fedotozine and Colonic-Diseases--Functional

Fedotozine [(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N- dimethyl-n-propylamine, (2S,3S-tartrate] is derived from the arylacetamide series. As with other compounds of this series, fedotozine is more or less selective of kappa(1)-opioid receptors and particularly for the kappa(1a)-receptor subtype, where it acts as an agonist. Pharmacological studies have shown that fedotozine exerts a peripheral antinociceptive action, comparable with that of other kappa-agonists. Its main effects have been demonstrated at the level of the afferent nerve pathways originating from the gut. Fedotozine alters the processing of visceral sensations along these pathways and hence, the perception of gut stimuli at the brain level. It modifies reflexes induced in various pathological conditions, like experimental inflammation of the gut, chemically-induced peritonitis or post-operative ileus. Fedotozine also decreases the nociceptive reflexes triggered by noxious gut distension in animals. In humans, fedotozine decreases the perception of gut distension, both in physiological and pathological conditions. Clinical trials undertaken in patients with functional digestive disorders, non-ulcer dyspepsia and irritable bowel syndrome, have shown that fedotozine relieves abdominal pain in these patients in 6-week treatments. kappa-Opioid receptors remain an interesting area for future development of new treatments for abdominal pain in patients with functional digestive disorders.

Topics: Animals; Benzyl Compounds; Colonic Diseases, Functional; Dyspepsia; Gastrointestinal Motility; Humans; Pain; Propylamines; Receptors, Opioid, kappa

Topics: Adult; Animals; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Benzyl Compounds; Biopsy; Colon; Colonic Diseases, Functional; Diarrhea; Electromyography; Female; Fluoxetine; Food Hypersensitivity; Gastrointestinal Motility; Guinea Pigs; Humans; Ileum; Imipramine; Inflammation; Male; Mental Disorders; Propylamines; Psychotherapy; Psychotropic Drugs; Rats; Selective Serotonin Reuptake Inhibitors; Sex Offenses; Time Factors

Topics: Abdominal Pain; Animals; Benzyl Compounds; Carbolines; Central Nervous System; Colitis, Ulcerative; Colon; Colonic Diseases, Functional; Colonoscopy; Controlled Clinical Trials as Topic; Diarrhea; Digestion; Electromyography; Female; Follow-Up Studies; Gastric Emptying; Gastroenteritis; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Intestines; Male; Myenteric Plexus; Neurons; Neurotransmitter Agents; Placebos; Pressure; Propylamines; Receptors, Opioid, kappa; Rectum; Risk Factors; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors; Time Factors

Irritable bowel syndrome is a very frequent cause for consulting. The clinical entity is ill-defined and diagnosis is based on clinical features (Rome criteria), as no specific feature helps guide the diagnosis. Since its pathophysiology is currently being better described, this study was aimed at reviewing recent data.. After involvement of the motor system had been suggested, more recent pathophysiological studies have focused on diffuse abnormalities of visceral perception with decrease in pain thresholds. Involvement of other physiopathological factors, particularly of psychological disturbances, has been suggested.. Management of patients suffering from irritable bowel syndrome is still disappointing as pharmacological agent acting on gut motility are only partly efficacious. Better understanding of its physiopathology will open new avenues for the development of therapeutical agents truly efficacious on visceral hypersensitivity.

Topics: Animals; Benzyl Compounds; Colonic Diseases, Functional; Esophagus; Gastrointestinal Agents; Gastrointestinal Motility; Granisetron; Humans; Intestine, Small; Octreotide; Propylamines; Receptors, Opioid, kappa; Rectum; Serotonin Antagonists; Sheep

Irritable bowel syndrome (IBS) continues to provide a major therapeutic challenge to clinicians and those involved in drug development. It seems unlikely from the data before us that this multisymptom syndrome with peripheral and central components is likely to respond reliably in all patients to the same single agent. There is still a lack of well designed, appropriately powered, randomised clinical trials and the problems of dealing with the high placebo response rate in this group of patients remains a dilemma for trial designers. There are, however, some new ideas, particularly those relating to the role of hyperalgesia in IBS. For many patients, abdominal pain and bloating are the most distressing symptoms of this disease and the new drugs targeted at pain control, such as kappa agonists and serotonin antagonists (5-HT3) and possibly 5-HT4), may eventually find a place in the clinical management of this syndrome. Other candidates include somatostatin analogues and antidepressants, the latter predominantly for their effects on increasing pain threshold. More speculative new drugs for IBS include cholecystokinin antagonists such as loxiglumide and the gonadotrophin-releasing hormone analogue, leuprorelin (leuprolide). The results of on-going randomised clinical trials are still awaited for some of these newer agents. The irritable bowel syndrome (IBS) is the most common gastrointestinal condition encountered by general practitioners and is reported to account for up to 50% of the work of gastroenterologists in secondary care. However, most people with the symptoms of IBS (60 to 75%) do not consult a doctor. Its cause is unknown, its development is poorly understand and, perhaps not surprisingly, no universally agreed approach to treatment exists.

