chapter  25
8 Pages

Clinical Significance of the Long-Acting Formulation Sandostatin LAR

INTRODUCTION In 1973, Brazeau et al. isolated somatotropin-release inhibiting factor (SRIF) from the ovine hypothalamus and discovered that it strongly inhibited the secretion of rat or human growth hormones (GH) (1). SRIF, more commonly referred to as somatostatin, was subsequently shown to be a secretory product of pancreatic D cells in the upper gastrointestinal tract (2). The actions of somatostatin on pancreatic and gastrointestinal function suggested that it may play an important role not only in pituitary GH or thyroid stimulating hormone secretion but also in digestive physiology, such as secretion of gastrin, vasoactive intestinal polypeptide (VIP), cholecystokinin, gastric acid, and glucagon or insulin release (3-5). Early studies suggested there were specific somatostatin binding sites in GH-secreting pituitary adenomas (6,7). During early experiments with octreotide, it was thought that there were two different binding sites for somatostatin (8,9). Thereafter, six somatostatin receptor subtypes, sst1, sst2A, sst2B, sst3, sst4, and sst5 were cloned and identified (10). Octreotide, a long-acting analogue of somatostatin, was synthesized by Sandoz Pharmaceuticals Ltd. in 1980 (11), whereupon it underwent clinical development. During the 1980s, Sandostatin1 (octreotide SC injection formulation) was approved in several countries for the treatment of patients with acromegaly and symptoms associated with neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) that cause the overproduction of several peptides and neuroamines, including serotonin. Although Sandostatin is considered a milestone in the treatment of patients with GEP-NETs and acromegaly, patients are required to receive three injections of Sandostatin every day for control of their symptoms. To provide patients with improved clinical application of this compound, a novel and proprietary depot formulation of octreotide was developed, which could greatly reduce the injection frequency while retaining the efficacy and safety of the subcutaneous formulation.