Jacques Frexinos

Mediators and Pharmacology of Visceral Sensitivity: From Basic to Clinical Investigations

Over the last decade, the role of visceral sensitivity has been largely recognized in the pathophysiology of functional digestive disorders, particularly in the irritable bowel syndrome. These studies have highlighted the role of afferent pathways arising from the gut as a possible target for new treatments intended to relieve pain or modify altered reflexes present in such patients. These pharmacological targets have been identified mainly by studies on animal models of visceral hyperalgesia of various origins including local inflammation. Locally, several mediators are of paramount importance for sensitization of nerve endings: 5-hydroxytryptamine, bradykinin, tachykinins, calcitonin gene-related peptide, and neurotrophins. Selective antagonists to various subtypes of their receptors are currently available and have been shown to be active in these animal models. Other substances, such as somatostatin, opiold peptides, cholecystokinin, oxytocin, and adenosine, modulate the transmission of nociceptive inputs from the gut to the brain and are of clinical interest. This article reviews the current understanding of these mediators. Although these agents seem to be promising tools for the treatment of visceral hyperalgesia and its consequences (abdominal pain and disturbed reflexes), their clinical efficacy remains to be shown. A better understanding of the nature and the location of the defect in the sensory pathways may permit the selection of subgroups of patients for treatment according to the pharmacological properties of these new therapeutic agents.

The κ agonist fedotozine relieves hypersensitivity to colonic distention in patients with irritable bowel syndrome

Abstract Background & Aims: Visceral hypersensitivity plays a major role in the pathophysiology of inflammatory bowel syndrome (IBS). Opioid κ receptors on afferent nerves may modulate it and may be the target of new IBS treatments. The aim of this study was to evaluate the effects of fedotozine, a potent and selective κ agonist, on responses to colonic distention and colonic compliance in patients with IBS. Methods: Fourteen patients with IBS (Rome criteria; 50 ± 12 years; 6 men and 8 women) were included in a randomized double-blind, crossover trial comparing the effect of an intravenous infusion of 100 mg fedotozine or saline on sensory thresholds elicited by left colon phasic distention (4–mm Hg steps for 5 minutes) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure-volume curves built on placebo and on fedotozine. Results: In the fedotozine group, thresholds of first perception (28.7 ± 5.9 mm Hg) and pain (34.7 ± 5.5 mm Hg) were significantly greater than with placebo (23.3 ± 4.5 and 29.0 ± 3.5 mm Hg, respectively; P = 0.0078). Colonic compliance was 9.20 ± 3.87 mL · mm Hg −1 with placebo and 8.73 ± 3.18 mL · mm Hg −1 with fedotozine (not significant). Conclusions: Fedotozine increases thresholds of perception of colonic distention in patients with IBS without modifying colonic compliance. Fedotozine seems capable of reversing visceral hypersensitivity observed in these patients and could have some beneficial action on their symptoms. GASTROENTEROLOGY 1999;116:38-45

Evaluation of colonic sensory thresholds in IBS patients using a barostat. Definition of optimal conditions and comparison with healthy subjects.

To study the role of abnormal visceral perception in the pathophysiology of the irritable bowel syndrome (IBS), we evaluated colonic tone and visceral perception during intracolonic distension using a flaccid balloon connected to a computerized barostat and placed in the descending colon of IBS patients and healthy controls. In the first part of the study, basal colonic tone and response to pharmacological (neostigmine and glucagon) and physiological (1000-kcal meal) stimuli were recorded in nine IBS patients. Colonic tone increased by 72±27% after injection of neostigmine and decreased by 88±62% after glucagon. After the meal, the maximal increase in colonic tone was 76±31% with the total response to the meal lasting 109.7±32.0 min. In the second part of the study, symptomatic responses (discomfort and pain thresholds) and pressure variations were evaluated during two different methods of distension (stepwise and intermittent) in a randomized order in the nine IBS patients and six healthy controls. Each distension method was repeated twice in IBS patients to study reproducibility. In IBS patients, the mean discomfort threshold volume was 172±76 ml when using stepwise and 167±43 ml when using intermittent distension. The mean pain threshold volume was 250±25 ml when using stepwise and 211±22 ml when using intermittent distension, this difference being statistically significant (P<0.02). Discomfort and pain threshold volumes recorded during the first session of the same distension method were not different from those recorded during the second one. When comparing IBS patients to controls, the pain threshold was reached at a volume ≤300 ml in all IBS patients versus only one control when using stepwise distensions (P<0.001) and in all IBS patients versus no control when using intermittent distensions (P<0.001). Intracolonic pressure-volume curves were similar in patients and controls. In conclusion, isovolumic distension of the colon is a reproducible method of evaluating viscerosensitivity, which is significantly increased in IBS patients. This increased viscerosensitivity is not related to abnormal colonic compliance and may, alone or in combination with other colonic abnormalities, explain the symptoms of irritable bowel syndrome.

