In 2016, ESPEN published the guideline for Chronic Intestinal Failure (CIF) in adults. An updated version of ESPEN guidelines on CIF due to benign disease in adults was devised in order to incorporate new evidence since the publication of the previous ESPEN guidelines.

The grading system of the Scottish Intercollegiate Guidelines Network (SIGN) was used to grade the literature. Recommendations were graded according to the levels of evidence available as A (strong), B (conditional), 0 (weak) and Good practice points (GPP). The recommendations of the 2016 guideline (graded using the GRADE system) which were still valid, because no studies supporting an update were retrieved, were reworded and re-graded accordingly.

The recommendations of the 2016 guideline were reviewed, particularly focusing on definitions, and new chapters were included to devise recommendations on IF centers, chronic enterocutaneous fistulas, costs of IF, caring for CIF patients during pregnancy, transition of patients from pediatric to adult centers. The new guideline consist of 149 recommendations and 16 statements which were voted for consensus by ESPEN members, online in July 2022 and at conference during the annual Congress in September 2022. The Grade of recommendation is GPP for 96 (64.4%) of the recommendations, 0 for 29 (19.5%), B for 19 (12.7%), and A for only five (3.4%). The grade of consensus is "strong consensus" for 148 (99.3%) and "consensus" for one (0.7%) recommendation. The grade of consensus for the statements is "strong consensus" for 14 (87.5%) and "consensus" for two (12.5%).

It is confirmed that CIF management requires complex technologies, multidisciplinary and multiprofessional activity, and expertise to care for the underlying gastrointestinal disease and to provide HPN support. Most of the recommendations were graded as GPP, but almost all received a strong consensus.

A high-output stoma (HOS) or fistula is when small bowel output causes water, sodium and often magnesium depletion. This tends to occur when the output is >1.5 -2.0 L/24 hours though varies according to the amount of food/drink taken orally. An HOS occurs in up to 31% of small bowel stomas. A high-output enterocutaneous fistula may, if from the proximal small bowel, behave in the same way and its fluid management will be the same as for an HOS. The clinical assessment consists of excluding causes other than a short bowel and treating them (especially partial or intermittent obstruction). A contrast follow through study gives an approximate measurement of residual small intestinal length (if not known from surgery) and may show the quality of the remaining small bowel. If HOS is due to a short bowel, the first step is to rehydrate the patient so stopping severe thirst. When thirst has resolved and renal function returned to normal, oral hypotonic fluid is restricted and a glucose-saline solution is sipped. Medication to slow transit (loperamide often in high dose) or to reduce secretions (omeprazole for gastric acid) may be helpful. Subcutaneous fluid (usually saline with added magnesium) may be given before intravenous fluids though can take 10-12 hours to infuse. Generally parenteral support is needed when less than 100 cm of functioning jejunum remains. If there is defunctioned bowel in situ, consideration should be given to bringing it back into continuity.

The ability to provide parenteral support represents a revolutionary change in medical therapy for patients with temporary and inadequate intestinal absorptive capacity or for patients with chronic intestinal failure due to digestive diseases. Nevertheless, due to the rarity of intestinal failure, a de facto policy of "discrimination by organ failure treatment" exists in many countries whereby this problem is under-recognized and under-treated. With the increasing recognition of the pathophysiological consequences of intestinal resection and the occurrence of new pro-adaptive treatments for patients suffering from short bowel syndrome, this review reflects on the history of developments in this area and discusses current practice and future directions of the field.

The use of somatostatin to manage diarrhea associated with the short gut syndrome is impractical because of its need to be given by continuous infusion and a rebound effect on stool output with cessation of therapy. Octreotide has been used more successfully to control stool and electrolyte losses in patients with shortened gastrointestinal tracts. In published series and studies, all subjects appear to decrease stool losses, but clinical benefit for long-term use is not achieved for all patients. In the patients who do respond, the need for parenteral nutrition and intravenous hydration has been decreased or eliminated. The optimal dose is unclear, but many patients respond to 50-micrograms injections twice daily. Several investigations noted no additional beneficial effects with escalating dosages. Adverse effects include impairment of fat absorption, which may offset the therapeutic benefits of octreotide. The patients with the greatest response appear to have the least fat malabsorption. Other adverse effects noted when using octreotide for control of the short gut syndrome include pain associated with subcutaneous injection and abdominal complaints. Other potential concerns include the effect on gallstone formation in this high-risk population and intestinal adaptation.

