Future

Medical

Prospects

for Sandostatin

Alan G. Harris Because of its widespread distribution within the nervous system and gastroenteropancreatic(GEP) system, and its diverse physiologicalinhibitory actions on various gastrointestinalfunctions, including endocrine and exoerine secretion, motility. liver, and splanchnicbkxx! flow and absorptkm,native somatostatinhas been viewed as a possibletherapy for many diseases.However. its short duration of action and consequent limited clinical usefulness have been overcome with the availabilityof Sandostatin” (octreotide, Sandoz Ltd), a long-acting, synthetic octapeptide analog of the naturally occurring hormone. Sandostatin represents a significantadvance in the treatment of growth hormone (GH) and thyrotmpin (TSH)-secretingpituitarytumors and GEP endocrine tumors (carcinoidtumor, VIPoma, glucagonoma, insulinoma, and gastrinoma). Preclinicalin vitro and animal studies have shown the antineoplastic activity of the compound. Moreover, because of a possible direct effect on somatostatin receptor-positive endocrinetumor cellsand an indirectaffectwhereby Sandostatinlowers GH, insulin-likegmwth factortype 1 (IO&l), and numemus gastrointestinalpeptides, Sandostatinmay pmve useful as an adjunctivetherapy in cancer patients. In vivo labelingof somatostatin receptor-positivetumors with radiolabeledsomatostatin analogs now allows localizationof such tumors and their metastases. In addition, targeted i~adia~n of these tumors by @ pa~cle-em~ing isotopes attached to such somatostatin analogs may become possible. The use of Sandostatin in acute esophageal variceal bleeding, pancreatic pseudocysts. gastrointestinal,and pancreatic external fistulae. short bowel syndrome, dumping syndrome and acquired immunodeficiency syndrome (AIDS)-related refractory hypersecretorydiarrheahas providedencouragingresults.Preliminaryreportsindicateefficacyof Sandostatinin psoriasis,autonomic neuropathy (postprandial and orthostatic hypotension), and its ability to reduce height velocity in tall adolescents. The ultimate roleof Sandostatinas a therapeuticagent in these disordersis being exploredin prospective, clinicaltrials.Other potentialapplications include control of pain, headache, rheumatoid arthritis, and diabetic microangiopathy (retinopathy, nephropathy, neumpathy), as well as prevention of postoperative pancreatic complications (fistulae, pancreatitis,abscess). 0 1990 by W.3. S%un&rs Company.

S

OMATOSTATIN has a wide distribution within the nervous system and gastroenteropancreatic (GEP) system and many physiological and pharmacological actions. It has thus been considered as a possible treatment for a number of diseases. Its properties include inhibition of gastrointestinal endocrine and exocrine secretion and motility, as well as hepatic and splanchnic blood flow. Unfo~unately, the usefulness of somatostatin is limited by a short duration of action and a lack of selectivity. These problems have been addressed by the development of Sandostatin@ (octreotide, SMS 20 l995), which has a longer duration of action and is more selective in reducing growth hormone (GH) secretion than insulin or glucagon.‘,2 In addition, Sandostatin is more potent than the native hormone in inhibiting GH secretion. The introduction of Sandostatin is a major therapeutic advance in the management of GEP endocrine tumors and acromegaly and is now approved for the treatment of these disorders in a number ofcountries. in addition, ongoing clinical research in some 30 countries is providing a large database of literature on other indications for the drug. Having been involved in the international clinical development of Sandostatin during the past 5 years, I would like to highlight some of my projections for its future therapeutic applications. This review cannot be totaliy exhaustive, as the findings of many inves-

From the Department of Neuroendocrinology, Clinical Research, SANDOZ Pharma Ltd. Basle, Switzerland. Address reprint requests to Alan G. Harris, MD, Department of Neuroendocrinology, Clinical Research. SAND02 Pharma Ltd, CH4002 Basle, Switzerland. 0 1990 by W.3. Saunders Company. 0026-0495/9~/3909-2046$03.00/O

