Effects of 3-days' intake of a sustained-release preparation of the nitric oxide donor, isosorbide dinitrate, on oesophageal motility.

BACKGROUND: Nitric oxide plays an important role in gastrointestinal motility. We evaluated the effects of a sustained-release preparation of the nitric oxide donor isosorbide dinitrate on swallow-initiated oesophageal contractions and the lower oesophageal sphincter. METHODS: Twelve healthy men, aged 23-32 years, received, at 1-week intervals and under random double-blind conditions, for 3 days either 20 mg isosorbide dinitrate, 40 mg isosorbide dinitrate or placebo twice daily (b.d.). One hour after a further dose on day 4, oesophageal motility was recorded for 30 min using a multilumen catheter with a Dent sleeve straddling the lower oesophageal sphincter and side-hole openings 0, 3, 6 and 9 cm proximal to the sleeve. Contractile responses to twelve 5-mL water swallows were evaluated. RESULTS: Amplitude, duration, propagation velocity and onset latency of oesophageal contractions were not affected by either dosage of isosorbide dinitrate. Lower oesophageal sphincter resting pressure was significantly lower after 40 mg (15.1 mmHg +/- 1.2 S.E.M.) and 20 mg isosorbide dinitrate b.d. (15.0 +/- 1.0 mmHg) than after placebo (17.9 +/- 1.7 mmHg; P < 0.025). Headache was reported by all subjects on 40 mg isosorbide dinitrate, seven subjects on 20 mg and by one on placebo. CONCLUSIONS: Twenty and 40 mg sustained-release isosorbide dinitrate twice daily had no effect on swallow-initiated oesophageal contractions but decreased lower oesophageal sphincter resting pressure.

Gastric emptying, body weight and symptoms in primary anorexia nervosa. Long-term effects of cisapride.

In a double-blind trial, 12 out-patients with primary anorexia nervosa received, for six weeks, either 10 mg cisapride or placebo, three times a day. Cisapride accelerated gastric emptying of a radiolabelled semisolid meal in all six patients; five gained weight and symptoms of gastric retention ameliorated in four. With placebo, three of six had emptying enhanced, four gained weight, and one's symptoms improved. For another six weeks, all patients received cisapride. In five of the patients who had received cisapride, emptying further accelerated or remained stable; in one it slowed. Of the six patients who received placebo, four had emptying accelerated, five gained weight, and symptoms improved in four. Longer administration of cisapride may, by enhancing gastric motor activity, alleviate symptoms of retention and thus help to change eating behaviour.

Erythromycin effects on gastric emptying, antral motility and plasma motilin and pancreatic polypeptide concentrations in anorexia nervosa.

In primary anorexia nervosa, gastric motility is often impaired and ensuing symptoms further discourage eating. Prokinetic agents have been shown to accelerate gastric emptying in affected patients. This study investigated whether emptying of a radiolabelled semisolid 1168 kJ meal and antral contractility were enhanced by intravenous erythromycin. Eight women and two men with anorexia nervosa (21-46 years, 50-75% of ideal body weight) received 200 mg erythromycin or placebo under crossover double blind conditions. Gastric emptying and antral contractility were recorded scintigraphically for 90 minutes. In addition, plasma motilin and pancreatic polypeptide concentrations were determined. With placebo, antral contractions were of regular 3 cycles/minute frequency. With erythromycin, less frequent and partly arrhythmic long duration contractions set in and emptying was accelerated: after 90 minutes, the activity remaining in the stomach was markedly less than with placebo in all patients (Sign test, p < 0.002). Basal motilin and pancreatic polypeptide concentrations were normal and showed a normal response to the meal in all patients. Motilin concentrations decreased slightly more and pancreatic polypeptide concentrations increased markedly more with erythromycin than with placebo, possibly because the meal reached the intestine earlier. In conclusion, erythromycin accelerated emptying markedly and in most patients induced an antral motor activity characterised by long duration contractions occurring at often irregular intervals.

Effects of the prodrug loperamide oxide, loperamide, and placebo on jejunal motor activity.