Chronic Intestinal Failure (CIF) is the long-lasting reduction of gut function, below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth. CIF is the rarest organ failure. Home parenteral nutrition (HPN) is the primary treatment for CIF. No guidelines (GLs) have been developed that address the global management of CIF. These GLs have been devised to generate comprehensive recommendations for safe and effective management of adult patients with CIF.

The GLs were developed by the Home Artificial Nutrition & Chronic Intestinal Failure Special Interest Group of ESPEN. The GRADE system was used for assigning strength of evidence. Recommendations were discussed, submitted to Delphi rounds, and accepted in an online survey of ESPEN members.

The following topics were addressed: management of HPN; parenteral nutrition formulation; intestinal rehabilitation, medical therapies, and non-transplant surgery, for short bowel syndrome, chronic intestinal pseudo-obstruction, and radiation enteritis; intestinal transplantation; prevention/treatment of CVC-related infection, CVC-related occlusion/thrombosis; intestinal failure-associated liver disease, gallbladder sludge and stones, renal failure and metabolic bone disease. Literature search provided 623 full papers. Only 12% were controlled studies or meta-analyses. A total of 112 recommendations are given: grade of evidence, very low for 51%, low for 39%, moderate for 8%, and high for 2%; strength of recommendation: strong for 63%, weak for 37%.

CIF management requires complex technologies, multidisciplinary and multiprofessional activity, and expertise to care for both the underlying gastrointestinal disease and to provide HPN support. The rarity of the condition impairs the development of RCTs. As a consequence, most of the recommendations have a low or very low grade of evidence. However, two-thirds of the recommendations are considered strong. Specialized management and organization underpin these recommendations.

Short bowel syndrome (SBS) is the most common cause of intestinal failure in children. It is defined as the inability to maintain adequate nutrition enterally as a result of a major loss of the small intestine. SBS is a life-threatening entity associated with potential significant morbidity and mortality. The etiology in the pediatric age group includes necrotizing enterocolitis (32%), atresia (20%), volvulus (18%), gastroschisis (17%), and aganglionosis (6%). It is characterized by substrate malabsorption, electrolyte imbalance, intestinal bacterial overgrowth, steatorrhea, and weight loss. Current medical management includes parenteral nutrition, progressive feeds as tolerated, various medications, and surgical manipulations. However, frequently this management is not successful in achieving the goal of attaining normal growth and development without parenteral nutrition. It has been known for decades that there is a normal physiologic response of the residual intestine to massive bowel resection referred to as intestinal adaptation. The mechanisms that control this process are unknown. Unfortunately, intestinal adaptation and the current management are not always successful. As a result of new knowledge regarding the pathophysiology of SBS over the past two decades, several novel strategies have been developed in experimental animal models as well as limited clinical trials in infants and children. They can be divided into several categories that potentially influence intestinal (1) absorption, (2) secretion, (3) motility, and (4) adaptation. More recently, newer modalities have been studied including small intestine transplantation, and the use of specific intestinal growth factors. Ultimately, tissue and organ engineering will become the treatment for infants and children with SBS.

To evaluate the efficacy of octreotide in the treatment of chemoradiotherapy (CRT)-induced diarrhea (CRTID) refractory to conventional loperamide treatment in this pilot study.

Forty-two rectal carcinoma (T(3-4)N(0-2)M(0)) patients with grade 2 or 3 diarrhea refractory to loperamide were enrolled to receive octreotide. Eligible patients were treated with pelvic radiotherapy combined with bolus 5- fluorouracil CRT. Octreotide was administered subcutaneously, 150 microg three times daily, for 5 consecutive days. Only complete resolution of diarrhea was considered as therapeutic success.

Diarrhea mainly occurred in the first 4 weeks of CRT (83.3%) and completely resolved in 34 patients (80.9%) following octreotide administration. Mean time to response was 2.7 days: 27 patients (64%) responded during the first 3 days, and the remaining 7 (17%) on days 4 and 5. No significant side effect was reported. Eight patients (19.1%) with refractory diarrhea were hospitalized for additional treatment. No treatment delay was reported in complete responders, whereas an average 7.7-day delay was observed in refractory patients. Antidiarrheal treatment was administered on an outpatient basis in the response group, whereas refractory patients were hospitalized for an average of 8.8 days.