180

tigators have not yet been published. However. extensive reviews of clinical uses of Sandostatin have been published recently.3 The results of most of the studies in potential indications of Sandostatin reviewed hereafter must be considered preliminary pending confirmation from prospectively planned controlled trials. Moreover, the limited scope of this discussion of unpublished negative results also found with Sandostatin in some of these disorders. CANCER

The antiproliferative effects of somatostatin and Sandostatin have been demonstrated in human breast cancer cell lines and in rat mammary glands.4-7 Sandostatin inhibits a rat pancreatic acinar tumor cell line and antagonises the mitogenic effects of epidermal growth factor at doses that involve somatostatin receptor occupancy and may control pancreatic growth at the cellular level.* In addition, Sandostatin inhibited the growth of two human pancreatic tumor types grown in mice.’ Sandostatin can partially inhibit the growth of transplanted prostate tumors in rats.” It seems that the effects of Sandostatin on serum gastrin levels may have reduced the growth of human gastric cancer cell lines in rats. The antian~ogenetic activity of Sandostatin shown in vitro may also account for a potential antitumoml effect of the analog in cancer. Sandostatin may act as an antineoplastic agent directly through interaction with somatostatin receptorpositive tumor cells, and indirectly by lowering insulin-like growth factor type I (IGF- 1) levels, which stimulate growth of IGF- 1 receptor-positive tumors. The favorable clinical results obtained with Sandostatin in carcinoid tumors and VIPomas suggest that this drug may be a useful adjunctive therapy for hormone-de~ndent can-

Merabdism,

Vol39, No 9, SuppI

(September).

1990: pp 180-l 85

181

FUTURE MEDICAL PROSPECTS FOR SANDOSTATIN

cers. Indeed, tumor size reduction has been reported in Sandostatin-treated patients with carcinoid syndrome and VIPoma. Long-term Sandostatin therapy of 66 carcinoid patients was associated with a threefold increase in median survival (>36 months) compared with that reported with combination chemotherapy. i’ Likewise, Sandostatin has been shown to enhance natural killer cell function and to increase resting lymphocyte blastogenesis in patients with carcinoid and islet cell cancer. Eight patients with refractory, nonendocrine solid tumors of exocrine pancreas, ovary, breast, kidney, and colon, who were treated with Sandostatin 400 fig subcutaneously (SC) three times daily, showed a significant reduction in basal stimulated serum GH and serum IGF-1.12 In addition, Sandostatin 100 fig SC twice daily produced tumor stabilization in three of 14 patients with advanced breast cancer.13 A pilot trial in heavily pretreated breast cancer patients showed the usefulness of combined administration of Sandostatin and Parlodel” (bromocriptine).‘4 Prospective trials are being set up to assess the role of Sandostatin in various cancers. The identification of ~mat~tatin-binding receptors (SS-R) in human endocrine tumors, may constitute the molecular basis for the remarkable therapeutic action of Sandostatin in GEP endocrine tumors.” The SS-R content of tumor tissue from patients with carcinoid syndrome, VIPoma, insulinoma, or acromegaly shows a positive correlation with hormonal secretion and responsiveness to Sandos~tin.” Besides, SS-R status may have prognostic value in breast cancer and small-cell lung cancer and may serve as a marker for tumor di~rentiation in the brain. The new technique of scintigraphic imaging with a radioiodinated analogue of somatostatin ‘231-Tyr-SMS 201-995, which allows in vivo localization of SS-R-positive tumors and their metastases, may help to predict and monitor responses to Sandostatin and may also detect tumor recurrence.‘6 It is conceivable that target irradiation of these tumors by /3 ~~cl~mitting isotopes attached to such somatostatin analogs may become possible.16 Positron emission tomography (PET) studies using “C-J_methionine-labeled somatostatin analogs, which provide an in vivo quantitative dynamic regional autoradiography of SS-R-positive tumors, are under way. PET studies have already shown that Sandostatin can reduce amino acid turnover in GH-secreting pituitary tumors,” and this technique may help to monitor the possible antitumoral effects of Sandostatin. PAIN

