Successful management of intractable cryptosporidial diarrhea with intravenous octreotide, a somatostatin analogue

A 38-year-old man with AIDS and intractable large-volume diarrhea due to a cryptosporidial infection was successfully treated with intravenous octreotide, a somatostatin analogue. The volume of diarrhea, 10-12 liters with 8-13 movements per day, was reduced to three to four semi-formed to formed stools per day when the patient was treated with 400 micrograms intravenous octreotide daily. The patient's intravenous hyperalimentation was discontinued and he returned to oral feeding. He quickly regained his normal weight and has now resumed his normal activities. For those patients who cannot tolerate subcutaneous administration, intravenous octreotide therapy may not only be life-saving but may also markedly increase the quality of life. Roxithromycin, a macrolide antibiotic, was also administered to this patient with cryptosporidiosis but efficacy was not demonstrated.     

The use of the long-acting somatostatin analogue, octreotide acetate, in patients with islet cell tumors

Octreotide lowers plasma concentrations of the marker peptide in the majority of patients with islet cell tumors. However, as described above the effect of octreotide on plasma concentrations of marker peptides is not necessarily related to the effect on symptoms. Nevertheless octreotide is capable of producing symptomatic relief in a large proportion of patients with islet cell tumor syndromes. The data on the effect of octreotide on the symptoms due to VIPoma and due to the carcinoid syndrome (presumably including some who have islet cell tumors) are strong and the drug has been approved for these indications by the Food and Drug Administration. With respect to the other islet cell tumor syndromes, the published data suggest that the utility of octreotide differs in the different syndromes. Insulinomas are usually single, benign, and can and should be removed surgically, resulting in cure. Octreotide therefore has no role to play in such patients, particularly since the response of insulinomas is variable. However in the 10 per cent of insulinomas that are malignant octreotide is certainly effective in at least a portion of cases, although as yet the true response rate and efficacy compared with diazoxide is not clear. Although octreotide is effective at reducing acid output, and thus improving symptoms in patients with Zollinger-Ellison syndrome, because of the effectiveness of histamine H2-receptor antagonists and omeprazole, there is no need for octreotide in this syndrome. For patients with glucagonoma, GHRHoma, Cushing's syndrome, and other rare islet cell tumor syndromes octreotide may well be of benefit and should be considered. The current data do not support the use of octreotide for an antitumor effect.     

Use of the somatostatin analogue octreotide to localise and manage somatostatin-producing tumours

^a Department of Gastroenterology, University "La Sapienza", Rome, Italy, ^b Department of Nuclear Medicine, ^c Department of Surgery, ^d Department of Pathology, University of Parma, Parma, Italy

Correspondence to: Dr G Delle Fave, Cattedra di Gastroenterologia I, Clinica Medica 2, Policlinico Umberto I°, 00161 Roma, Italy.

Accepted for publication 19 January 1998

Background—Somatostatin receptor scintigraphy (SRS) and octreotide therapy have both changed the management of gastroenteropancreatic endocrine tumours, but very few data are available on the use of SRS and octreotide to visualise and treat somatostatinomas.
Method—The results of SRS and octreotide treatment in three somatostatinoma patients were examined.
Results—SRS was able to detect extensive hepatic involvement in patient 1, one hepatic and one pancreatic lesion in patient 2, and one hepatic lesion in patient 3. Octreotide therapy (0.5 mg/day subcutaneously) was effective in decreasing plasma levels of somatostatin in all three patients. Symptoms (diabetes and diarrhoea) were greatly improved in the two patients with "somatostatinoma syndrome".
Conclusion—The study shows that somatostatinoma, like most other gastroenteropancreatic endocrine tumours, possesses functioning somatostatin receptors.
(GUT 1998;:792-794)

Keywords: somatostatin;  octreotide;  somatostatin receptor scintigraphy;  gastroenteropancreatic endocrine tumour;  somatostatinoma

     

Acute in vivo effect of octreotide acetate, a somatostatin analogue on the cellular function of gastric mucosa in the rat

Somatostatin is known to suppress various cellular functions of the gastrointestinal tract. In the present study, octreotide acetate, a synthetic long-acting somatostatin analogue was tested for its effects on some cellular functions of gastric mucosa. Octreotide raised the gastric mucosal pH within 1 h after a single subcutaneous injection to rats at doses of 1-100 microg/kg bodyweight. Serum gastrin levels increased transiently at a dose of 10 microg/kg bodyweight but not at 100 microg/kg. Basal levels of serum gastrin were not affected, while famotidine-induced gastrin secretion was suppressed by octreotide at a single dose of 100 microg/kg. The increase in the intragastric acidity and histidine decarboxylase activity following pentagastrin treatment was significantly reduced by octreotide. These results suggested that this somatostatin analogue inhibits the function of not only the parietal cell and G cell but also the enterochromaffin-like (ECL) cell, resulting in intraluminal hypoacidity.     

