M. J. G. Farthing

Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome

Background: Antidepressants are used in the treatment of irritable bowel syndrome but it is unclear whether any symptomatic improvement is due solely to correction of an associated affective disorder, or whether these drugs have effects on bowel function which may be of therapeutic benefit. Intestinal transit is known to be abnormal in some irritable bowel syndrome patients.

Effect of a tricyclic antidepressant on small intestinal motility in health and diarrhea-predominant irritable bowel syndrome

Antidepressants are used in irritable bowel syndrome (IBS) and may have effects on the gut independent of improving mood. We have investigated the actions of a tricyclic antidepressant on small intestinal motor function in eight healthy volunteers and in six patients with diarrhea-predominant IBS. Fasting ambulatory motility was recorded from six small intestinal sites for 16–18 hr while on no drug (baseline) and while taking imipramine for five days. Orocecal transit time (OCTT) was measured by lactulose hydrogen breath test, during baseline and imipramine administration. Imipramine did not alter migrating motor complex periodicity, but slowed jejunal phase III propagation velocity in controls from 7.5±1.1 to 3.6±0.5 cm/min (P<0.01) and in IBS from 7.8±0.6 to 4.4±0.5 cm/min (P<0.0001). Phase III duration at each site was increased, and total recorded phase III was greater during imipramine than baseline studies. Imipramine increased the amplitude of phase III contractions. There was no effect of imipramine on non-phase-III motility index or discrete clustered contractions. Imipramine prolonged OCTT from 73±6 min to 97±8 min in controls (P<0.05) and from 61±9 min to 89±8 min in IBS (P<0.05). Although OCTT was shorter in this IBS group, no motility differences were seen between controls and IBS. This demonstration that a tricyclic antidepressant can modify small intestinal motor function in health and in IBS supports the view that these drugs may have therapeutic actions in IBS unrelated to mood improvement.

Pathogenesis of Giardiasis

Giardiasis is the most common small intestinal protozoal infection and is found worldwide. The mechanisms by which Giardia duodenalis (= G. lamblia) produces chronic diarrhoea and malabsorption have still not been clearly defined. Many infections are associated with mild to moderate mucosal damage which, in animal models of infection, have functional correlates. Possible mechanisms include direct physical injury, release of parasite products such as proteinases or lectin, and mucosal inflammation associated with T cell activation and cytokine release. Other possible mechanisms of malabsorption include associated bacterial overgrowth and bile salt deconjugation, bile salt uptake by the parasite with depletion of intraluminal bile salts, and inhibition of pancreatic hydrolytic enzymes. Thus, there is no single mechanism to explain the diarrhoea and malabsorption caused by Giardia, which currently should be regarded as a multifactorial process.

Effect of octreotide on mouth-to-caecum transit time in healthy subjects and in the irritable bowel syndrome

The effect of a single subcutaneous injection of octreotide (50 μg) on mouth‐to‐caecum transit time was determined in patients with the irritable bowel syndrome who complained of bowel frequency, and in healthy volunteers. The assessment of mouth‐to‐caecum transit time was performed by monitoring breath hydrogen concentration and noting a sustained 10 p.p.m. rise after ingestion of lactulose 40 ml. Measurements were performed fasting, and on a separate day, after a standard breakfast which included 40 ml lactulose. The studies were performed double‐blind in a pre‐determined random order. Octreotide prolonged mouth‐to‐caecum transit time in irritable bowel syndrome patients and healthy subjects by factors of 2.4 and 2.6 after lactulose when fasting, respectively, and by factors of 2.8 and 2.6 after the breakfast which contained lactulose. The upper gastrointestinal transit rate was similar in irritable bowel syndrome patients and healthy controls.