Endoscopic ultrasonography in chronic pancreatitis: a comparative prospective study with conventional ultrasonography, computed tomography, and ERCP.

The usefulness and accuracy rate of endoscopic ultrasonography (EUS) in the diagnosis of chronic pancreatitis (CP) were prospectively evaluated in 81 patients with suspected pancreatic disease. All underwent EUS, abdominal ultrasonography (AUS), and computed tomography (CT), and endoscopic retrograde cholangiopancreatography (ERCP) was performed in 55 of the cases. The diagnosis of CP was established in 44 patients (CP group) including 24 with a calcified form. No pancreatic disease was observed in 18 patients (control group), and 19 patients had a pancreatic tumor. In the CP group AUS was less accurate than EUS in visualizing the pancreas, performances of CT scan being identical to EUS in this respect. A good correlation was observed between EUS and ERCP for visualization and measurement of the Wirsung duct. The most significant changes observed by EUS in the CP group were dilatation of the main pancreatic duct, heterogeneous echogenicity of the pancreatic parenchyma, and cysts <20 mm in size even in noncalcified CP or with normal pancreatograms. Sensitivity of EUS for diagnosis of CP was 88% (AUS, 58%; ERCP, 74%; CT scan, 75%), the specificity being 100% for ERCP and EUS, 95% for CT scan, and 75% for AUS. The good performances of EUS allow early diagnosis of CP in symptomatic patients since heterogeneous echogenicity of the pancreatic parenchyma seems to be almost specifically associated with the disease.

Diurnal Changes in Myoelectric Spiking Activity of the Human Colon

Using an intraluminal probe supporting eight groups of electrodes, the myoelectrical activity of the proximal, transverse, and distal colon was recorded during 24-h sessions in 10 healthy subjects receiving evening and noon meals (greater than 800 kcal) and breakfast (less than 300 kcal). At each colonic site considered, the electromyograms exhibited two kinds of spike bursts: (a) short spike bursts localized at one electrode site and appearing rhythmically at a frequency of 10.6 +/- 0.3/min and (b) long spike bursts isolated or propagated orally or aborally. A peculiar pattern consisting of nearly permanent short spike bursts at a rate of 6.7 +/- 0.4/min was observed at the rectosigmoid junction. Computerized analysis of the duration of each kind of spike burst showed that the long spike burst activity increased by 63%-129% (p less than 0.05) during 2 h after each meal (but not after breakfast) at each colonic site. Furthermore, a significant (p less than 0.05) decrease in the long spike burst but not short spike burst activity was observed during sleep. These results provide evidence for circadian variations of colonic motility associated with eating and sleeping in the healthy human.

