Somatostatin and its synthetic analogue octreotide have been used in gastroenterology as antisecretory and "antimotility" agents. There is no difference in the actions of somatostatin and octreotide (14) except for the duration of their effects. The circulating half-life of somatostatin is 2 minutes (15). Octreotide, after subcutaneous administration, has a half-life of 1 to 2 hours, with prolonged duration of action (6-12 hours), because of resistance to biodegradation and a high affinity with somatostatin receptors (15).
The inhibitory effects of octreotide on gastrointestinal motility are used for treating dumping syndrome (15,16), controlling bleeding from esophageal varices and peptic ulcers, and reducing the volume of diarrhea of patients with ileostomy, short bowel syndrome, intestinal graft-versus-host disease, radiation colitis, intestinal fistula, and vasoactive intestinal peptide-secreting tumors (17). In healthy subjects, a subcutaneous dose of octreotide accelerates the initial phase of gastric emptying but prolongs intestinal transit time (18,19). Other studies have reported significant inhibitors of solid and liquid gastric emptying after intravenous infusion of somatostatin (20) and gastric food retention after subcutaneous octreotide administration in healthy subjects (21). Verne et al (22) recorded improvement of gastrointestinal symptoms in adults with CIP (idiopathic or secondary to scleroderma) but only in patients with five or more phase IIIs after octreotide injection (22). Other investigators recorded symptomatic improvement in a 51-year-old woman with scleroderma and intestinal pseudo-obstruction treated with octreotide for 10 months (23).
In our study, we showed that a subcutaneous injection of octreotide induced phase IIIs in almost all children, regardless of the type and severity of the underlying bowel disease. Such phase IIIs have amplitude and frequency similar to the spontaneous phase IIIs but start in the duodenum, are longer, and migrate faster than the spontaneous phase IIIs. Some of the phase IIIs recorded after octreotide administration are repetitive and do not migrate. In a minority of children, we also identified retrograde clusters of contractions. This phenomenon has been described in healthy control subjects who had 14 simultaneous and one retrograde cluster out of 34 recorded phase III-like clusters (10).
The effect of octreotide injection differs from the action of intravenous erythromycin. Erythromycin induces fasting phase IIIs recorded always in the stomach and propagating to the duodenum, but only in children who have spontaneous phase IIIs. Octreotide-induced phase IIIs originate in the small bowel and are associated with inhibition of antral motility. The mechanisms by which octreotide may affect antroduodenal motility can be several. There could be a direct local effect on the small bowel. In the dog, only the intraarterial and not the intravenous infusion of somatostatin-induced ectopic phase IIIs which started just below the perfused segment (24). The investigators hypothesized that somatostatin relieved the intestine locally from an inhibitory mechanism. The rise of endogenous plasma somatostatin associated with spontaneous phase III would therefore facilitate its migration from stomach to small bowel. The action of octreotide could also be mediated by suppression of motilin release. Motilin seems to be among the hormones with the greatest sensitivity to the suppressive action of octreotide (25). Antral phase IIIs are induced by motilin or motilin agonists such as erythromycin, and octreotide inhibits antral phase IIIs (26). Soudah et al. (11) showed a reduction in motilin concentration during octreotide treatment in patients with scleroderma and in normal subjects. We have previously recorded antral contractions during administration of octreotide after pretreatment with erythromycin (27).
We have also noted that the inhibition of antral motility is overcome by the meal. Normally the meal has a disruptive effect on MMCs. This effect is related to multiple factors including the energy content of meal, the nature of nutrients, and the frequency of meals and is mediated by neuronal and hormonal factors (28). In our study, after infusion of octreotide, the meal overcame octreotide's inhibition of antral motility but did not disrupt the duodenal fasting pattern. Gastric distention, intraduodenal acid, fat, and bile salts are potent stimuli for release of motilin. Our observations support the hypothesis of octreotide's inhibiting antral motility by effecting motilin release, with the meal relieving the inhibition.
We did not elicit any differences in motility activity between the two doses of octreotide. In dogs, low doses of intravenous somatostatin induced an isolated phase III, whereas the frequency of stationary phase III increased with higher doses (29).
It has been suggested that long-term use of octreotide could have noxious effects on other gastrointestinal organs. Octreotide inhibits gallbladder emptying, thus predisposing to formation of gallstones. The latter effect seems to vanish after 6 days of treatment, probably because of desensitization of the target organ (30). Other investigators have shown that long-term octreotide treatment increases the fasting and the residual postprandial gallbladder volume by reducing the rate and extent of gallbladder emptying (31). An increase in oral intake in patients previously dependent on parenteral nutrition may balance the lithogenic effect of octreotide.
In conclusion, low doses of subcutaneous octreotide induced phase IIIs which differed from spontaneous phase IIIs of MMCs and persisted for up to 1 hour after injection. The effects of octreotide were elicited even in children with severe motility disorders. The inhibitory effect of octreotide during fasting on the stomach suggests a rationale for its use, especially in patients fed through jejunostomies or for its use in combination with erythromycin or the ingestion of a meal.
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