This crossover, double-blind study investigated the effects of single oral doses of the prodrug loperamide oxide, which is reduced gradually to loperamide in the intestine, and loperamide on jejunal motor activity in 12 fasting healthy men. Five minutes after a phase III of the migrating motor complex (MMC), 2 mg loperamide oxide, 4 mg loperamide oxide, 4 mg loperamide, or placebo were administered. Thereafter, motor activity 10-30 cm abroad the ligament of Treitz was recorded with five catheter orifices at 3-cm intervals over 4 hr. Number of contractions and area under curve increased significantly with 4 mg loperamide and 4 mg loperamide oxide, the increases with loperamide oxide occurring more gradually. Placebo and 2 mg loperamide oxide had no discernible effects. With both 4 mg loperamide and 4 mg loperamide oxide, phase I of the MMC was slightly prolonged and phase II and the time from drug administration to the onset of the first phase III slightly shortened. The percentage of aborally propagated contractions in phase II increased with all active treatments, whereas the occurrence of phases III was not altered.

High incidence of esophageal motor disorders in consecutive patients with globus sensation.

Thirty consecutive patients with globus sensation who were referred to a psychosomatic clinic prospectively underwent otolaryngological, videokinematographic, and manometric examinations of pharynx and esophagus to evaluate whether morphological abnormalities or motility disorders underlay their symptom. When indicated by findings, 24-hour pH-metry, scintigraphy of bolus transport, and esophagogastroscopy were performed. Seven patients were shown to have achalasia, 10 had "hypochalasia" (lower esophageal sphincter relaxation less than 75% with esophageal contraction abnormalities but no complete distal aperistalsis), and 1 had diffuse esophageal spasms; 2 patients had also hyperplastic lingual tonsils, 1 had tonsillitis, and 1 had a cervical spondylophyte. Nutcracker esophagus and nonspecific contraction abnormalities were found in 7 patients, and gastroesophageal reflux with esophagitis and a low lower esophageal sphincter resting pressure was found in 1; only 3 patients had normal esophageal motility. None had volunteered dysphagic symptoms at primary evaluation. Psychometric investigations in consenting patients showed no higher mean scores for state and trait anxiety, depression, hysteria, and hypochondriasis than in general medical outpatients. Esophageal motor disorders may, before giving rise to dysphagia, be sensed more vaguely and induce the globus sensation. However, only disappearance of the sensation after treatment allows inferring an etiological significance of such a disorder.

Lack of systematic effects of the 5-hydroxytryptamine 3 receptor antagonist ICS 205-930 on gastric emptying and antral motor activity in patients with primary anorexia nervosa.

1. The 5-hydroxytryptamine 3 receptor antagonist, ICS 205-930, has been reported to have potent effects on gastric smooth muscle and to enhance gastric emptying in animals, but findings in man have been inconsistent. 2. This study investigated the effects of ICS 205-930 on gastric emptying of an isotopically labelled semisolid 1168 kJ meal and on antral contractility in patients with primary anorexia nervosa, a condition frequently associated with impaired gastric motor function. 3. Thirteen female patients (age 18-39 years, median 22 years; percentage of ideal body weight 52-90%, median 66%) participated each in two studies, in which 0.15-0.18 mg kg-1 ICS 205-930 or placebo were infused i.v. in crossover, double-blind fashion. Gastric emptying and antral contractility were recorded scintigraphically for 50 min. 4. ICS 205-930 did not affect gastric emptying: the mean percentage of meal remaining in the stomach after 50 min (69.6% +/- 3.2 s.e. mean) was nearly identical to that after placebo (70.7 +/- 3.3%). 5. Amplitude, frequency and propagation velocity of antral contractions differed only little after ICS 205-930 and placebo, respectively. 6. The results show that ICS 205-930 has no effect on the impaired gastric motor activity in primary anorexia nervosa and thus provide further evidence that the compound does not have prominent prokinetic effects in man.

Fat preload delays gastric emptying: reversal by cisapride.