Treatment of gastrointestinal acute graft-versus-host disease

Opinion statement Therapy of acute graft-versus-host disease (GVHD) aims to selectively alter the grafthost interactions to foster antitumor effect and minimize antihost effects. The immunosuppression produced by the various therapies ranges from broad, nonselective effects to relatively narrow targeted impact. Despite advances in understanding the pathophysiology of GVHD, newer agents with more selective effects have not yet produced therapeutic advances. The newer targeted agents continue to produce a degree of immunosuppression in which infection and relapse of malignancy are all too common. High-dose systemic steroids remain, as they have for two decades, the initial treatment of choice. Patients failing to respond to steroids continue to represent a challenge, as no second-line therapy is clearly superior to the others. However, some of the new agents appear to be particularly effective in certain organs involved with acute GVHD. For those patients with steroid-refractory GVHD involving primarily the gut, we favor infliximab with concomitant antifungal therapy. For those with primarily skin or liver disease, we favor extracorporeal photochemotherapy.     

Single-dose response study of the somatostatin analogue octreotide in acromegaly

The recommended dosage schedules for intermittent sc therapy with the somatostatin analogue octreotide in acromegaly vary widely, from 100 to 1500 micrograms daily. As acute administration of octreotide has been shown to predict its long-term response, we performed a single-dose response study in 5 patients with active acromegaly using doses of 25, 50, 100, 200 and 400 micrograms octreotide as well as a placebo injection. Plasma GH of 2 patients did not normalize after any of the injections, but nadir plasma GH overall gradually decreased as doses were increased from 25 to 400 micrograms. The 400 micrograms octreotide dose was superior with regard to the duration of plasma GH suppression to below 5 micrograms/l or 25% of the basal GH level, the mean GH as a percentage of the basal level over the first 4 and 8 h, and the integrated reduction of plasma GH during the first 4 and 8 h. The postprandial integrated insulin secretion during the first 3 h after injection of the octapeptide was significantly lower after 50, 100 and 400 micrograms than after the placebo injection. The mean plasma glucose as a percentage of the basal level during the first 8 h was significantly higher after octreotide after the 200 and 400 micrograms injections. Minor adverse events were seen in 2 patients after injection of 200 and 400 micrograms octreotide. Within the limitations of this single-dose response study it was concluded that injection of 400 micrograms octreotide yields the best results with regard to suppression of GH secretion, whereas the 50, 100 and 200 micrograms doses are superior to 25 micrograms, but do not differ from each other.     

Role of intra-arterial steroid administration in the management of steroid-refractory acute gastrointestinal graft-versus-host disease

We report here a case of severe steroid-refractory gastrointestinal graft-versus-host disease treated with intra-arterial administration of corticosteroids. A 53-year-old female with non-Hodgkin's lymphoma received peripheral blood hematopoietic stem cell transplant from her HLA-matched sibling. She developed grade II skin and grade IV gastrointestinal graft-versus-host disease with no hepatic involvement. Therapy with oral prednisone easily controlled her skin rash but she had profuse diarrhea that did not respond to high dose intravenous corticosteroids and denileukin diftitox. Infusion of methyl-prednisolone into superior and inferior mesenteric arteries produced dramatic improvement of diarrhea, with complete resolution of gastrointestinal graft-versus-host disease.     

