Development of analogues: successes and failures.

Abstract

The search for new pharmaceutical treatments has led to the isolation of products from a range of natural sources. Analogues synthesized from these products may possess an improved therapeutic effect over their natural counterparts. Two natural peptides, vasopressin and somatostatin, possess pronounced in vivo effects, so do their analogues terlipressin and octreotide. Vasopressin is a powerful vasopressor, reducing portal pressure, and has been used to treat gastrointestinal haemorrhages. However, a number of adverse cardiovascular effects resulting from an increase in peripheral vascular resistance have been associated with this drug. Terlipressin, however, is more effective, has an improved safety profile and is associated with fewer side effects than vasopressin. Somatostatin, a growth regulatory hormone, achieves haemostasis by decreasing splanchnic blood flow, and is effective in preventing early rebleeding. Somatostatin is effective in treating bleeding oesophageal varices (BOV) and is associated with fewer and more transient side effects than terlipressin. Octreotide, however, has greater stability and a longer half-life than somatostatin, but has a less favourable safety profile. Octreotide displays a number of therapeutic advantages over somatostatin, but not in the treatment of gastrointestinal indications. The development of terlipressin from vasopressin has demonstrated a number of clinical advantages, while the development of octreotide from somatostatin has not shown any significant advantage in the treatment of BOV.