Role of EUS in the management of pancreatic and ampullary carcinoma: a prospective study assessing resectability and prognosis☆☆☆

BACKGROUND Endoscopic ultrasonography (EUS) is highly accurate for the staging of tumors, but its role in the management of periampullary carcinoma is still being defined. METHODS Seventy-nine patients with pancreatic (n = 73) or ampullary (n = 6) carcinoma underwent prospective evaluation by means of assessment of resectability and survival according to the following three-step staging algorithm: (1) ultrasonography and computed tomography; (2) if tumor appears resectable, EUS; (3) if criteria of resectability are found at EUS, laparotomy for curative resection. RESULTS The first step of the algorithm helped predict unresectability of tumors and need for palliative treatment for 36 patients. Among the other 43 patients EUS revealed signs of unresectability in 20 additional patients who then underwent palliative surgical or medical treatment (median survival time 7 to 8 months). Twenty-three carcinomas were considered resectable according to EUS findings: Palliative surgery was performed in 9 cases (survival time 6 months), and 14 tumors could be resected in a curative way with a median survival period of 15 (pancreatic) to 16 months (ampullary). In evaluation of resectability, EUS had a 50% sensitivity (positive examination), 100% specificity, 100% positive predictive value, 61% negative predictive value, and 72% accuracy. CONCLUSIONS EUS is accurate for evaluating resectability of ampullary and pancreatic cancer. EUS staging can prevent unnecessary surgery, and the findings correlate well with prognosis. The management of ampullary and pancreatic cancer could be improved with EUS.

Octreotide increases thresholds of colonic visceral perception in IBS patients without modifying muscle tone.

Effects of octreotide (1.25 µg/kg subcutaneously) on colonic tone and visceral perception were evaluated in 10 IBS patients, using a barostat and compared to placebo in a double-blind crossover study. Colonic sensory thresholds were also studied in healthy controls for comparison with IBS patients. Colonic tone was reflected by variations in volume of the barostat balloon. Baseline volume was 117±38 ml and was not modified by placebo (122±40 ml) or octreotide (106±42 ml). After the meal, maximal decrease in balloon volume was 75±4% following placebo (P<0.001) beginning after 9±3 min and lasting 136±17 min. Following octreotide, the maximal decrease was 69±16% (NS vs placebo), after 10±3 min and lasting 140±22 min. In the second part, discomfort and pain thresholds were evaluated during isobaric distensions (4 mm Hg increments, 5-min duration, 5-min interval with return to pressure 0 between each). The pressure inducing discomfort was 21.2±5.9 mm Hg following placebo vs 29.6±6.6 mm Hg following octreotide (P<0.01). The pressure inducing pain was 24.8±7.3 mm Hg following placebo vs 33.2±7.3 mm Hg following octreotide (P<0.01). In healthy subjects, discomfort and pain were induced by colonic distensions at a mean intraballoon pressure of 32.7±5.8 mm Hg and 36.7±3.9 mm Hg, respectively. Compliance curves were not different following placebo and octreotide. Octreotide significantly increases thresholds for visceral perception in IBS patients without modifying compliance during distension nor colonic tone.

Impact of irritable bowel syndrome (IBS) on health-related quality of life (HRQOL)

AIMS To assess the impact of irritable bowel syndrome (IBS) on patient-reported health-related quality of life (HRQOL). METHODS Two HRQOL instruments were administered by telephone interviews to a sample of 253 IBS French patients recruited from the general population. IBS was diagnosed according to the Manning, Rome I and Rome II criteria. Patients with organic diseases were excluded from the study. A generic instrument, the Short Form 36 (SF-36), and an IBS disease-specific instrument, the IBSQOL, were used. RESULTS Patients with IBS had statistically significant (P<0.05) lower scores for all SF-36 QOL domains compared with the general French population. Women (N=192) reported significantly (P<0.05) poorer HRQOL on both the SF-36 and the IBSQOL scores than men (N=61) for all domains except energy on the SF36 and the sleep on the IBSQOL. HRQOL deteriorated with time since onset of IBS symptoms for some domains such as diet. For both instruments, a positive correlation was observed between low scores and intensity of pain and discomfort. IBS patients with a predominance of diarrhea (N=72) exhibited significantly greater impairment of HRQOL in the emotional domain than IBS persons with constipation predominance (N=65) (P<or=0.05). CONCLUSION IBS has a significant impact on HRQOL of patients. In addition, specific characteristics such as gender, symptom severity and time since onset of symptoms are predictive of more impaired health-related quality of life.

