Kiertisin Dharmsathaphorn

Somatostatin inhibits diarrhea in the carcinoid syndrome.

Excerpt Recent studies in rats indicate that somatostatin inhibits jejunal fluid secretion induced by prostaglandin E1and theophylline in vivo (1) and the effect of vasoactive intestinal polypeptid...

Clonidine and lidamidine to inhibit watery diarrhea in a patient with lung cancer.

A patient with watery diarrhea syndrome secondary to bronchogenic carcinoma responded to treatment with clonidine and lidamidine. Stool weight decreased to 43% and 53% of control on two separate trials of clonidine. Stool weight decreased to 35% of control during a trial of lidamidine. Both clonidine and lidamidine increased sodium and chloride absorption in vitro in human intestine. Clonidine, lidamidine, or drugs that are structurally similar may become therapeutic choices for secretory diarrhea.

Effect of somatostatin on ion transport in the rat colon.

The effect of somatostatin (SRIF) on ion transport was determined in the rat colon in vitro. SRIF produced a sustained decrease in the short circuit current (Isc) (-0.8 +/- 0.1 mueq/h x cm2) and increased net Cl absorption (0.9 +/- 0.3 mueq/h x cm2). The threshold effect of SRIF on Isc was observed at 6 nM. 10 microM serotonin decreased net Na absorption (-2.6 +/- 0.4 mueq/h x cm2), net Cl absorption (-3.6 +/- 0.5 mueq/h x cm2) and increased Isc (0.7 +/- 0.1 mueq/h x cm2); these changes were totally blocked by 0.1 microM SRIF. SRIF completely blocked net Cl secretion induced by 10 mM theophylline (-2.5 +/- 0.7 to +4.1 +/- 2.0 muq/h x cm2) and partially blocked theophylline-induced inhibition of net Na absorption (0.7 +/- 0.5 to 2.1 +/- 0.4 mueq/h x cm2). SRIF also blocked prostaglandin E1 (PGE1) induced increase in potential difference and Isc (P < 0.001). Mucosal cyclic AMP levels were increased by theophylline and PGE1 but not by serotonin. SRIF had no effect on basal or theophylline- and PGE1-stimulated cyclic AMP levels. These results indicate that SRIF blocks both cyclic AMP and noncyclic AMP mediated changes in ion secretion and suggest that SRIF is acting at a step in the secretory process beyond the formation of cyclic AMP.

Preferential binding of vasoactive intestinal polypeptide to basolateral membrane of rat and rabbit enterocytes.

Binding of radioiodinated vasoactive intestinal polypeptide (VIP) to intestinal cell membranes of the rabbit ileum and rat jejunum was investigated. Specific binding of 125I-labeled VIP could be demonstrated only on the basolateral membrane and not on the brush border membrane. This corresponded with the lack of an effect on ion transport when VIP was applied to the mucosal side of an in vitro preparation of rabbit ileum. VIP altered ion transport only when it was applied to the serosal side. The binding of 125I-VIP was specific and dependent upon incubation temperature. There was a close correlation between the potency of VIP for inhibition of 125I-VIP binding and that for increasing adenylate cyclase activity. These observations demonstrate that VIP receptors are located on the basolateral membrane.

Structure-Activity Relationships of Somatostatin Analogs in the Rabbit Ileum and the Rat Colon

UNLABELLED Somatostatin increases absorption of electrolytes and inhibits diarrhea in patients with endocrine tumors and short bowel syndrome. In an attempt to develop a gut-specific somatostatin analog, each amino acid in the somatostatin molecule was replaced with L-alanine, deleted, or substituted with its D-isomer. The potency of each analog to stimulate ion transport in the rabbit ileum was then determined using the modified Ussing chamber technique. The results were compared to the ability of each analog to inhibit the stimulated release of growth hormone from cultured rat anterior pituitary cells and to inhibit the arginine-stimulated release of insulin and glucagon in the rat in vivo. Analogs that showed gut selectivity were then tested for their ion transport properties in the rat colon. RESULTS (a) Substitution with L-alanine or deletion of the amino acid at position 6, 7, 8, or 9 and deletion of Threonine(10)-produced analogs with significantly reduced ion transport properties to <4% of somatostatins action. The substitution also markedly reduced the ability of the compounds to inhibit the release of growth hormone, insulin, and glucagon. (b) Selectivity of intestinal ion transport was achieved by any one of the following alterations: L-alanine substitution at Phenylalanine(11), deletion of Phenylalanine(11), substitution with D-lysine at Lysine(4), or substitution with L-alanine at Lysine(4). These compounds had intestinal ion transport properties of 52, 34, 139, and 94%, respectively, while demonstrating little or no inhibition of growth hormone, insulin or glucagon release. CONCLUSIONS (a) Phenylalanine(6), Phenylalanine(7), Tryptophan(8), and Lysine(9) are required for the ion transport and other biologic actions of somatostatin, whereas Threonine(10) serves as an essential spacer. (b) Alteration at Phenylalanine(11) or Lysine(4) yields analogs that are selective for ion transport in the rabbit ileum and rat colon. These findings should be taken into consideration when developing a gut-specific somatostatin analog that can be useful in the treatment of diarrhea.