Daily subcutaneous octreotide administration (150 microg t.i.d.) for 5 days is apparently an effective, tolerable treatment modality for concurrent CRTID refractory to loperamide.

Short bowel syndrome is a chronic malabsorptive state usually resulting from extensive small bowel resections. A combination of diarrhea, nutrient malabsorption, dysmotility, and bowel dilatation may constitute the clinical symptomatology of this syndrome. The remaining bowel undergoes a process called adaptation, which may replace lost intestinal function. Chronic complications include nutrient, electrolyte, and vitamin deficiencies. Therapy depends largely on the administration of various factors stimulating intestinal adaptation of the remaining bowel. If the patient despite medical therapy fails to return to oral diet alone, then long-term parenteral nutrition is required. However, long-term parenteral nutrition may gradually induce cholestatic liver disease. Surgical methods may be required for treatment including intestinal transplantation, as a last resort for the treatment of end-stage intestinal failure. The goal of this review is to analyze the clinical spectrum and pathophysiologic aspects of the syndrome, the process of intestinal adaptation, and to outline the medical and surgical methods currently used to treat this complicated group of patients.

Somatostatin and octreotide have multiple effects which make them ideal for treating diarrhoea of different aetiologies. Their use in a variety of conditions with refractory diarrhoea, however, is based on a limited number of studies.

We undertook a systematic review of the available English literature to maximize an evidence-based approach to the treatment of refractory diarrhoea. We tested the hypothesis that efficacy is independent of aetiology.

A Medline and individual article search from 1965 to 2000 was undertaken on the use of somatostatin and octreotide in diarrhoea. All reports containing at least five subjects were included. The percentage response in case series and randomized controlled trials was compared, and a meta-analysis of randomized controlled trials where patient level data were provided was carried out. There were 30 publications found (18 case series, 12 randomized controlled trials). The response percentage was 73% overall in case series and 64% in randomized controlled trials (not significant). A meta-analysis of nine randomized controlled trials revealed significant heterogeneity despite an overall relative risk of 0.5 (95% confidence interval, 0.27-0.91). Subgroup analysis of the largest aetiological groups showed that acquired immunodeficiency syndrome studies were homogeneous, but somatostatin and octreotide were less effective. Post-chemotherapy studies remained heterogeneous and somatostatin and octreotide were highly effective.

While this review strengthens the consensus guidelines on the use of somatostatin and octreotide for refractory diarrhoea, evidence-based support requires additional studies.

A review of the pharmacologic substances and growth factors that have been studied experimentally and administered clinically for the management of short bowel syndrome is presented. The medical management of short bowel syndrome is multifaceted. In the acute phase, efforts focus on fluid and electrolyte management and the reduction of gastric acid output. As enteral feeding is initiated, antimotility and antisecretory agents may be effective in reducing gastrointestinal losses. Additional modalities of management, including nutrients and growth factors, may be directed at maximizing absorptive function beyond that which occurs with intestinal adaptation. Continued research aimed at further elucidating the process of intestinal adaptation may allow us to use the various peptides and hormones that act as growth factors for the bowel mucosa. Knowledge gained from these studies combined with gene therapy techniques will result in the permanent enhancement of intestinal function beyond the normal adaptation process, eliminate the dependence on total parenteral nutrition, and avoid the need for intestine transplantation.

Octreotide, an analogue of somatostatin with a more favorable pharmacokinetic profile, is a new drug that may offer some advantages in the palliative care setting. It has been used with favorable results in the management of some gastrointestinal disorders, such as gastrointestinal hemorrhage, diarrhea, short-bowel syndrome, fistula, and intestinal occlusion in the palliative care setting. These favorable results occurred without important side effects, underlining the potential role of this drug. The cost-benefit ratio of this expensive drug must be considered, however.

This chapter reviews the therapeutic use of octreotide in a variety of pancreatic disorders, including acute pancreatitis, in the prevention of postoperative and post-ERCP pancreatitis, in the control of postoperative pancreatic fistulae, and in chronic pancreatitis for the control of pain and of pseudocysts and ascites. The review also discusses the use of octreotide in intestinal disorders of motility, gastrointestinal bleeding, intestinal fistulae and refractory diarrhoea, including the diarrhoeas of AIDS, diabetes, short gut, chemotherapy, ileostomy and gastric surgery. The use of octreotide in neuroendocrine tumours, both for therapy and diagnostic imaging, is reviewed briefly. The paucity of adequately controlled studies in many of these situations is indicated and the potential usefulness of octreotide estimated.