Topics: Adult; Anti-Anxiety Agents; Antidepressive Agents; Antidiarrheals; Benzyl Compounds; Colonic Diseases, Functional; Female; Gastrointestinal Agents; Gastrointestinal Transit; Granisetron; Humans; Leuprolide; Male; Octreotide; Ondansetron; Propylamines; Receptors, Opioid, kappa; Serotonin Antagonists

Functional gastrointestinal disorders are best understood by applying a bio-psycho-social model. The diseases are strongly associated with psychological factors, and in functional dyspepsia, low vagal activity might be a mediating mechanism by which psychological factors (like neuroticism and stress) influence gastrointestinal physiology and cause epigastric discomfort. Low vagal activity may be a manifestation of stress and a cause of impaired gastric accommodation to meals. Epigastric discomfort is elicited when the stomach is distended without prior (vagal) reflex relaxation. Conventional therapy for acid-related dyspepsia does not improve accommodation and hence, is ineffective. The beneficial effect of experimental therapy, like glyceryl trinitrate and sumatriptan, which improve gastric accommodation, gives very good prospects for further development. For patients with irritable bowel syndrome, today's therapy seems similarly inefficacious, but several new potentially effective drugs are at present undergoing clinical trials.

Topics: Antacids; Benzyl Compounds; Cisapride; Clinical Trials as Topic; Colonic Diseases, Functional; Dyspepsia; Gastrointestinal Agents; Gastrointestinal Diseases; Humans; Propylamines; Receptors, Opioid, kappa

Visceral hypersensitivity plays a major role in the pathophysiology of inflammatory bowel syndrome (IBS). Opioid kappa 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 kappa agonist, on responses to colonic distention and colonic compliance in patients with IBS.. 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.. 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).. 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.

Topics: Adult; Benzyl Compounds; Colon; Colonic Diseases, Functional; Cross-Over Studies; Double-Blind Method; Eating; Female; Humans; Infusions, Intravenous; Male; Manometry; Middle Aged; Pain Threshold; Propylamines; Receptors, Opioid, kappa; Sensory Thresholds

The efficacy and safety of the peripheral kappa agonist fedotozine was evaluated in a double-blind, multicenter study involving 238 patients with the irritable bowel syndrome. After a two-week washout, patients were assigned to one of four groups to receive either placebo or fedotozine three times a day at doses of 3.5, 15, or 30 mg for six weeks. Patient assessment of mean symptom intensity indicated that the 30-mg dose of fedotozine was superior to placebo in relieving maximal daily abdominal pain (P = 0.01), mean daily pain (P = 0.007), and abdominal bloating (P = 0.02). Changes in bowel function and defecation disorders could not be evaluated reliably. According to the investigators, the highest dose of fedotozine markedly reduced overall disease severity (P = 0.003) and the pain component of the symptomatic profile (P = 0.009). Clinical and laboratory safety was very good. Fedotozine 30 mg three times a day therefore appears to be effective and safe in the treatment of the abdominal pain and bloating associated with IBS.

Topics: Adult; Analysis of Variance; Belgium; Benzyl Compounds; Colonic Diseases, Functional; Dose-Response Relationship, Drug; Double-Blind Method; France; Humans; Placebos; Propylamines; Receptors, Opioid, kappa; Remission Induction; Tunisia

Topics: Acupuncture Therapy; Benzyl Compounds; Carbolines; Colonic Diseases, Functional; Data Interpretation, Statistical; Double-Blind Method; Gastrointestinal Agents; Humans; Parasympatholytics; Propylamines; Quality of Life; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Receptors, Opioid, kappa; Serotonin Antagonists; Surveys and Questionnaires; Time Factors

Topics: Abdominal Pain; Benzyl Compounds; Colonic Diseases, Functional; Humans; Propylamines; Receptors, Opioid, kappa