fedotozine and Dyspepsia

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

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

Topics: Analgesics; Benzyl Compounds; Dyspepsia; Humans; Propylamines; Receptors, Opioid, kappa; Treatment Outcome; Viscera

Peripheral kappa receptor agonists may provide a new therapeutic approach for the treatment of functional dyspepsia.. To evaluate, in a large multicentre trial, the use of the kappa receptor agonist fedotozine to improve symptoms associated with functional dyspepsia.. Two or more of the following persistent symptoms were required for inclusion: epigastric pain, early satiety, epigastric fullness or distension, nausea, vomiting, and a feeling of slow digestion. On completing a two week placebo washout, 271 patients were randomised into two groups to receive 30 mg fedotozine three times daily or placebo for six weeks under double blind conditions.. The improvement in the overall intensity of dyspeptic symptoms (main efficacy criterion) was significantly more pronounced in the fedotozine group (p = 0.002) compared with placebo, as was epigastric pain (p = 0.004) and nausea (p = 0.01); the improvement in postprandial fullness was nearly significant (p = 0.052). Inability to finish a meal and slow digestion were unaffected. The patient global score, the average of the five individual symptoms, was notably ameliorated with fedotozine (p = 0.021). The safety of fedotozine was excellent.. Fedotozine at 30 mg three times daily is safe and more effective than placebo for the relief of key symptoms associated with functional dyspepsia.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Benzyl Compounds; Chi-Square Distribution; Double-Blind Method; Dyspepsia; Female; Humans; Male; Middle Aged; Propylamines; Receptors, Opioid, kappa

The efficacy and safety of the peripheral kappa-receptor agonist fedotozine was investigated in a double-blind, placebo-controlled, dose-ranging study involving 146 patients with nonulcer dyspepsia (NUD). 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 10, 30, or 70 mg for six weeks. Analysis of mean symptom intensity scores showed that the 30-and 70-mg doses of fedotozine were superior to placebo in relieving postprandial fullness, bloating, abdominal pain, and nausea. Eructation and early satiety were marginally affected. The 30-mg dose was significantly more effective than placebo in reducing the total symptom score. Eight-two mostly minor adverse effects were recorded, but no significant differences in distribution emerged between placebo and treatment groups. The number of withdrawals declined significantly as a function of increasing dose. These results indicate that 30 mg three times a day is the minimal effective dose of fedotozine in the treatment of NUD symptoms and that this treatment is safe.

Topics: Adult; Benzyl Compounds; Double-Blind Method; Dyspepsia; Female; Humans; Male; Middle Aged; Propylamines