Characteristics of acromegalic patients with a good response to octreotide, a somatostatin analogue

BACKGROUND AND OBJECTIVES In GH-secreting pituitary tumours somatostatin receptor density has been correlated with octreotide responsiveness. Little is known about the other endocrine characteristics of patients with good responses to octreotide. The purpose of this study was to determine the characteristics of these patients. PATIENTS We studied 30 patients with active acromegaly. Five had been treated with either transsphenoidal adenomectomy or conventional radiotherapy without cure of GH excess. DESIGN Patients were divided into good or poor octreotide responders. Patients whose GH level decreased to less than 20% of basal and below 20 mU/l after a subcutaneous injection of 100 μg of octreotide were defined as good octreotide responders. We compared tumour size, basal GH secretory pattern, responses to TRH, GnRH and bromocriptine, and mutation of the α-subunit of stimulatory GTP-binding protein (Gα) between the two groups. MEASUREMENT Tumour size was determined by CT or MRI. Basal GH level was measured hourly between 0800 and 1600 h. GH responses to TRH and GnRH were measured every 30 minutes for 2 hours, and the GH response to oral bromocriptine was measured hourly for 6 hours. The mutation of Gα gene between codons 184 and 251 was examined by direct sequencing using PCR in 5 patients of each group whose tumour tissues were available for the genomic DNA extraction. RESULTS Seventeen patients (57%) were good octreotide responders (group I) and 13 (43%) were poor responders (group II). The mean age, sex, tumour size, tumour grade and the basal OH secretory pattern were not significantly different between the two groups. Group I responded more frequently than group II to TRH (65 vs 25%). Fifty-three per cent of group I patients and none of group II were good bromocriptine responders. Forty-one per cent of group I patients responded to both TRH and bromocriptine. Three of 5 group I tumours had point mutations at codon 201 of the Gα, gene, none of 5 group II tumours had mutations. CGT(Arg) was replaced with TGT(Cys) in two tumours and with AGT(Ser) in one. No mutations were found at codon 227. All three tumours with mutations were from patients responsive to TRH. Two of the three were also good bromocriptine responders. CONCLUSIONS These data Suggest that good octreotide responders are more likely to respond to TRH or bromocriptine. Good octreotide responders may include subgroups with different levels of TRH and dopamine receptor expression. A possible relation between octreotide response and the mutation of Gα gene should be investigated.     

Effective treatment of diabetic diarrhoea with somatostatin analogue, octreotide.

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.     

Treatment of severe orthostatic hypotension with the somatostatin analogue octreotide

The long-acting somatostatin analogue octreotide was used in a patient with severe orthostatic hypotension resistant to conventional treatment. 0.4 ug/kg octreotide given subcutaneously abolished the postural drop in systolic blood pressure for about four hours and was more effective than a combination of fludrocortisone and pindolol.     

Reversible shrinkage of a growth hormone-secreting pituitary adenoma by a long-acting somatostatin analogue, octreotide

Octreotide acetate (SMS-201-995), a somatostatin analogue, was used to treat an acromegalic patient harboring a growth hormone-secreting pituitary macroadenoma. Intermittent subcutaneous administration of octreotide suppressed growth hormone and insulin-like growth factor-I (IGF-I) levels and ameliorated clinical symptoms. Magnetic resonance imaging performed after 16 weeks revealed a 70% shrinkage of the pituitary mass, with a resultant partially empty sella turcica. To document that this shrinkage occurred as a result of octreotide treatment and not spontaneous tumor infarction, the medication was withdrawn for 4 weeks. A second magnetic resonance image disclosed regrowth of the tumor accompanied by rebound of growth hormone and IGF-I secretion. Subsequent biochemical remission has been sustained with preservation of anterior pituitary function since the drug was reinitiated. These findings suggest that intermittent subcutaneous administration of octreotide may provide potent medical ablation of growth hormone-secreting macroadenomas.     

No effect of the long-acting somatostatin analogue octreotide in patients with insulinoma

The efficacy of subchronic (3 weeks) treatment with the long-acting somatostatin analogue octreotide was studied in four patients with symptomatic benign insulinoma. No clinical or biochemical effect on serum glucose, insulin, C-peptide or glucagon was observed in all four patients despite clearly detectable serum levels of octreotide. The resistance to octreotide therapy in these patients might be explained by the absence of somatostatin analogue receptors on their tumours.     