Influence of acoustic stress by noise on gastrointestinal motility in dogs

The effects of acoustic stress (AS) on gastrointestinal motility and their prevention by previous treatment with naloxone, phentolamine, propranolol, muscimol, and diazepam were investigated in intact and vagotomized fasted dogs fitted with chronically implanted strain gauges on the antrum at 10 cm from pylorus and on the jejunum at 70 and 140 cm from the pylorus. These effects were compared to those produced by intracerebroventricular administration of ovine corticotropin releasing factor (oCRF). Beginning 40–50 min after the occurrence of a gastric migrating motor complex (MMC), a 1-hr hearing of prerecorded intense music through earpieces (<100 dB) delayed the occurrence of the next gastric MMC observed after 2.8±1.2 hr, while jejunal MMC were still present at a normal frequency. During AS, heart rate and plasma cortisol were significantly increased by 32.7 and 215%, respectively, 10–15 min after the beginning of hearing. The AS-induced lengthening of the gastric MMC cycle as well as cortisol increase were abolished after previous administration of diazepam (0.5 mg/kg intramuscular) or muscimol (10 μg/kg intravenous), while they were still present after naloxone (0.1 mg/kg intravenous), phentolamine (0.2 mg/kg intravenous), or propranolol (0.1 mg/kg intravenous). CRF administered intracerebroventricularly (100 ng/kg) also delayed the occurrence of gastric MMC without affecting jejunal motility, and this effect was not antagonized by previous treatment with diazepam or muscimol. Both the effects of AS and CRF were abolished after bilateral thoracic vagotomy. These results suggest that the selective inhibition of gastric motility induced by noise in dog is due to the CNS release of CRF which affects, in turn, the vagal output to the stomach. The suppressive action of diazepam or GABA agonist on noise-induced gastric hypomotility may be related to blockade of the AS-induced CRF release.

Intraduodenal Free Fatty Acids Rather than Triglycerides Are Responsible for the Release of Cck in Humans

Exocrine pancreas from different species behaves differently in response to the presence of intact or digested nutrients in the duodenum. A failure of cholecystokinin (CCK) release after a meal has been shown among patients with exocrine pancreatic insufficiency. This abnormality could be restored by the administration of pancreatic extracts, suggesting that digested rather than intact nutrients are responsible for the release of CCK and subsequently gallbladder contraction in humans. The aim of this study was to determine the specific role of different lipidic stimuli in humans. Seven male patients (mean age, 52 years) with pancreatic insufficiency secondary to chronic pancreatitis were selected. Pancreatic insufficiency was considered severe in five of them (lipase output, < 1,000 IU/min) and moderate in another two (lipase output, > 1,000 and <2,300 IU/min). Plasma CCK (by bioassay), gallbladder contraction (by ultrasound), and enzyme output (chymotrypsin) in response to duodenal administration of either oleic acid as free fatty acids or 20% Intralipid as triglycerides were measured in each patient with at least a 48-h interval between each test. In all these patients with pancreatic insufficiency, duodenal perfusion of free fatty acids generated a more pronounced (91 ± 11 vs. 49 ± 21 pM) and faster (15 vs. 30 min) (p < 0.05) CCK release than triglycerides. Furthermore, gallbladder contraction was more efficient when free fatty acids instead of triglycerides were administered in the duodenum (86 ± 5 vs. 69 ± 4%) at 10 min (p < 0.05) and (73 ± 8 vs. 51 ± 5%) at 15 min (p < 0.03). Among patients with measurable residual pancreatic function, enzyme outputs were shown to be higher during free fatty acid than triglyceride perfusion. In humans, free fatty acids rather than triglycerides, when present in the duodenum, stimulate CCK release and gallbladder contraction. In patients with moderate pancreatic insufficiency this phenomenon may increase residual enzymatic secretion. These results allow us to encourage the development of enzymatic preparations as acid-resistant lipases that cause a fast release of free fatty acids in the duodenum.