1. Meals empty more slowly when they contain fat. 2. This study investigated whether an intragastric fat preload in comparison with a water preload affected gastric emptying of a semisolid meal and antral motor activity, and whether cisapride reversed such effects. 3. Twelve healthy subjects were studied under three conditions each: (A), preload of 50 ml water orally; (B) and (C), preload of 50 ml cream (20 g fat). After preloads, subjects reclined right sided for 20 min. Thereafter, placebo in conditions (A) and (B) and 10 mg cisapride in (C) were administered i.v. in a random double-blind fashion and subjects ingested a semisolid radiolabelled 1150 kJ meal. Gastric emptying and antral motor activity were recorded scintigraphically for 50 min using a dual-headed gamma camera. 4. Gastric emptying was significantly slower (P less than 0.005) after fat preload and placebo than after water preload and placebo. Cisapride administered after fat preload abolished the delaying effect of the fat preload (P less than 0.001). 5. Antral contraction amplitudes after fat preload and placebo were higher (P less than 0.01) than after water preload and placebo as well as fat preload and cisapride at the start of recording and decreased slightly thereafter, whereas slight increases occurred in the other conditions. Frequency and propagation velocity of contractions were not differently affected. 6 Gastric emptying is delayed after prior fat ingestion and this effect is abolished by cisapride.

Effects of the 5-HT3 receptor antagonist ICS 205-930 on fat-delayed gastric emptying and antral motor activity.

1. The selective 5-HT3 receptor antagonist, ICS 205-930 (Sandoz), has been reported to have potent effects on gastric smooth muscle in vivo and to enhance gastric emptying in animals and in man. 2. This study investigated the effects of ICS 205-930 on fat-delayed gastric emptying of a semisolid meal and antral motor activity in humans. 3. Twelve healthy men participated in each of three studies in which 10 or 20 mg of ICS 205-930 or placebo were infused i.v. in a random double-blind fashion. Gastric emptying and antral motor activity were studied scintigraphically. 4. Gastric emptying was not altered after 10 mg but slower after 20 mg of ICS 205-930 than after placebo. Emptying after 20 mg of ICS 205-930 was significantly slower than after 10 mg of ICS 205-930. 5. Antral contraction amplitude was slightly lower after 20 mg of ICS 205-930 than after placebo, whereas the effects of 10 mg ICS 205-930 did not differ from those of placebo. 6. The results suggest that the investigated doses of ICS 205-930 have only slight effects on gastric motor activity of healthy young men, with 20 mg reducing the rate of emptying.

Oesophageal and gastric motor activity in patients with bulimia nervosa.

Previous studies showed that symptoms of oesophageal motor disorders can be misinterpreted as indicating anorexia nervosa and that in primary anorexia nervosa gastric motility is frequently impaired. We investigated in 32 women with bulimia nervosa whether symptoms of oesophageal motor disorders could be obscured by or be mistaken as forming part of bulimic behaviour, and whether impaired gastric motility was frequent as well. Oesophageal motility was normal in 18 of 26 patients studied, another four had incomplete lower oesophageal sphincter relaxation. Two patients had vigorous achalasia and each one achalasia and diffuse oesophageal spasm, all of whom experienced two types of vomiting: one self-induced and one involuntary, in which the vomit was non-acidic and tasted as the preceding meal. Gastric emptying of a semisolid meal was studied in all patients except of the eight with oesophageal motor abnormalities. Emptying was significantly slower than in healthy controls and grossly delayed in nine of 24 patients. Antral contraction amplitudes were lower and increased less postcibally than in controls. In conclusion (i) bulimic behaviour can obscure symptoms of oesophageal motor disorders and (ii) gastric emptying is frequently delayed in bulimia nervosa.

Effects of a 5-hydroxytryptamine3 receptor antagonist (ICS 205-930) on colonic motor activity in healthy men.