A double-blind, placebo-controlled study of Sandostatin 100 MgSC in two acromegalic patients with intractable headache demon~ted sustained analgesic effect of the analog. In another double-blind, placebo-controlled cross-over study, Sandostatin (100 pg SC three times daily) produced analgesia, which lasted for up to 6 hours, in four of six patients with headaches due to pituitary tumors. One patient continued with treatment for 6 months and there were no clinical or biochemical adverse effects or deterioration of analgesia.i8 Six other patients with acromegaly obtained relief of headache

within minutes of receiving Sandos~tin and continued to receive it for 5 to 12 months with sustained pain relief.” In an open-label study, intrathecal administration of Sandostatin reduced pain signifi~ntly in five of six terminal cancer patients, and an intravenous (IV) bolus of 250 pg Sandostatin produced analgesia in eight patients with pain due to bone metastases.20 The analgesic effect of Sandostatin is not opioiddependent, as it is not abolished by naloxone, but it may be related to the inhibition of substance P release, which is involved in the transmission of painful impulses. Similar analgesic properties of Sandostatin have been reported in posthysterectomy pain. Sandostatin administered SC has also been shown to be effective in relieving musculoskeletal pain associated with carcinoid syndrome.” Sandostatin may become a useful analgesic agent in the treatment of various pain disorders such as rheumatoid arthritis as has been shown with native somatostatin. PORTAL HYPERTENSION AND VARICEAL 6LEEDING IN PATIENTS WITH CIRRHOSIS

Somatostatin and Sandostatin have been shown to reduce splanchnic blood llow and portal venous pressure in patients with cirrhosis.22 Acute Yariceal Bleeding

The acute effects of Sandostatin in patients with cirrhosis and portal hypertension include rapid reductions in wedged hepatic venous pressure, with minimal reduction in heart rate or increase in arterial blood pressure, Randomized controlled studies have demonstrated the efficacy of somatostatin in controlling acute variceal bleeding. Results of a preliminary trial comparing the efficacy of injection sclerotherapy and somatostatin in the control of severe variceal hemorrhage suggest that there is no significant difference between the two treatmentsz3 The results of a 4%hour randomized comparative trial of IV infusion of Sandostatin or esophageal tamponade in 40 patients with variceal hemorrhage suggest that the drug may be a useful adjuvant therapy prior to sclerotherapy for the temporary control of acute variceal bleeding.24 Long- Term management

ofPortal Hypertension

Administration of Sandostatin to cirrhotic animals or portal hypertensive patients produces a sustained decrease in portal pressure, suggesting that the compound may reduce the risk of recurrent variceal hemorrhage. The preliminary results of a randomized controlled trial comparing injection sclerotherapy alone and combined with Sandostatin to pg SC twice daily, indicate that the analog appears to reduce the risk of recurrent variceal bleeding and shortens the time to oblitemtion of the varices (S. Jenkins, personal communication). Further randomized controlled comparative trials are needed in order to determine the place of Sandos~tin in therapy in both the management of acute variceal bleeding episodes and the long-term management of portal hypertension in patients with cirrhosis, but p~limin~ findings have been encouraging.

182

ALAN G. HARRIS

PROPHYLAXIS OF POSTO~RATIVE

PEPTIC ULCER BLEEDING

In a large multicenter double-blind trial in patients with important peptic ulcer bleeding, Sandostatin had no benefit over placebo.*’ However, although Sandostatin is ineffective in patients with an active {oozing) lesion, the m~i~ation may be. useful in patients whose ulcers have stigmata such as spurting bleeding, or a nonbleeding visible vessel.26 SECRETORY DIARRHEAS

infants with severe refractory secretory diarrhea, Sandostatin administered SC twice daily reduced stool output.” Sandostatin has also been shown to control chronic refractory diabetic diarrhea.” In

Profuse watery diarrhea in patients who are positive for the human immunodeficiency virus (HIV) has clinical features suggestive of secretory diarrhea. This diarrhea, which may cause marked debility and shorten life expectancy in patients with acquired immun~eficiency syndrome (AIDS), is one in which the etiology is unknown and where there is no effective therapy. The efficacy of Sandostatin appears to be related to its ability to inhibit release of several gut hormones (VIP, motilin, gas&in) and to enhance water and electrolyte absorption, while slowing ~trointestinal transit time. These properties have led to the successful use of Sandostatin in the treatment of several HIV-positive patients with severe refractory diarrhea. 2g.30A prospective study of Sandostatin is now in progress. PANCREATIC AND ENTEROCUTANEOUS