The management of short bowel syndrome requires long-term nutritional support and monitoring, medication, and occasionally additional surgical procedures. Constant attention is required to ensure adequate adaptation of the gut. This article reviews the normal function of the small bowel, adaptation following resection, total parenteral and enteral nutrition, and the role of adjunctive surgical procedures in the management of short bowel syndrome.

The effect of octreotide, a synthetic analogue of somatostatin, on the modulation of the acetic acid model of experimental colitis was examined. Colitis was induced by intracolonic administration of 2 ml of 5% acetic acid. The inflammatory response elicited by the acetic acid resulted in increased colonic synthesis of platelet activating factor, leukotriene B4 and decreased mucosal somatostatin levels. Subcutaneous administration of octreotide (10 micrograms/rat) 1 hour before or immediately after damage induction, as well as 1 and 23 hours after acetic acid application, resulted in a significant reduction in mucosal damage. The protective effect was accompanied by a significant reduction in platelet activating factor activity, leukotriene B4, and vasoactive intestinal peptide concentrations. There were no significant changes in mucosal leukotriene C4 and calcitonin gene related peptide levels. This study shows that acetic acid induced colitis is pharmacologically manipulated by octreotide. The mechanism of action of octreotide has not yet been fully determined. The potential use of octreotide in treating active inflammatory bowel disease remains to be evaluated.

A 22 year old insulin dependent diabetic with high volume, secretory chronic diarrhoea refractory to standard andiarrhoeal drugs was treated with the somatostatin analogue octreotide, 50 micrograms twice daily by subcutaneous injection. She improved markedly with a decrease in mean stool weight from 1170 g/24 h range 440-2900 g) to 440 g/24 h (range 180-800 g) (p < 0.05). Stool frequency also decreased from six (range two to 12) to one (range one to three) bowel movements per day (p < 0.01). Mouth to caecum transit time increased from 45 minutes to > 210 minutes, although total gut transit time was unchanged and remained rapid at nine hours. Thus octreotide can reduce stool volume and frequency in high volume diabetic diarrhoea when conventional antidiarrhoeal agents have failed. Its therapeutic benefit appeared to be predominantly related to a marked increase in mouth to caecum transit time.

Investigators are now predicting that nearly 100% of the estimated 12 million HIV-positive persons in the world will develop AIDS. Most persons with AIDS will experience progressive weight loss and malnutrition prior to death. Because nutritional therapy clearly has a beneficial effect on the clinical course and immunologic status of the critically ill general population, one must not disregard its potential for benefits in the treatment of persons with AIDS. As a result of the escalating cost of medical therapy and the inevitable AIDS epidemic, the nutritional management of persons with AIDS must be simple to administer and cost effective. The author has developed nutritional screening criteria to identify those patients who would most benefit from nutritional therapy. Because these patients differ in their nutritional requirements, diet tolerance, and degree of gut dysfunction, there is no single nutritional therapy that can be used routinely to treat all malnourished persons with AIDS.

Advances in long-term venous access devices and in parenteral nutrition solutions have made it possible for patients with severe short bowel syndrome to survive and to live in our society. The spectrum of this disease is such that some patients may be able to lessen their dependence or even become free from parenteral therapy. This review will discuss the role of nutrition support in the patient with short bowel syndrome.

Post-resectional hyperplasia is the phenomenon in which residual small bowel increases in size and absorptive capacity after segmental enterectomy. This experiment studied the effect of somatostatin analogue therapy on the development of two structural parameters of post-resectional hyperplasia in rats subjected to 40% proximal small bowel resection. Octreotide acetate-treated rats failed to develop increased villus height (902 +/- 50 microns) relative to saline-treated rats (1,103 +/- 98 microns). Augmentation of residual intestinal weight was also significantly impaired in analogue-treated rats (92 +/- 3 versus 118 +/- 5 mg/cm). We conclude that somatostatin analogue treatment during the early postoperative period does impair the growth of residual bowel in rats. These findings raise concern regarding the use of this drug for postoperative patients who have undergone massive small bowel resection in whom the process of post-resectional adaptation may be critical to allow sustenance with enteral nutrition.