1. ICS 205-930 (Sandoz) is a selective antagonist at 5-hydroxytryptamine3 receptors and exerts marked effects on gastrointestinal motility in animals. 2. This study investigated, under random double-blind conditions, the effects of 10 and 20 mg ICS 205-930 infused intravenously in comparison with placebo on colonic motor activity. 3. Twelve healthy men participated each in three studies in which they received, in random double-blind fashion, each of the treatments. Colonic pressures were recorded pneumohydraulically with four catheter orifices 20-40 cm from the anal verge. Treatments were administered after a basal 30 min. One hour later, subjects ingested a 4200 kJ meal and 90 min thereafter, 1 mg neostigmine was administered intramuscularly and recording continued for another 90 min. 4. After both doses of ICS 205-930, the number of contractions as averaged over the entire recording time was slightly but significantly higher than after placebo. 5. After 10 mg but not after 20 mg ICS 205-930, amplitude of contractions and area under the curve as averaged over the entire recording time were significantly higher than after placebo. 6. ICS 205-930 induced few and mild side effects, but significantly more self-rated drowsiness and tiredness than placebo.

Effects of cisapride on postcibal jejunal motor activity.

In the jejunum of fasting humans, cisapride induces a phase 2-like, highly propagative motor pattern. This study investigated cisapride's effects on the fed pattern of the jejunum. Starting 5 min after a phase 3 of the migrating motor complex, 18 healthy men received 5 or 10 mg cisapride or placebo orally in random double-blind fashion and ingested meals containing 1000 and 4200 kJ, respectively. Jejunal pressures were recorded pneumohydraulically with five catheter orifices 10-30 cm aboard the ligament of Treitz. After the 4200-kJ meal, total number and number of propagated contractions as well as area under the curve increased significantly more than after 1000 kJ. Following the 1000-kJ but not the 4200-kJ meal, 10 mg cisapride increased total number of contractions, number of propagated contractions, mean amplitude, and area under curve significantly more than placebo. Fed-pattern duration increased with the meal's caloric content but was not influenced systematically by cisapride. In conclusion, cisapride stimulates jejunal motor activity and induces a propagative pattern after a 1000-kJ but not after a 4200-kJ meal, suggesting that it can produce no further stimulation when motor activity is near maximally enhanced already.

Effects of graded oral doses of a new 5-hydroxytryptamine/noradrenaline uptake inhibitor (Ro 15-8081) in comparison with 60 mg codeine and placebo on experimentally induced pain and side effect profile in healthy men.

1. Ro 15-8081 (Hoffmann-La Roche, Basle, Switzerland) is a novel mixed 5-HT/noradrenaline uptake inhibitor producing potent antinociceptive effects in animal pain models. 2. In healthy man, two models with electrically and thermally induced pain, respectively, have been shown to reliably discriminate between the effects of opioid as well as of antipyretic analgesics and placebo. 3. This study investigated the effects of single oral doses of 10, 25, and 50 mg Ro 15-8081 in comparison with 60 mg codeine and placebo on threshold and tolerance to electrically induced pain and on threshold to thermally induced pain. Furthermore, the effects on psychomotor function, self-rated subjective feelings, and side effect profile were studied. 4. Twenty healthy males participated each in five experiments in which they received, in random double-blind fashion, each of the treatments. Every experiment comprised two series of measurements before and twelve after drug administration, carried out at 30 min intervals. 5. Ro 15-8081 produced marked elevations of threshold and tolerance to electrically and of threshold to thermally induced pain. The effects of all doses of Ro 15-8081 were significantly superior to those of placebo. Threshold and tolerance to electrically induced pain were not affected differently by the three doses of Ro 15-8081, whereas the threshold to thermally induced pain was elevated significantly more by 50 mg than by 10 and 25 mg Ro 15-8081. 6. Codeine 60 mg had a more rapid onset of action and greater maximal effects than Ro 15-8081.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of oral cisapride on interdigestive jejunal motor activity, psychomotor function, and side-effect profile in healthy man.

Intravenous cisapride was shown to induce a phase-2-like pattern of human interdigestive jejunal motor activity containing an increased number of propagated contractions. This study investigated the effects of oral cisapride in 12 fasting healthy males. Jejunal pressures were recorded by a pneumohydraulic system and five catheter orifices positioned 10-30 cm aborad the ligament of Treitz. Single oral doses of 5 and 10 mg cisapride, administered 5 min after an activity front under random double-blind conditions, induced a phase-2-like jejunal motor pattern with a significantly higher number and amplitude of contractions and significantly more aborally propagated waves than placebo (P less than 0.001), while the number of subjects with activity fronts decreased with increasing dose. Five and 10 mg cisapride administered tid for three days affected psychomotor function, subjective feelings, and side-effect frequency, apart from increases in systolic blood pressure and heart rate, no more than placebo. It is concluded that in fasting man, oral cisapride induces a highly propagative phase-2-like jejunal motor pattern causing only minor side effects.

