Review: loperamide--a potent antidiarrhoeal drug with actions along the alimentary tract.

The synthetic opioid, loperamide, reduces stool weight, frequency of bowel movements, urgency and faecal incontinence in acute and chronic diarrhoea. In man, the mechanism of action of loperamide is primarily the retardation of small-intestinal transit, and the stimulation of anal sphincter pressure and of faecal continence. This mechanism increases mucosal contact time, allowing more complete absorption of electrolytes and water. Studies in animals have demonstrated inhibitory effects of opiates and opioids, including loperamide, on fluid and electrolyte secretion induced by various secretagogues. By comparison, opiates have smaller if any antisecretory or pro-absorptive actions in man. The discrepancies between the results obtained in animal and human experiments are most certainly due to the large differences between drug doses used. Besides its opiate-receptor binding and stimulating activity, loperamide also behaves as a calcium-calmodulin antagonist and as a calcium channel blocker. These two other mechanisms might contribute to loperamide's antidiarrhoeal activity. Loperamide is more effective and safer than other opiates or opioid drugs in the treatment of both infantile and adult diarrhoea of various causes, although adequate fluid and electrolyte replacement remain the prime need.

Effect of two potent calmodulin antagonists on calcium transport of brush border and basolateral vesicles from human duodenum.

In the present in-vitro study we investigated the possible role of the calmodulin-antagonistic drugs loperamide and calmidazolium in the regulation of transepithelial Ca2+ transport of human duodenum. Brush border membrane vesicles and basolateral membrane vesicles were simultaneously prepared from surgically resected pieces of morphologically intact human duodenum with a modified Percoll-gradient centrifugation method. Brush border and basolateral membrane vesicles were characterized using enzyme marker analysis and electron microscopy: alkaline phosphatase was enriched 20-fold in brush border membrane vesicles, whereas [Na+ + K+]-stimulated adenosine triphosphatase was enriched 15-fold in basolateral membrane vesicles. Calmodulin activity was determined by a specific radioimmunoassay after solubilizing brush border and basolateral membrane vesicles in 1% Triton X-100. In basolateral membrane vesicles, we found no calmodulin activity. In brush border membrane vesicles calmodulin activity was impaired by 50% after pre-incubation with loperamide or calmidazolium. We measured calcium, sodium, D-glucose and D-mannitol uptake with a rapid filtration technique. Before the transport experiments, brush border and basolateral membrane vesicles were pre-incubated with 5 microM loperamide or 5 microM calmidazolium for 60 min at 5 degrees C. In drug-pretreated, brush border membrane vesicles calcium uptake was significantly reduced after 1 min incubation (-25% +/- 5%, P less than 0.05); this effect was completely reversed in the presence of 5 microM calmodulin. In basolateral membrane vesicles, we found two Ca2+ transport systems: (1) Na+/Ca2+ exchange and (2) ATP-dependent Ca2+ transport. In basolateral membrane vesicles loperamide had no effect. Calmidazolium had no effect on Na+/Ca2+ exchange, but significantly inhibited ATP-dependent Ca2+ transport. This effect could not be reversed by calmodulin.

Acute ulcerative colitis--a rare complication of sulfasalazine therapy.

A 43-year-old female suffering from ulcerative colitis did not improve under therapy with sulfasalazine. Following withdrawal of sulfasalazine and its replacement by systemic steroids and metronidazole++ she went into clinical and endoscopic remission. A second trial with sulfasalazine was, again, followed by a rapid and sever relapse of the colitis. On discontinuation of sulfasalazine therapy, gross inflammation resolved immediately. This adverse reaction to sulfasalazine has been reported previously in only four cases. The pathophysiology of this event is unknown.

Functional defect of zinc transport in patients with Crohn's disease.

In the present study, we investigated the question whether the zinc deficiency in Crohn's disease is, at least partly, related to defective zinc entry at the jejunal brush border membrane. Brush border membrane vesicles (BBMV) were prepared from surgically resected pieces of morphologically intact human jejunum by a Mg++ precipitation method. We studied zinc, D-glucose, sodium and D-mannitol uptake into BBMV in 27 patients: 1) 20 patients with Crohn's disease 2) 7 controls. In 8/20 patients with Crohn's disease we found a significant decrease in zinc uptake (-25% +/- 5%, p less than 0.05) into BBMV. This impairment of zinc uptake in 40% of our patients with Crohn's disease was not associated with changes in the transport rates for D-glucose, sodium or D-mannitol. In addition no differences in enzyme marker concentrations or electron microscopic appearance were found.

Gastric mucosal cell loss caused by aspirin and alcohol.

Gastric epithelial cell loss was studied in healthy volunteers before and after intragastric instillation of four aspirin (ASA) formulations and three strengths of alcohol. Each test solution was administered three times over a period of three hours during one of the experiments. Three of the four aspirin formulations significantly increased gastric epithelial cell loss. Microencapsulated aspirin increased gastric epithelial cell loss significantly, but only after the third dose. Alcohol, 10% (wine), increased cell loss to a similar extent as did microencapsulated aspirin. Alcohol, 20% (campari), and 40% (whisky), significantly enhanced cell loss to such a degree as was elicited by the two strengths of soluble aspirin. Thus, gastric cell loss increased dose-dependently after both aspirin and alcohol. The data suggest that, in man, gastric epithelial cell damage caused by different aspirin formulations and alcohol concentrations is reproducible and dose-dependent.