Histopathological changes in the liver after allogeneic bone marrow transplantation

Postmortem and surgical specimens of liver from 20 patients who had undergone allogeneic bone marrow transplantation for a variety of disorders were examined. The lesions fell into five major categories: bile duct atypia often associated with portal tract fibrosis (8 cases), veno-occlusive disease (2 cases), small foci of non-zonal hepatocyte necrosis (3 cases), opportunistic infections (3 cases), and a miscellaneous group of non-specific abnormalities. Our findings, in conjunction with those in experimental animals, point strongly to the bile duct lesion being a specific manifestation of graft versus host disease (GvHD). Veno-occlusive disease has also been reported recently as a possible manifestation of a graft versus host reaction and, although both our patients with this lesion had evidence of GvHD in the skin and gastrointestinal tract, both had also received irradiation and 6-thioguanine, and these may have been responsible. The foci of hepatocyte necrosis could not be attributed to GvHD with any confidence as the lesion was of only minor severity, infrequent, highly non-specific in appearance and, furthermore, did not correlate well with the presence of bile duct lesions. The absence of specific clinical and biochemical findings in human hepatic GvHD stresses the need for biopsy to make a firm diagnosis. However, the patchy distribution of the bile duct lesion and its absence from the needle biopsies examined in this study suggest possible sampling problems, and further study is necessary to assess its value.

5-Hydroxytryptamine and 5-hydroxytryptamine-3 receptor antagonists.

5-Hydroxytryptamine (5-HT) is present throughout the gastrointestinal tract, which acts as the major reservoir of this substance in the body. Its physiologic role has not been clearly established, although it seems likely that 5-HT is involved in the regulation of aspects of intestinal motility such as peristalsis and the migrating motor complex. In disease states the contribution of 5-HT is perhaps more clearly established, particularly its role in chemotherapy-induced emesis, in the carcinoid syndrome, and, possibly, in mediating the effect of some intestinal secretagogues, notably cholera toxin. Many of the functions of 5-HT in the gut have been elucidated as a result of the development of antagonists to 5-HT receptors. However, some of these compounds have 5-HT agonist activity as well as 5-HT receptor blocking activity, making interpretation of their effects in health and disease difficult. Nevertheless, 5-HT receptor antagonists are finding an important place in the management of the carcinoid syndrome and in chemotherapy-induced emesis and may well evolve as important agents for modulating gut motility and for inhibiting secretory states in the small and large intestine. The suggestion that 5-HT3 receptor antagonists might also modulate visceral sensation in the gut is of great interest because of their potential to relieve symptoms of functional bowel disorders such as pain, urgency, and bowel frequency.

Activity of metronidazole, azithromycin and three benzimidazoles on Giardia lamblia growth and attachment to a human intestinal cell line

Background: Attachment of Giardia lamblia trophozoites to enterocytes is essential for colonization of the small intestine and is considered a prerequisite for Giardia‐induced enterocyte damage. Inhibition of attachment may therefore have therapeutic potential

A randomized prospective comparison of clarithromycin versus amoxycillin in combination with omeprazole for eradication of Helicobacter pylori

Aim: To compare H. pylori eradication rates using omeprazole in conjunction with either amoxycillin or clarithromycin.

Dominant role for osmolality in the efficacy of glucose and glycine-containing oral rehydration solutions: studies in a rat model of secretory diarrhoea

The effect of osmolality on the efficacy of oral rehydration solutions (ORS) and the contribution of the amino acid glycine to water absorption from ORS have been studied in an animal model of secretory diarrhoea. After exposure to pure cholera toxin, rat small intestine (excluding the duodenum) was perfused in situ with seven different ORS. All ORS were derived from a “basic” solution containing Na 50, K 25, Cl 75 and glucose 50 mmol/l to which 25 or 50 mmol/l of glycine, glucose, or mannitol was added. All ORS reversed water secretion to absorption, but maximum water absorption was obtained with the “basic” solution with an osmolality of 200 mOsm/kg. When the osmolality of the “basic” solution was raised to 225 and 250 mOsm/kg by adding mannitol, water absorption decreased. At each of these osmolalities, substitution of mannitol by glycine or glucose resulted in similar increases in water absorption, but all modifications compared unfavourably with the “basic” solution. Net sodium secretion occurred with all ORS tested, despite net water absorption. These findings in a perfusion model of rat small intestine suggest that osmolality is a key factor influencing the efficacy of ORS and that addition of a second substrate, such as glycine, has no beneficial effects. Our results suggest that there is a maximal rate for water absorption from the small intestine which is inversely related to the osmolality of the perfusate.

Disease-related animal models for optimising oral rehydration solution composition.

Farthing, M. J. G. (Department of Gastroenterology. St Bartholomews Hospital, London, U.K.). Disease‐related animal models for optimising oral rehydration solution composition. Acta Paediatr Scand Suppl 364:23. 1989.