FISTULAE

Pancreatic fistulae are usually caused by external drainage of a pseudocyst or abscess, complicating pancreatitis, erosion of a peptic ulcer into the pancreas or pancreatic trauma during surgery; they are complicated by fluid and electrolyte disturbances, sepsis, and malnutrition. Case reports have suggested that Sandostatin is useful for achieving closure of pancreatic fistulae.3’ Significant reductions in pancreatic fluid output, bicarbonate output, and also decreased pancreatic amylase and lipase production, with concomitant increases in chloride and potassium levels were obtained. This suggests that Sandostatin may also be a useful prophylactic tool for the prevention of postoperative fistula formation.32 A more recent study in 27 patients with postoperative enterocutaneous tistulae, treated with total parenteml nutrition (TPN) and Sandostatin 100 pg SC every 8 hours, has confirmed that within 24 hours mean fistula output was reduced by 55%. In addition, spontaneous closure occurred in 77% of the patients after a mean treatment duration of 5.8 days compared with 3 to 5 weeks with TPN alone.33 SHORT BOWEL SYNDROME

Sandostatin has been shown to reduce the daily requirements of parenteral nutrition by improving absorption of water, sodium, and nutrients in patients with short bowel syndrome.34

AND ENDOSCOPlCAL

RETROGRADE CHOLANGIOPANCREATOGRAPHY (ERCP) PANCREATITIS

Prophylactic somatostatin has been reported to reduce the h~ramyla~mia, pain, and complication rates after ERCP and sphincteropiasty, possibly through inhibition of pancreatic secretion. Somatostatin and Sandostatin may reduce the complications (acute pancreatitis, fstulae) after surgery and prophylactic Sandostatin prevents postoperative pancreatitis in patients undergoing pancreas transplan~tion.3s CHRONIC PANCREATITIS

Pain in chronic pancreatitis has been attributed to increased cholecystokinin levels and ductular hypertension, which is reduced by Sandostatin in rats with chronic pancreatitis. Moreover, preoperative Sandostatin abolished pain in patients scheduled for pancreatic resection (S. Jenkins, personal communication). Thus, Sandostatin may be an alternative to resection in patients with intractable pain related to chronic pancreatitis. DIABETES MELLITUS

Somatostatin improves glucose tolerance by delaying intestinal ~r~hydmte absorption and inhibiting the counterregulatory hormones glucagon and GH. However, a longer duration of action and less insulin inhibitory activity make Sandostatin potentially more useful in these patients. Glycemic and ~eta~~l~c Control

Insulin requirements are decreased by Sandostatin in insulin-dependent diabetic patients (IDDM).36,37 Besides, the inhibitory effect of Sandostatin on endogeneous insulin secretions has also been shown in non-insulin~e~ndent diabetic (NIDDM) patients. 3*,3qInterestingly, insulin-treated NIDDM patients have been shown to reduce their postprandial glycemic peaks when Sandostatin 100 pg SC is administered 30 minutes before breakfast and dinner.40 As hyperinsulinism is considered a risk factor for macroangiopathy in diabetes, Sandostatin may reduce the progression of vascular disease in NIDDM and IDDM. There have been conflicting reports about the efficacy of Sandostatin in the reduction of postprandial hyperglycemia.4’-1R Although bedtime ( IO to 1I:00 PM) administmtion of Sandostatin is associated with a significant reduction of blood glucose and GH levels for 4 to 6 hours.44.4’ the medication fails to prevent early morning hyperglycemia (“dawn phenomenon”). It is possible that a slow release formulation of ~ndos~tin may help to achieve this goal. It is noteworthy that Sandostatin reduces late-night insulinopenic ketogenesis as reflected by the lower plasma levels of 3-hydroxybutyrate compared with placebo44 and that Sandostatin significantly reduced ketogenesis resulting from insulin-dep~vation.45 This suggests that Sandostatin may be useful in the prophylactic treatment of diabetic patients at risk of frequent ketoacidosis.