Gastric cytoprotection by antacids and papaverine in rats.

Prostaglandin E2 (PGE2) prevented hemorrhagic ulceration of rat stomach mucosa induced by various procedures when given orally at a non-antisecretory dose. This effect of PGE2 is called gastric cytoprotection. We used absolute ethanol, 0.6 N hydrochloric acid and 0.2 N sodium hydroxide as damaging agents. Ranitidine at an antisecretory dose did not exhibit any cytoprotective effect. However, the poorly absorbable antacids, magnesium hydroxide plus aluminium hydroxide and aluminium phosphate inhibited the development of hemorrhagic lesions significantly. A similar protective effect was seen after intragastric administration of papaverine, which is known to stimulate endogenous prostaglandin synthesis. However, the question as to whether or not stimulation of endogenous prostaglandin synthesis is the mode of action of the cytoprotective effect of papaverine and poorly absorbable antacids, cannot yet be answered.

[Therapeutic guidelines in diarrhea]. / Therapeutischer Leitfaden bei Diarrhoe.

In acute diarrhea water and electrolyte losses are compensated for by oral or intravenous rehydration. Oral rehydration solutions contain primarily glucose or glucose polymers and sodium as well as other electrolytes. In acute and chronic diarrhea, loperamide is the most potent and safe antidiarrheal drug. Antibiotics are used without hesitation only in invasive diarrhea. In chronic diarrhea, diagnostic work up must precede therapy. Potentially diarrheogenic drugs or foods have to be eliminated. In most cases, when the diagnosis has been established, specific therapeutic measures are available.

[Diagnostic guidelines in diarrhea]. / Diagnostischer Leitfaden bei Diarrhoe.

Acute diarrhea is usually short-lasting; therefore, diagnostic procedures are mainly concerning the degree of dehydration. With longer duration of high fever or bloody diarrhea, microbiologic stool tests are necessary. Proctosigmoidoscopy is indicated in case of dysenteric disease or suspected antibiotic-as-associated pseudomembranous colitis. In chronic diarrhea, the most important diagnostic procedure is a careful history. Side effects of drugs and food-related causes are especially noticeable, as are indices of an organic origin, e.g. unwanted weight loss or blood in the stools. Also, careful history and physical examination are essential for the decision about laboratory tests, tests of gastrointestinal function or endoscopy.

Antacids and gastric mucosal protection.

Aluminum hydroxide-containing antacids have a protective effect on the stomach in that they prevent grossly visible mucosal necrosis and hemorrhages produced by noxious agents, such as aspirin or absolute ethanol. Histologically, this protective effect is mainly confined to the tissue located deep in the gastric mucosa, essentially comprising gastric glands, while the damage to the surface epithelium is not significantly lessened. Accordingly, integrity parameters of the superficial epithelial layer (potential difference, mucous secretion, cell desquamation) do not indicate a protective action of antacids against damage by necrotizing agents. By contrast, significantly diminished microbleeding rates do suggest that protection by antacids works at a deeper level within the mucosa. The protective action of antacids may be mediated, at least partly, by endogenous prostaglandins, which were found to be elevated in this context.

Effect of 13-Nle-motilin on small intestinal transit time in healthy subjects.

In 6 female subjects without gastrointestinal diseases, 13-norleucine motilin (13-Nle-M) synthetic and biological analogue of the duodenal polypeptide, motilin, caused acceleration of intestinal transit time. Intravenous infusion of 0.4 mug/kg-h of 13-Nle-M reduced mean transit time by 50 percent. No side effects occurred during infusion of the polypeptide. Radiographic appearance of small intestinal peristalsis and mucosal relief was not influenced by 13-Nle-M.

Effect of 13-Nle-motilin in postoperative ileus patients: a double-blind trial.

In this study, the effect of 13-norleucine motilin (13-Nle-M) on post-cholecystectomy ileus was assessed in 6 female patients. 13-Nle-M given by continuous i.v. infusion (0.4 mug/kg-h) on the second and third day following surgery did not influence the manifestation and duration of intestinal paralysis in comparison to 6 control patients treated with 0.9% saline. Bowel sounds, however, were more pronounced in the 13-Nle-M-group. Blood pressure and pulse rate were not influenced by the polypeptide, and no other side effects were seen, either.

Motilin-induced electrical activity in the canine gastrointestinal tract.

Myoelectric activity induced by a synthetic analogue of the duodenal polypeptide motilin, was studied in isolated vascular-perfused canine duodenum and stomach, and in conscious dogs with serosal electrodes implanted in the stomach and the small intestine. In the isolated preparation, the duodenum was found to be four times as sensitive as the antrum to the polypeptide, showing a dose-dependent increase in spike activity within two minutes after administration of the polypeptide. By contrast, in the conscious fasted animal, the only response to motilin, above a threshold dose, was the interpolation of a premature migrating myoelectric complex in the spontaneous interdigestive sequence, appearing fifteen to twenty minutes after the start of infusion. Since the essential difference between the ex vivo and the intact intestine was the preservation of efferent and afferent nervous connections in the latter, it seems that in the conscious animal, the response to exogenous motilin is modulated by the innervation of the intestine, or, alternatively, motilin interacts with the centre controlling the pattern of motor activity in the small intestine rather than directly with smooth muscle. The latter hypothesis is supported by the observation that motilin had no effect on the motor activity of the small intestine during the infusion of pentagastrin which abolishes spontaneous migrating myoelectric complexes.