The effect of a long acting somatostatin analogue SMS 201-995 on stomal effluents in patients with severe short bowel syndrome was investigated in a double blind placebo controlled balance study. Six patients, five with Crohn's disease and one with radiation enteropathy were studied. Five patients had a jejunostomy and one an ileostomy. The patients had a normal food intake, but because of severe malabsorption had received home parenteral nutrition for several years. Faecal mass was reduced (p less than 0.005) and intestinal net sodium absorption was increased (p less than 0.005) by intravenous infusion of SMS 25 micrograms/h. Net absorption of potassium, calcium, magnesium phosphate, zinc, nitrogen and fat was not influenced. Subcutaneous injections of 50 micrograms SMS every 12 hours had a similar effect on net intestinal absorption of sodium and water. Four patients continued with a five to six months open follow up study when subcutaneous SMS in the same dose was administered by the patients at home. The effect on faecal sodium loss persisted, but in one patient faecal mass gradually increased and finally exceeded pretreatment values. SMS may decrease net absorption of water and sodium following reduced secretion of digestive juices rather than by increasing absorptive capacity. SMS may be useful as an antidiarrhoeal drug in patients with high output jejuno- or ileostomies, but in patients who need permanent parenteral nutrition the effect is too small to significantly alter management.

Four agents, which could delay intestinal transit, were tested in six short-bowel patients (jejunal length 30-120 cm) on long-term nutritional/electrolyte replacement therapy. Intestinal transit time of a liquid test meal and nutrient, water and sodium absorption were measured during a control study and with each test agent on separate days. Soy polysaccharide tended to increase transit time, but decreased the absorption of water, sodium and nutrients. Codeine phosphate and loperamide caused inconsistent and clinically unimportant changes. Octreotide, a long-acting analogue of somatostatin, delayed transit and increased water, sodium and calorie absorption from the meal. Octreotide appears to have the potential to reduce the need for electrolyte and nutritional supplements in patients with the short-bowel syndrome.

Cryptosporidiosis commonly causes severe diarrhea in immunosuppressed patients. There currently are no antiparasitic drugs consistently effective for this infection. This case describes a 26-year-old hemophiliac patient with acquired immunodeficiency syndrome and cryptosporidiosis whose diarrhea improved with continuous intravenous administration of a long-acting somatostatin analog, octreotide. Somatostatin has a variety of inhibitory effects on gastrointestinal hormones as well as a possible nonspecific effect on gastrointestinal mucosal fluid and electrolyte secretion. The somatostatin analog should be considered for patients with secretory diarrhea refractory to other forms of therapy.

This article is aimed at reviewing and analyzing studies that are related to the possible therapeutic use of a potent and ubiquitously-distributed hormone--somato-statin (SS-14), and its analogues. Administration of these substances has provided beneficial effects in treating acromegaly, gastro-intestinal hemorrhagic and hypersecretory disorders, acute pancreatitis, diabetes mellitus, and certain types of cancer. Further studies with SS-14-analogues might provide new therapies for treating certain life-threatening disorders of man.

Successful treatment of severe diarrhea has traditionally relied upon opiates or opiate derivatives. Recent advances in our understanding of intestinal fluid and electrolyte absorption have provided the opportunity to develop therapeutic agents specific for various points in the secretory and absorptive process. Present and proposed antidiarrheal agents, in addition to antimotility activity, will be capable of stimulating intestinal fluid absorption, inhibiting intestinal fluid secretion, or both. The mechanism(s) of action and clinical implications for proposed antidiarrheal agents are reviewed.