183

FUTURE MEDICAL PROSPECTS FOR SANDOSTATIN

Diabetic Nephropathy Renal h~~rop~y-hy~~ltration, which accompanies early diabetes, is considered to be a forerunner of end-stage diabetic renal failure. Sandostatin has been shown to reduce kidney growth and renal phosphoribosyl Qyrophosphate in early alloxan-indu~d renal hy~~rophy in diabetic rats.46 Sandostatin has been shown to prevent the obligatory increase in kidney IGF-I content, as well as kidney growth, both in experimental diabetes and after uninephrectomy in rats.47 Moreover, Sandostatin seems able to inhibit both circulating and tissue levels of IGF- 1 independently of circulating GH.48 The renal response to increasing doses of Sandostatin (50, 100, and 200 pg/d over 3 days), in seven IDDM patients without microalbuminuria, has been investigated.49 Reduction of glomerular filtration rate (GFR) was pronounced in four of the patients, ofwhom three fell into the normal range. Similarly, it was also found in another study that constant IV infusion of Sandostatin 8 fig/h acutely reduced renal hyperfiltration in 13 patients with IDDM.50 Sandostatin has also been shown to significantly reduce or normal& microalbuminuria, which suggests that the drug may delay or prevent progression to late diabetic nephropathy. Diabetic Retinopathy Excessive production of GH/IGF- 1 has been implicated in the development of diabetic microan~opathy. In vitro studies have indicated that Sandostatin inhibits new vessel growth and endothelial cell replication, In a patient with diabetic retinopathy, Sandostatin reversed some of the retinal vascular complications (hemo~hage, microaneu~sm) of diabetes meilitus induced by near-normalization of glucose levels.5’ Sandostatin 100 to 200 rg/d has been associated with improved visual acuity in patients with preproliferative diabetic retinopathy and macular edema. GH secretion and IGF- 1 level? are markedly reduced by Sandostatin therapy in patients with proliferative and preproliferative diabetic retinopa~y. Prospective studies to investigate whether longterm Sandostatin therapy will influence the progression of diabetic retinopathy are currently in progress. Diabetic ~~iropathy The analgesic properties of Sandostatin and improvement of orthostatic and postprandial hypotension in diabetic and nondiabetic patients suggest that the drug may be useful in refractory diabetic neuropathy. ORTHOSTATIC

HYPOTENSION

Sandostatin has a pressor effect in patients with progressive autonomic neuropathy, but not in those with sympathotonic orthostatic hypotension.53.54 The Qressor effect of Sandostatin, which is efficiently potent to prevent o~os~tic h~tension, may be ascribed to the vasoconstriction of spianchnic circulation and inhibition of vasoactive peptides. POSTPRANDIAL

HYPOTENSION

A single injection of Sandostatin 50 I.rg SC successfully prevented the reduction in blood pressure and tachycardia

induced by oral glucose loading in 10 normotensive and 10 hypertensive elderly subjects. 55 Similarly, in seven patients with chronic idiopathic autonomic failure, a reduction in mean blood pressure of 2 1% after glucose loading was abolished by Sandostatin 50 hg SC.56 In another study, Sandostatin prevented postprandial h~otension in five patients with progressive autonomic failure and in six patients with multiple system atrophy. ” Sandostatin thus may become a useful therapeutic agent in refractory hypotension. PSORIASIS

Sandostatin produced improvements in seven of nine patients with psoriasis vulgar-is.58Controlled, double-blind trials are in progress to verify this finding. TALL-STATURE

CHILDREN

Sandostatin treatment significantly reduced height velocity in seven children with tall stature.59 A study performed in four boys and six girls with constitutionally tall stature, aged 11 to 17 years, treated with twice-daily SC injections of Sandostatin 250 pg also produced encouraging resuits.” Reduction of growth rate was achieved in nine children and correlated with reduction of 24-hour GH Qulsatility, and mean bone age increased from 13.3 years to 14.5 and 15.8 years after 6 and 12 months, respectively. The predicted mean reduction of adult height was 4.5 cm at 6 and 12 months of treatment. The combination of effects on growth rate and bone maturation indicate that Sandostatin could become an alternative to existing treatments used for the reduction of adult height. However, whether Sandostatin therapy should be started before puberty or in the early stages of puberty remains to be defined. The minimal effective dose, the OQtimum mode of administration, the duration of therapy and the long-term effects also need to be addressed. ADVERSE EFFECTS

