 40 μg/kg. followed by an infusion of 60 μg · kg−1· h−1that was continued during testing of the duodenal infusates. Before naloxone administration, intraduodenal lipid produced significant increases in the rate of isolated pyloric pressure waves and basal pyloric tone when compared with saline (P= 0.009 and 0.027, respectively). The pyloric motor responses were unchanged after administration of naloxone, indicating that in humans, naloxone-sensitive opioid mechanisms are not involved in the mediation of lipid-induced pyloric motor responses.

Without Abstract:

BACKGROUND: Distension and electrical stimuli in the esophagus alter heart rate variability (HRV) consistent with activation of vagal afferent and efferent pathways. Sham feeding stimulates gastric acid secretion by means of vagal efferent pathways. It is not known, however, whether activation of vagal efferent pathways is organ- or stimulus-specific.OBJECTIVE: To test the hypothesis that sham feeding increases the high frequency (HF) component of HRV, indicating increased neurocardiac vagal activity in association with the known, vagally mediated, increase in gastric acid secretion.METHODS: Continuous electrocardiography recordings were obtained in 12 healthy, semirecumbent subjects during consecutive 45 min baseline, 20 min sham feeding (standard hamburger meal) and 45 min recovery periods. The R-R intervals and beat-to-beat heart rate signal were determined from digitized electrocardiography recordings; power spectra were computed from the heart rate signal to determine sympathetic (low frequency [LF]) and vagal (HF) components of HRV.RESULTS: Heart rate increased during sham feeding (median 70.8 beats/min, 95% CI 66.0 to 77.6; P<0.001), compared with baseline (63.6, 95% CI 60.8 to 70.0) and returned to baseline levels within 45 min. Sham feeding increased the LF to HF area ratio (median: 1.55, 95% C.I 1.28 to 1.77; P<0.021, compared with baseline (1.29, 95% CI 1.05 to 1.46); this increase in LF to HF area ratio was associated with a decrease in the HF component of HRV.CONCLUSIONS: Sham feeding produces a reversible increase in heart rate that is attributable to a decrease in neurocardiac parasympathetic activity despite its known ability to increase vagally mediated gastric acid secretion. These findings suggest that concurrent changes in cardiac and gastric function are modulated independently by vagal efferent fibres and that vagally mediated changes in organ function are stimulus- and organ-specific.

OBJECTIVES: To investigate the impact of lower gastrointestinal (GI) symptoms in the general Canadian population, and to explore patient satisfaction with traditional therapies and the level of patient interest in new treatments.PATIENTS AND METHODS: Stage 1: A telephone survey of a weighted sample of 1000 adults (18 years of age or older) was conducted to determine the prevalence of five GI symptoms – abdominal pain, abdominal discomfort, bloating, constipation or constipation with occasional diarrhea -- that were present for 12 weeks or more (not necessarily consecutive) over the past year. Respondents with only abdominal pain were excluded. Stage 2: A telephone survey of 689 women (18 to 64 years of age), experiencing the GI symptoms described in stage 1, was conducted to assess symptom impact and treatment satisfaction.RESULTS: Overall, 5.2% of the Canadian population (2.3% men and 7.9% women) experienced one or more lower GI symptoms (excluding those reporting abdominal pain alone). In stage 2, 26.2% of respondents had previously been diagnosed with irritable bowel syndrome. Overall, 78.1% of participants experienced two or more symptoms. Bloating was the most common symptom (75.3%) and abdominal pain the most bothersome and most severe. Over the previous three months, 13.2% of respondents missed work or school and 28.8% were less productive. At least one physician (average of 2.2 physicians) was consulted for symptoms in 80.9% of respondents. Of the 63.8% women receiving treatment, most used nonprescription products. Patients receiving prescription treatments for constipation were most often dissatisfied (75%).CONCLUSIONS: Abdominal pain and discomfort, bloating and constipation are common, frequently occurring symptoms in the Canadian population and have a high burden on work performance and health care seeking. Most patients were dissatisfied with traditional therapies.

The present paper examines approaches to drug therapy for irritable bowel syndrome (IBS). Because IBS is associated with multiple symptoms, no single therapy is effective in all patients. However, issues such as affective and emotional factors also need to be addressed when treating patients with IBS. This paper emphasizes the importance of identifying new pharmaceutical approaches to treat a multitude of symptoms and obtaining a better understanding of the underlying mechanisms of IBS.

Objective: This study was designed to determine whether esophageal vago-afferent electrostimulation, over a wide range of stimulus intensities, can sustain a cardiac vago-efferent effect by way of central nervous system processing. Methods: Studies were performed in ten healthy male subjects (23.9±6.3 years). Esophageal electrostimulation was carried out using a stimulating electrode placed in the distal esophagus. Stimulation of esophageal vago-afferent fibres was employed using electrical impulses (200 µs at 0.2 Hz 128 s) varying from 2.7 to 20 mA. Respiratory frequencies, beat-to-beat heart rate autospectra and cerebral evoked potentials were recorded at baseline and at each stimulus intensity in random order. Results: With esophageal electrical stimulation, we observed a small non-significant decrease in heart rate. There was a dramatic shift of the instantaneous heart rate power spectra towards enhanced cardiac vagal modulation with intensities as low as 5 mA. This effect was sustained throughout all intensities with no further change in either the low frequency or high frequency power. Conversely, there was a linear dose response relationship between cerebral evoked potential amplitude and stimulus intensity mainly occurring above perception threshold (10 mA). Esophageal stimulation had no significant effect on heart rate or respiratory frequency at any stimulus intensity. Conclusions: These results indicate that electrical stimulation of the distal esophagus across a wide range of current intensities elicits a reproducible shift in the heart rate power spectrum towards enhanced vagal modulation. The data suggest a closed loop afferent/efferent circuitry wherein tonic visceral afferent impulses appear to elicit a phasic or modulatory vago-efferent cardiac response in healthy subjects.

Communications along the brain-gut axis involve neural pathways as well as immune and endocrine mechanisms. The two branches of the autonomic nervous system are integrated anatomically and functionally with visceral sensory pathways, and are responsible for the homeostatic regulation of gut function. The autonomic nervous system is also a major mediator of the visceral response to central influences such as psychological stress. As defined, functional disorders comprise a constellation of symptoms, some of which suggest the presence of altered perception, while other symptoms point to disordered gastrointestinal function as the cause of the symptoms. A growing number of reports have demonstrated disordered autonomic function in subgroups of functional bowel patients. While a number of different methods were used to assess autonomic function, the reports point to a generally decreased vagal (parasympathetic) outflow or increased sympathetic activity in conditions usually associated with slow or decreased gastrointestinal motility, while other studies found either an increased cholinergic activity or a decreased sympathetic activity in patients with symptoms compatible with an increased motor activity. Under certain conditions, altered autonomic balance (including low vagal tone and increased sympathetic activity) may alter visceral perception. Autonomic dysfunction may also represent the physiological pathway accounting for many of the extraintestinal symptoms seen in irritable bowel syndrome patients and some of the frequent gastrointestinal complaints reported by patients with disorders such as chronic fatigue and fibromyalgia.