SMS 201-995 (Sandostatin) was studied using low doses (50 to 100 micrograms) administered subcutaneously every 12 hours. A single 50-micrograms dose of SMS 201-995 effectively controlled gastric acid and blood gastrin levels for 12 hours in three patients with benign gastrinomas and was useful in their perioperative management. Higher doses of the agent (500 to 800 micrograms per day) had no effect on metastases in one of two patients with metastatic gastrinoma. In the other patient, one tumor shrank but the other continued to grow after three months of treatment while serum gastrin levels did not change. Cultured metastatic tumor tissue from this patient released different forms of gastrin; growth rates varied, independent of uptake of SMS 201-995, and gastrin release increased. A neonate with nesidioblastosis maintained normal blood glucose levels while receiving SMS 201-995 therapy following a 95 percent pancreatic resection. In two elderly patients with organic hypoglycemia--one with a single benign adenoma and one with multiple adenomatosis--the somatostatin analogue did not prolong the hypoglycemia-free interval. In nine patients with carcinoid syndrome, flushing was uniformly controlled with 50 micrograms of SMS 201-995 administered every eight to 12 hours. One of the nine required exocrine pancreatic replacement. After six months of treatment, three of the nine had no change in tumor size and one had remission of symptoms and stopped treatment. In two patients with vipoma, SMS 201-995 controlled diarrhea and reduced levels of vasoactive intestinal peptide; tumor necrosis occurred in one patient. In a patient with diabetic diarrhea unresponsive to all treatments, SMS 201-995 therapy controlled the diarrhea but did not interfere with control of the diabetes.

Somatostatin is present throughout the intestine, both in D cells at the luminal surface and in neural elements. It inhibits the release or action of many gut hormones known to regulate gastro-intestinal function and undoubtedly has a wide range of actions. In the intestine, available information indicates that somatostatin may have an important regulatory role for water and electrolyte absorption and secretion. The peptide affects both the epithelial transport function and the intestinal motility function. The outcome associated with administration of somatostatin is inhibition of water and electrolyte secretion. Somatostatin has been shown to effectively reduce stool output in diarrheal syndromes associated with endocrine tumor and other conditions. Clinical application of somatostatin in diarrhea still awaits development of an orally active and/or gut-specific analog. Some preliminary results indicate that this may be possible in the future.

Based upon the clinical finding that a Merck somatostatin-14 (S-14) analog induced steatorrhea in man, we sought to develop animal models to study the effects of S-14 and a series of synthetic analogs on absorption. Rats were trained to eat a diet (preweighed) containing 15% fat. Following the feeding period, the remaining diet was removed and the amount consumed recorded. This food conditioning of the rats was continued until the rats consumed approximately 15 g of the diet per day. Feces were collected and weighed prior to feeding periods. On test days, S-14 or analogs were administered sc to rats immediately prior to feeding. For each compound tested, fat absorption decreased in dose-dependent fashion. For example, S-14 at 0.5 mg/kg did not increase % of dietary fat in feces (% DFF). At 1.0 mg/kg, S-14 increased % DFF from 7.9 to 10.2 (p less than 0.01, pretest day vs test day), and at 10 mg/kg S-14, % DFF increased from 9.1 to 12.8 (p less than 0.001). For each analog, the subcutaneous dose required to decrease fat absorption in rats was several orders of magnitude higher than the intravenous dose required to inhibit insulin and glucagon. Moreover, the threshold for production of statistically significant increases in fecal fat differed among analogs when compared to their endocrine potencies. One analog administered in the model for 14 days was shown to produce consistent fat malabsorption throughout the entire test period; however, this lipid malabsorption was substantially more pronounced on the first three days of the treatment period. When the compound was not administered on day 15, the % DFF significantly decreased. In an attempt to develop a system more suitable for rapid screening, pancreatic secretagogues such as secretin or cholecystokinin, were administered intravenously to anesthetized rats whose duodena had been cannulated and perfused to enable collection of pancreatic secretions. Total amylase, lipase, and protein were determined in single animals in response to a secretagogue, both before and after iv pretreatment by S-14 or an analog. Pancreatic enzyme secretion in response to sequential secretagogue-stimulation was found to be reproducible for up to three injections and behaved in a dose-dependent fashion. In general, secretagogue-induced increases in amylase, lipase, and total protein were comparable. Pretreatment with the S-14 analogs substantially inhibited secretagogue-induced pancreatic exocrine secretion and was dose-dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

A woman presented with persistent ileostomy diarrhoea unresponsive to conventional drug treatment and necessitating parenteral nutrition. Output was four to six litres of watery fluid per 24 hours while she was receiving oral nutrition and two to three litres when she was starved. Treatment with a long acting analogue of somatostatin (50 micrograms subcutaneously every 12 hours) reduced the ileostomy output to 2.0-2.5 litres/24 hours with an oral diet and the effluent became semiformed. Parenteral fluids could be stopped. Somatostatin may have a role in the treatment of secretory diarrhoea, but prospective controlled trials are necessary.

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.

(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 somatostatin's 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.

(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.