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Characterization of stress-induced increased fecal pellet output and colonic transit
30 to 65% of long distance runners experience gastrointestinal (GI) symptoms related to exercise. Several hypotheses have been postulated; however, the aetiology and pathophysiology are far from clear.
The mechanical effect of running on the viscera must be involved in the development of GI symptoms in this sport. Reduction of splanchnic blood flow due to visceral vasoconstriction is another widely supported theory; nevertheless, it does not explain many of the clinical findings. Examination of the GI tract during exercise is a difficult task, and measurements of both orocaecal and whole-gut transit time have shown equivocal results. GI hormones, and especially prostaglandins, may be of crucial importance for the production of symptoms. Intestinal absorption, secretion and permeability may also be altered during exercise, provoking intestinal dysfunction. Factors such as stress, diet, dehydration, infections and other factors need to be analysed in order to present a global view of the hypotheses regarding the aetiology of this common and often overlooked problem.
The evaluation of a group of polyamine analogs as agents to ameliorate diarrhea-predominant irritable bowel syndrome is described. Each compound was assessed when administered subcutaneously in a psychological stress-induced model of irritable bowel syndrome in rodents for its ability to reduce stool output in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct compounds to treat irritable bowel syndrome. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. In addition to the subcutaneous studies, several compounds, N
1,N
11-diethylnorspermine, N
1,N
12-diethylspermine, N
1,N
12-diisopropylspermine, N
1,N
14-diethylhomospermine, N,N`-bis[5-(ethylamino)pentyl]-1,4-butanediamine, N,N`-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane, and N,N`-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine, were subsequently evaluated for oral efficacy. The remarkable activity of N,N`-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to explore this framework further as a pharmacophore for the construction of other analogues to relieve the symptoms of diarrhea-predominant IBS.
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