Diagnosis of Annular Pancreas with Endoscopic Retrograde Cholangiopancreatography

Two patients with annular pancreas are described. The diagnosis was established unequivocally with endoscopic retrograde cholangiopancreatography before operation. In both patients there was pancreatitis of the annular pancreas. The first patient also had congenital absence of the ventral pancreas and pancreatic insufficiency. The second patient subsequently developed gastric outlet obstruction. The literature is reviewed.

Increased risk of nephrolithiasis in patients with steatorrhea

Patients with ileal disease have increased absorption of dietary oxalate, hyperoxaluria, and an increased incidence of nephrolithiasis. Patients with steatorrhea of varying etiologies also have hyperoxaluria. To determine whether steatorrheaper se is associated with nephrolithiasis, we reviewed the charts of all adult patients who had a 72-hr fecal fat analysis from 1968 to 1978. The 159 patients with steatorrhea were compared to 162 patients without steatorrhea. The two groups were comparable in age, sex, urine specific gravity, and serum uric acid and phosphorus; serum calcium was slightly less in the steatorrhea group (8.7±0.1 vs 9.0±0.1,P<0.02). Although 19 patients with steatorrhea had nephrolithiasis compared to 7 control patients (P=0.01), 15 of these 19 patients had ileal disease and only 4 of the 118 patients with steatorrhea but without ileal disease had stones. Categorical data analysis revealed that steatorrhea, diarrhea (stool weight >225 g/day), male sex, and ileal disease were significantly associated with nephrolithiasis with a relative risk of 3.0, 2.7, 3.1, and 8.0, respectively. When patients without ileal disease were analyzed separately, however, steatorrhea, diarrhea, and sex were no longer risk factors. In contrast, in patients with ileal disease the incidence of nephrolithiasis increased with the severity of steatorrhea. The relative risk of nephrolithiasis in male patients with ileal disease and fecal fat >20 g/day was 26.3 (P<0.01). Thus, the presence of both ileal disease and steatorrhea greatly increases the risk of nephrolithiasis; however, neither steatorrhea alone nor ileal disease alone are risk factors for nephrolithiasis.

THE EFFECT OF SOMATOSTATIN AND ENKEPHALIN ON ION TRANSPORT IN THE INTESTINE

SRIF and enkephalin stimulate net Na and C1 absorption in the rabbit ileum and appear to do so primarily by stimulating the coupled influx of Na and C1 across the brush border membrane. The stimulatory effect of enkephalin on ion transport is blocked by verapamil and Ca-free solution, indirectly indicating that enkephalin may work as a Ca-channel blocker. The resultant lowering in cytosolic calcium level stimulates Na and C1 absorption. SRIF was able to block the effect of cyclic AMP-dependent and cyclic AMP-independent secretogogues in the rat colon without affecting cyclic AMP levels suggesting that it is inhibiting a distal step in the secretory pathway, probably involving a final common pathway. SRIF infusion blocked diarrhea in a patient with the carcinoid syndrome, indicating that it may be therapeutically useful in the treatment of secretory diarrheas. The antidiarrheal effect of opiates is probably due in part to their effect on electrolyte absorption, rather than an effect solely on intestinal motility.

Pharmacological Aspects of Therapy in Inflammatory Bowel Diseases: Antidiarrheal Agents

We review the use of antidiarrheal medications in inflammatory bowel disease, commenting on potential underlying immunologic mechanisms as a background for discussion of the clinical usage of antidiarrheal medications in this disease spectrum. We comment on new directions for the development of more effective therapeutic approaches and discuss the mechanism of action of antidiarrheal drugs, with emphasis on synthetic opiates.

Prevalence of Nephrolithiasis in Malabsorptive Syndromes

Patients with inflammatory bowel disease have an increased incidence of nephrolithiasis, especially after resection or bypass of part of the bowel1. Many of these stones are composed of calcium oxalate though uric acid stones appear to be more common after an ileostomy. Patients with ileal disease have increased absorption of dietary oxalate, with resultant hyperoxaluria, because of increased solubility of oxalate and increased permeability of the colon to oxalate1. Increased solubility is related to steatorrhea. Unabsorbed fatty acids bind to calcium preventing the formation of insoluble calcium oxalate, thus oxalate remains in solution available for absorption. Fatty acids (and bile acids) also increase the permeability of the colon to oxalate2.