Intravenous cisapride accelerates delayed gastric emptying and increases antral contraction amplitude in patients with primary anorexia nervosa.

Delayed gastric emptying is common in primary anorexia nervosa. We investigated in 12 patients whether gastric emptying could be accelerated by the prokinetic drug cisapride. Patients were studied on two occasions 1 wk apart and received, under random double-blind conditions, 8 mg of cisapride and placebo intravenously. Gastric emptying of an isotopically labeled semisolid meal and antral motor activity were measured using a dual-headed gamma-camera for 50 min. Emptying was significantly slower (half-emptying time, 50-191 min; median, 121 min) than in 24 healthy volunteers (half-emptying times, 21-119 min; median, 47 min). Cisapride accelerated emptying significantly (p less than 0.001; half-emptying time after cisapride, 22-80 min; median, 42 min). Antral contraction amplitude increased and contraction frequency decreased significantly (p less than 0.001), whereas the propagation velocity of contractions remained unchanged. We concluded that intravenous cisapride accelerates gastric emptying and increases antral contraction amplitude in patients with anorexia nervosa. Whether or not these effects can prove beneficial in diminishing the patients' symptoms and in helping them to gain weight can only be answered from studies involving long-term treatment with cisapride.

Effects of cisapride on jejunal motor activity in fasting healthy humans.

The effects of cisapride on jejunal interdigestive motor activity were studied in 12 healthy men participating in three experiments each. Five minutes after an activity front (phase III) they received, in random double-blind fashion, 10 mg of cisapride, 4 mg of cisapride, or saline placebo by intravenous injection. Motor activity was recorded for 4 h. A pneumohydraulic perfusion system and five catheters with orifices positioned 10-30 cm beyond the ligament of Treitz were used. Cisapride increased phase II-type activity (p less than 0.001) and reduced the number of activity fronts dose-dependently. Compared with phase II after placebo, the activity prevailing after cisapride was characterized by a significantly higher number and amplitude of contractions as well as by a significantly greater area under the pressure curve. Moreover, a significantly higher proportion of contractions was propagated aborally. Self-rated abdominal grumbling increased dose-dependently. Except for mild sedative effects, no side effects occurred. We conclude that cisapride induces a prolonged and highly propagative phase II-like jejunal motor activity in fasting humans.

Experimental pain induced by electrical and thermal stimulation of the skin in healthy man: sensitivity to 75 and 150 mg diclofenac sodium in comparison with 60 mg codeine and placebo.

Models with experimentally induced pain in healthy man might be useful for the screening for analgesic effects of new drugs. Experimental pain models have been shown to discriminate reliably between the effects of opioid analgesics and placebo but their sensitivity to nonsteroidal anti-inflammatory agents is disputed. This study investigated whether it would be possible by using electrically and thermally induced cutaneous pain to discriminate reliably the effects of single oral doses of 75 and 150 mg diclofenac sodium on the one hand and 60 mg codeine on the other from those of placebo. Forty-eight healthy subjects participated each in four experiments in which they received, in random double-blind fashion, each of the treatments. Every experiment comprised eight series of measurements, two before and six after drug administration, carried out at 30 min intervals. Diclofenac sodium produced significant dose-related increases of threshold and tolerance to electrically and threshold to thermally induced pain. Codeine 60 mg was significantly superior to placebo in all pain measures. Its analgesic effects were stronger than those of diclofenac 75 mg but weaker than those of diclofenac 150 mg. Neither 150 mg nor 75 mg diclofenac caused more side effects than placebo, whereas codeine 60 mg elicited a high frequency of side effects. No severe adverse effects occurred after any one treatment. The results suggest that both electrically and thermally induced cutaneous pain are well suited to evaluate analgesic effects not only of opioids but also of nonsteroidal anti-inflammatory drugs.