Adverse effects of Sandostatin are infrequent and predominantly transient. However, some patients treated with Sandostatin have been reported to deWlOp gallstones, but the incidence of this has not been clearly defined. The distribution is variable, as some populations do not produce gallstones despite the use of high doses of Sandostatin and high-cholesterol diets. Few of the patients who developed gallstones while receiving Sandostatin have developed symptoms and received surgery. Studies are currently in progress to establish the mechanism of Sandostatin-induced gallstone formation. These studies will also examine the incidence and risk factors predisposing patients to the development of gallstones associated with Sandostatin therapy. CONCLUSION It is difficult to predict exactly what future developments are most likely to occur for Sandostatin therapy because of the complexity of the disorders such as oncology in which it is now being studied. However, in addition to its established indications, acromegaly and GEP endocrine tumors, many new possible uses for Sandostatin are currently being investigated. Future uses for Sandostatin are potentially as wide

184

ALAN G. HARRIS

ranging as the role of somatostatin itself, provided that a more convenient mode of administration becomes available and that particular care is taken to conduct well-controlled studies. ACKNOWLEDGMENT I wish to thank Mrs. A. Albitz for her excellent technical assistance. 1 should like to acknowledge the Sandostatin research group at SAN-

DOZ, involved both in preclinical (W. Bauer, U. Briner, W. Doepfner. R. Hailer, R. Huguenin, P. Marbach, T.J. Petcher, and J. Pless) and clinical (V. Boerlin, K. Herold, M. Schweizer, M. Gnehm, G. Haas, and H. Prestele) phases of research, who have allowed us to introduce this therapy into the mainstream of medical practice. I should also like to express my deepest gratitude to the hundreds of clinical investigators who provided us with the data that has allowed us to demonstrate the clinical usefulness of Sandostatin@.

REFERENCES 1. Bauer W, Briner U, Doepfner W. et al: SMS 201-995: A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 3 1:I 133- 1140, 1982 2. Marbach P, Andres H, Azria M, et al: Chemical structure. Ph~ac~ynamic profile and pharma~kinet~cs of SMS 201-995 (Sandostatin”). in Lamberts SWJ (ed): Sandostatin in the Treatment of Acromegaly. Amsterdam, The Netherlands, Springer-Verlag. 1986, pp 53-60 3. Harris AC: Sandostatin Literature Review (1988). ~012. Basle, Switzerland, Sandoz Ltd. 1989 4. Scambia G, Panici PB, Baiocchi G, et al: Antiproliferative effects of somatostatin and the somatostatin analogue SMS 201-995 on three human breast cancer cell lines. J Cancer Res Clin Oncol 114:306308. 1988 5. Setyono-Itan B, Henkelman MS, Foekens JA, et al: Direct inhibitory effect of somatostatin (analogues) on the growth of human breast cancer cells. Cancer Res 47: 1566- 1570, 1987 6. Weber C, Merriam L, Koschitzky T: Inhibition of growth of human breast carcinomas in vivo by somatostatin analogue SMS 201-995: Treatment of nude mouse xenografts. Surgery 106:2:416422, 1989 7. Nagasawa H, Koshimizu U, Sakagami N: Counteraction by combined treatment with high dose of oestrogen and somatos~tin of mammary growth suppression in mice. In Vivo 2:167-169, 1988 8. Hajri A, Aprahamian M, Vonderscher J, et al: Antitumoral effect of Sandostatin in an exocrine pancreatic tumor transplanted in the rat. Bull Cancer 76504, 1989 9. Upp JR, Olson D, Poston GJ, et al: Inhibition of growth of two human pancreatic adenocarcinomas in vivo by somatostatin analog SMS 201-995. Am J Surg 155:29-35, 1988 10. Siegel RA, Tolcsvai L, Rudin M: Partial inhibition of the growth of tmnsplant~ Dunning rat prostate tumors with the longacting somatostatin analogue Sandostatin (SMS 201-995). Cancer Res 48:4651-4655, 1988 11. Kvols LK, Moertel C. Schutt A: Long term results of therapy with an analogue of somatostatin (SMS 201-995) for carcinoid tumors and the malignant carcinoid syndrome. Biomed Res 82:S-4. 1988 (suppl 1, abstr) 12. Polk& M, Polychronakos C: Somatostatin analogue SMS 201995 lowers IGF-I levels in patients with potentially IGF-I~e~ndent cancers. Anticancer Res 9889-892, 1989 13. Vermin P, Peyrat JP, Bonneterre J. et al: Effect of the longacting somatostatin analogue SMS 201-995 (Sandostatin’) in advanced breast cancer. Anticancer Res 9: 153- 155, 1989 14. Manni A, Boucher A, Demers L, et al: Endocrine effects of combined somatostatin analog and bromocriptine therapy in women with advanced breast cancer. Breast Cancer Res Treat 14:3:289-229, 1989 15. Reubi JC: Identification of somatostatin receptors in human tumors. Triangle 27:179-188, 1988 16. Krenning EP, Bakker WH, Breeman WAP, et al: Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet 1:242-245, 1989