Impact of octreotide, a long-acting somatostatin analogue, on glucose tolerance and insulin sensitivity in acromegaly

OBJECTIVE: We aimed to investigate the impact of a long-acting somatostatin analogue, octreotide, on glucose tolerance and on insulin sensitivity in acromegaly. DESIGN: We performed a non-randomized controlled trial. PATIENTS: Seven patients with active acromegaly were assessed before and during octreotide therapy given in a dose of 500 micrograms three times daily subcutaneously. MEASUREMENTS: The effects of octreotide on carbohydrate metabolism were assessed by performing a glucose tolerance test and a euglycaemic hyperinsulinaemic clamp. These latter tests were undertaken 8 hours after the last dose, allowing GH and glucagon to return to pretreatment levels during the study. RESULTS: Octreotide significantly reduced (P less than 0.05) mean +/- SEM 12-h GH (from 42 +/- 13 to 10 +/- 3 mIU/I) and IGF-I (from 4.2 +/- 0.5 to 2.1 +/- 0.5 U/ml) concentrations. Glucose tolerance was normalized in four of five patients with impaired glucose tolerance without a significant change in mean insulin concentrations. The improvement in fasting and mean blood glucose during glucose tolerance testing was dependent on the pretherapy blood glucose concentrations (r = -0.95, P = 0.002). The glucose infusion rate during the hyperinsulinaemic (5 U/h) clamp was significantly increased (P less than 0.05, 15.3 +/- 1.8 vs 24.2 +/- 5.4 mumol/kg min) following octreotide treatment. Insulin infusion during the glucose clamp completely suppressed hepatic glucose production during but not before octreotide treatment (7.9 +/- 2.4 vs 0.7 +/- 2.2 mumol/kg min, P = 0.02). Insulin-mediated stimulation of peripheral glucose uptake was unaffected by treatment. Mean GH and glucagon levels during both clamp studies were not significantly different. CONCLUSIONS: Octreotide improves whole body insulin sensitivity by an increased ability of insulin to suppress hepatic glucose production without affecting the substantial impairment of peripheral insulin action. Octreotide has beneficial effects on carbohydrate metabolism in acromegalic patients with glucose intolerance.     

Does the somatostatin analogue octreotide protect against ERCP induced pancreatitis?

This study evaluates the effect of the long acting somatostatin analogue octreotide on biochemical and clinical parameters of endoscopic retrograde cholangiopancreatography (ERCP) induced pancreatitis. Altogether 245 patients were randomised to receive either octreotide or isotonic saline. Octreotide (100 micrograms) was administered intravenously five minutes before ERCP and subcutaneously 45 minutes after ERCP. There were no significant differences in the median serum amylase and lipase activities at baseline, eight, and 24 hours after ERCP. Five patients (2%) developed clinical pancreatitis--three in the octreotide and two in the placebo groups. Excluding patients who developed pancreatitis, 43 (18%) developed abdominal pain after ERCP--21 in the octreotide and 23 in the placebo groups. There were no significant differences in the median serum amylase and lipase values between the treatment groups. None of the 52 patients who had therapeutic interventions developed pancreatitis. This study suggests that octreotide may not protect against ERCP induced pancreatitis.     

Effect of octreotide, a long-acting somatostatin analogue, on plasma amino acid uptake by the pancreas.

Octreotide (SMS 201-995) is a long-acting somatostatin analogue that inhibits exocrine pancreatic secretion and that has been proposed for treatment of various pancreatic disorders. To gain more information about the mechanism by which octreotide inhibits pancreatic enzyme secretion, we studied the effect of this compound on plasma amino acid uptake by the pancreas in six healthy volunteers aged 22-29 years. Pancreatic amino acid uptake was assessed by measuring plasma amino acid concentration before and during pancreatic enzyme synthesis stimulation with cerulein (50 ng/kg/h). The infusion of cerulein caused a significant decrease (p less than 0.001) in plasma amino acid concentration. The subcutaneous injection of octreotide at dosages of 12.5, 25, and 50 micrograms prevented this decrease in a dose-dependent manner. The decrease in amino acid concentration reached a maximum of 19.4 +/- 2.4% during cerulein infusion and a maximum of 10.7 +/- 2.5, 6.8 +/- 1.2, and 2.9 +/- 1.2% (means +/- SD) when cerulein was preceded by injection of octreotide at 12.5, 25, and 50 mg, respectively. These results indicate that octreotide is able to inhibit the plasma amino acid uptake by pancreatic acinar cells and, consequently, synthesis of pancreatic enzymes. Clinically, this effect could be useful in treatment of pathologic conditions of the pancreas in which it is desirable to suppress acinar cell activity and avoid accumulation of enzymes in acinar cells.     

Diagnosis and management of acute graft-versus-host disease

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of acute graft-versus-host disease. This guideline includes recommendations for the diagnosis and grading of acute graft-versus-host disease as well as primary treatment and options for patients with steroid-refractory disease. The goal of treatment should be effective control of graft-versus-host disease while minimizing risk of toxicity and relapse.