Plenary lecture

Somatostatin analogs: Future directions

Acromegaly is a chronic insidious disease characterised by growth hormone (GH) hypersecretion, typically from a pituitary adenoma. Effective treatment of acromegaly is vital because it is associated with a mortality rate more than twice that of the general population, an increased prevalence of colonic malignancy and many significant co-morbidities. Transsphenoidal adenoma resection is still the best first-line treatment for acromegaly but persistence (43%) or recurrence (2% to 3%) of GH hypersecretion after surgery remains a problem. Treatment options for acromegaly after failed initial therapy or recurrence include further surgery, radiotherapy, radiosurgery or medical therapies, including somatostatin analogues, dopamine agonists and growth hormone receptor antagonists. There has been a progressive lowering of the accepted GH level defining cure in acromegaly. This article reviews the efficacy and safety of the various treatment options for persistent or recurrent acromegaly and the changing definition of cure.

The neuroendocrine differentiation in PC could potentially represent a new finding with diagnostic, prognostic and therapeutic implications. This study aimed at evaluating the clinical usefulness of CgA as a neuroendocrine (NE) serum-marker. We investigated the role of the serum concentration of CgA in a study group of patients with PC. CgA was significantly higher in the patients affected by PC as compared with the group of healthy subjects (HS) and those with chronic pancreatitis (CHP) (p < 0.001). Also the HS group differed significantly from the CHP control group in the serum CgA levels (p < 0.001). The serum carbohydrate antigen (CA19-9) level displayed a significant difference (p < 0.001) between the PC and the HS group. The PC and CHP groups, as well as the HS and CHP groups showed also significant differences in the CA19-9 levels (p < 0.001). One can conclude that the patients with higher CgA levels had poorer prognosis and survival, as compared to those with lower CgA levels. These results support the notion that the determination of serum CgA level before treatment may be a potential prognostic factor for PC.

The present review focuses on promising new opportunities for anti-inflammatory and analgesic therapy. The theoretical background is an original observation based on our own experimental results. These data demonstrate that somatostatin is released from capsaicin-sensitive, peptidergic sensory nerve endings in response to noxious heat and chemical stimuli such as vanilloids, protons or lipoxygenase products. It reaches distant parts of the body via the circulation and exerts systemic anti-inflammatory and analgesic effects. Somatostatin binds to G-protein-coupled membrane receptors (sst₁–sst₅) and diminishes neurogenic inflammation by prejunctional action on sensory-efferent nerve terminals, as well as by postjunctional mechanisms on target cells. It decreases the release of pro-inflammatory neuropeptides from sensory nerve endings and also acts on receptors of vascular endothelial, inflammatory and immune cells. Analgesic effect is mediated by an inhibitory action on peripheral terminals of nociceptive neurons, since circulating somatostatin cannot exert central action.

Somatostatin itself is not suitable for drug development because of its broad spectrum and short elimination half life, stable, receptor-selective agonists have been synthesized and investigated. The present overview is aimed at summarizing the physiological importance of somatostatin and sst receptors, pharmacological significance of synthetic agonists and their potential in the development of novel anti-inflammatory and analgesic drugs. These compounds might provide novel perspectives in the pharmacotherapy of acute and chronic painful inflammatory diseases, as well as neuropathic conditions.

Somatostatin analogues have been the mainstay of symptomatic management of patients with neuroendocrine tumours (NETs) for two decades with the main mechanism of action being inhibition of peptide release. Evidence base for interferon use is perhaps less clear. It may contribute to symptom control by abrogating peptide release, and there is some evidence that it has an anti-proliferative action. Combination of somatostatin analogues and interferon provides symptom control, mainly by effecting a reduction in the amount of circulating, physiologically active, peptide hormones. Treatment can also provide disease stabilisation in a proportion of patients. In a minority of patients treatment may lead to partial response.

This chapter provides an overview of non-peptide somatostatin receptor ligands. Somatostatin (somatotropin release-inhibiting factor, SRIF) was originally isolated from mammalian hypothalamus as a potent inhibitor of pituitary growth hormone (GH) secretion. It occurs in two biologically active forms, a tetradecapeptide somatostatin-14 and an N-terminal elongated 28-residue peptide somatostatin-28. Cortistatin, possibly a third endogenous ligand, has been identified. Somatostatin is widely distributed throughout the endocrine and central nervous systems and peripheral tissues. It affects diverse biological processes such as hormone secretion, neurotransmission, cell proliferation, smooth muscle. Somatostatin elicits its effects through a family of G-protein-coupled receptors (GPCR) with seven transmembrane (TM) domains that are encoded by nonallelic genes located on separate chromosomes, contraction, nutrient absorption, and inflammation. It is expected that somatostatin receptor modulation will continue to be the focus of research because it provides opportunities for intervention in a number of therapeutic targets. Clinical data derived from octreotide in the treatment of a variety of diseases reiterates the validity of this approach. It is anticipated that medicinal chemistry efforts will continue to develop potent, selective and orally bioavailable agents for each of the receptor subtypes.