17. Muhr C, Bergstrom M. Lundberg PO. et al: Pituitary imaging with positron emission tomography, in Imura H. Shizume K, Yoshida S (eds): Progress in Endocrinology, vol I Amsterdam. The Netherlands, Excerpta Medica, 1988, pp 567-578 18. Williams G, Ball JA, Lawson RA. et al: Analgesic effect of somatostatin analogue (Octreotide) in headache associated with pituitary tumours. Br Med J 295:247-248. 1987 19. Barnard LB. Grantham WG, Lamberton P, et al: Treatment of resistant acromegaly with a long-acting somatostatin analogue (SMS 201-995). Ann Intern Med 105:856-861, 1986 20. Agnusdei D, Civitelli R, Gonnelli S, et al: Calcitonin- and somatostatin-induced analgesia in pain from cancer. in Genazzani AR, Nappi G, Facchinetti F. et al teds): Pain and Reproduction. USA, Parthenon, 1988, pp 23-29 2 1. Pincus T, Smith S, Oates JA: Somatostatin analogue octreotide is effective in relieving musculoskeletal pain associated with carcinoid syndrome. Arthritis Rheum 32:4, 1989 (suppl p. S7 1, abstr Bl27) 22. Pringle SD, McKee RF, Garden OJ. et al: The effect of a longacting somatostatin analogue on portal and systemic haemodynamics in cirrhosis. Aliment Pharmacol Ther 2:45 I-459, I988 23. Jenkins SA, Baxter JN, Ellenbogen S, et al: A prospective randomised controlled clinical trial comparing ~matos~tin and injection ~lerotherapy in the control of acute variceal haemorrhage: Preliminary results. Gut 29:A 1431, 1989 24. McKee R: A study of octreotide in oephageal varices. Digestion 45:60-65, 1990 (suppl 1) 25. Christiansen J, Ottenjann R. Von Arx F, et al: Placebo-controlled trial with the somatostatin analogue SMS 201-995 in peptic ulcer bleeding. Gastroenterology 97:568-574, 1989 26. Peterson Wt: Pharmacotherapy of bleeding peptic ulcer--Is it time to give up the search? Gastroenterology 97:796-797, 1989 (editorial) 27. Jaros W, Biller J, Greer S, et al: Successful treatment of idiopathic secretory diarrhea of infancy with the somatostatin analogue SMS 201-995. Gastroenterology 94: 189-193, 1988 28. Dud1 R, Anderson DS, Forsythe AB, et al: Treatment of diabetes diarrhea and orthostatic hypotension with somatostatin analogue SMS 201-995. Am J Med 83:584-588, 1987 29. Katz MD, Erstad BL, Rose C: Treatment of severe cryptospoodium-rests diarrhoea with octreotide in a patient with AIDS. Drug Intel1 Clin Pharm 22: 134-136, 1988 30. Robinson EN, Fogel R: SMS 20 l-995, a somatostatin analogue, and diarrhea in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 109:680-68 1, 1988 3 1. Prim RA, Pickleman J, Hoffman JP: Treatment of pancreatic cutaneous listulas with a somatostatin analogue. Ann J Surg 155:3642, 1988 32. Cooper MM, Wright FH, Smith JL, et al: Succwful treatment ofa high-output fistula with a somatostatin analogue following pancreas transplantation. Transplant Proc 21:3738-3741. 1989 33. Nubiola P, Badia JM, Martinez-Rodenas F. et al: Treatment of 27 postoperative enterocutaneous fistulas with the long half-life somatostatin analogue SMS 201-995. Ann Surg 2 10:56-58, 1989

FUTURE MEDICAL PROSPECTS FOR SANDOSTATIN

34. Ladefoged K, Christensen KC, Hegnhej JS: Effect of a long acting somatostatin analogue SMS 20 l-995 on jejunostomy effluents in patients with severe short bowel syndrome. Gut 30~943-949, 1989 35. Daloze P, Beauregard H, Louis GS, et al: Clinical pancreas transplantation: a learning curve of its management. Transplant Proc 21:1:2858-2861, 1989 36. Serrano Rios M, Navascues I, Saban J, et al: Somatostatin analog SMS 201-995 and insulin needs in insuiin~e~ndent diabetic patients studied by means of an artificiaI pancreas. J Chn Endocrinol Metab 63:1071-1074, 1986 37. Nosari I, Lepore G, Querci F, et al: Effects of a somatostatin derivative (SMS 201-995) on postprandial hyperglycemia in insulindependent diabetics studied by means of a closed-loop device. J Endocrinol Invest 124 13-4 17, 1989 38. Williams G, Fuessl HS, Burrin JM, et ah Postprandial glycemic effects of a long-acting somatostatin analogue (Octreotide) in noninsulin dependent diabetes mellitus. Horm Metab Res 20:168-70, 1988 39. Haupt E, Getter E, Rosak C, Harris AG: The effect of the octapeptide somatostatin analogue Sandostatin in type II (non-insulin dependent) diabetes. Diabetologia 30:528A-529A, 1987 (abstr 207) 40. Candrina R, Coppini A, Graffeo M, et al: SMS 201-995 improves glucose tolerance in insulin-treated type II diabetic patients. Diabetes Care 10:534-35, 1987 (letter) 41. Gsei K, O’Dorisio M, Malarkey WB, et al: Metabolic effects of long-acting somatostatin analogue (Sandostatin@) in type I diabetic patients on conventional therapy. Diabetes 38:704-709, 1989 42. Grossmann LD, Shumak SL, George SR, et ah The effects of SMS 201-995 (~nd~~tin) on metabolic profiles in insulinde~ndent diabetes mellitus (IDDM). J Clin Endocrinol Metab 68:63-67, 1989 43. Spinas GA, Bock A, Keher U: Reduced postprandial hyperglycemia after subcutaneous injection of a somatostatin-analogue (SMS 201-995) in insulin-dependent diabetes mellitus. Diabetes Care 8429-435, 1985 44. Aarsen RSR, Bruining GJ, Grose WFA, et al: Long-acting somatostatin analogoue (Sandostatin) reduces late night insuhnopenic ketogenesis in diabetic teenagers. Acta Endocrinol I 1645-53, 1987 (suppl286) 45. Seaquist ER, Diem P, Goetz FC: Preventive effects of the somatos~tin analog SMS 201-995 on diabetic ketogenesis. Diabetes 38:76A, 1989 (suppl 2, abstr 301) 46. Steer KA, Sochor M, Kunjara S, et al: The effect of a somatostatin analogue (SMS 20 l-995, Sandostatin) on the concentration of phosphoribosyl pyrophosphate and the activity of the pentose phosphate pathway in the early renal hy~~rophy of experimental diabetes in the rat. B&hem Med Metab Biol39226233, 1988 47. Fiyvberg A, Frystyk J, Thorlacius-Ussing 0, et al: Somatostatin

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