Joost van der Hoek

A Case Series of Proton Pump Inhibitor–Induced Hypomagnesemia

Proton pump inhibitor (PPI)-induced hypomagnesemia has been recognized since 2006. Our aim was to further characterize the clinical consequences and possible mechanisms of this electrolyte disorder using 4 cases. Two men (aged 63 and 81 years) and 2 women (aged 73 and 62 years) had been using a PPI (esomeprazole, pantoprazole, omeprazole, and rabeprazole, 20-40 mg) for 1-13 years. They developed severe hypomagnesemia (magnesium, 0.30 +/- 0.28 mEq/L; reference, 1.40-2.10 mEq/L) with hypocalcemia (calcium, 6.4 +/- 1.8 mg/dL), relative hypoparathyroidism (parathyroid hormone, 43 +/- 6 pg/mL), and extremely low urinary calcium and magnesium excretion. One patient was admitted with postanoxic encephalopathy after a collapse likely caused by arrhythmia. The others had electrocardiogram abnormalities (prolonged QT interval, ST depression, and U waves). Concomitant hypokalemia (potassium, 2.8 +/- 0.1 mEq/L) was considered the trigger for these arrhythmias. Hypomagnesemia-induced kaliuresis (potassium excretion, 65 +/- 24 mEq/L) was identified as the cause of hypokalemia. This series of PPI-induced hypomagnesemia shows that this is a generic effect. It also indicates that hypomagnesemia may occur within 1 year of PPI therapy initiation and can have serious clinical consequences, likely triggered by the associated hypokalemia. A high index of suspicion is required in PPI users for unexplained hypomagnesemia, hypocalcemia, hypokalemia, or associated symptoms.

The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients

Objective  Recently, our first clinical study with the novel multiligand somatostatin (SRIF) analogue SOM230 in acromegalic patients showed that SOM230, due to its beneficial inhibitory effects on GH levels compared with octreotide (OCT), might increase the number of patients that can be biochemically controlled. Since SRIF analogues are also known to interact with other metabolic pathways, IGF‐I, IGFBP‐1, glucose and insulin concentrations on the control day (CD) and on treatment days following a single s.c. injection SOM230 100 and 250 µg, were compared to those following OCT 100 µg.

Pharmacokinetic‐pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly

Acromegaly is a serious hormonal disorder resulting from a pituitary adenoma causing excess growth hormone (GH) production. Somatostatin analogs such as octreotide have been the medical treatment of choice. SOM230, a novel somatostatin analog, was compared with octreotide with respect to pharmacokinetic (PK) profiles and inhibition of GH secretion in acromegalic patients.

Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas

The patho-physiological role of somatostatin receptor subtypes (sst) in neuro endocrine diseases has gained enhanced scientific interest in the past few years. The development of novel somatotropin-release inhibiting factor analogs, both sst-specific and universal ligands, seem promising as a tool to further increase fundamental insights in sst function. Eventually, this research should result in novel medical therapeutic opportunities in patients suffering from neuro-endocrine diseases. In the present review, the functional role of sst in all types of pituitary adenomas, based on recent preclinical and clinical studies, is being discussed.

The Role of Somatostatin Analogs in Cushing's Disease

Somatostatin (SRIF) has been proposed to be of therapeutic interest in the medical treatment of Cushings disease. While in vitro data demonstrate the presence of SRIF-receptor subtype (sst) expression in corticotroph adenomas, the current clinically available SRIF-analog Octreotide, predominantly targeting sst2, is ineffective in lowering ACTH levels in Cushings disease and only appears to inhibit the release of ACTH in Nelsons syndrome. In the present review, current knowledge on the physiological role of SRIF in the regulation of ACTH secretion by the anterior pituitary gland, as well as by corticotroph tumor cells is summarized. In addition, the role of glucocorticoids in regulating sst-mediated inhibition of ACTH release by corticotroph adenoma cells is discussed. Recently, it was reported that the novel multiligand SRIF-analog SOM230 might have the potential to be of therapeutic interest for Cushings disease. On the basis of the potent suppressive effects on ACTH release by SRIF-analogs with high binding affinity to sst5 and the observation that sst5 expression and action is relatively resistant to glucocorticoid treatment, including the recent observation that sst5 is the predominant sst expressed in human corticotroph adenomas, it is hypothesized that sst5 may be a new therapeutic target for the control of ACTH and cortisol hypersecretion in patients with pituitary dependent Cushings disease.

Novel subtype specific and universal somatostatin analogues: Clinical potential and pitfalls

The isolation and purification of somatostatin (SS), exactly 30 years ago, has led to the elucidation of physiologic actions of SS. This cyclic peptide is produced in the hypothalamus, throughout the central nervous system, as well as in most major peripheral organs and inhibits hormone release from the anterior pituitary gland, pancreas and the gastro-intestinal tract. The potent inhibitory actions of SS not only led to the clinical application of this peptide, but also resulted in the development of SS-analogues, among which octreotide and lanreotide are most well known and clinically used for several distinct disorders. Almost ten years ago, five different SS receptor subtypes (sst(1-5)) were identified. These receptor subtypes are variably expressed in distinct tissues and bind with varying affinity to the different SS-analogues, providing an excellent tool to unravel the (patho-) physiological function of the five sst subtypes. Following an overview upon the latest developments in SS receptor physiology and established diagnostic and therapeutic efficacy of SS-analogues in several challenging neuroendocrine disorders, this review predominantly focuses upon the latest developments of (clinically) potential novel sst subtype specific analogues as well as universal binding SS-peptides. Also, the role of potential SS antagonists is assessed. Furthermore, the most recent insights concerning targeted sst-mediated chemo- or radiotherapy are discussed, which offers new therapeutic and diagnostic opportunities for patients harbouring sst-positive neuroendocrine diseases. Finally, acknowledged side effects and possible pitfalls of the use of SS-analogues are discussed.

Severe hyponatremia with high urine sodium and osmolality

A 49-year-old woman (previous history of childhood asthma, no medication) presented to the emergency department with nausea and vomiting that had occurred for 5 days and slurred speech for 1 day prior to presentation. The patient denied use of alcohol and illicit drugs. Physical examination revealed her blood pressure to be 125/70 mmHg; she had no postural drop and had a regular pulse of 72 beats/min. She had no fever and no signs of contracted extracellular fluid volume. Results of further physical and neurological examination were unremarkable and revealed no goiter, pigmentation, or vitiligo. Her laboratory results are shown in Table 1⇓ . Additional diagnostic tests included chest x-ray, abdominal ultrasound, and brain computed tomography, none of which revealed abnormalities. The syndrome of inappropriate antidiuretic hormone secretion (SIADH)1 was suspected. However, fluid restriction (500 mL/day) did not lead to increased serum sodium. View this table: Table 1. Laboratory results. Because of the lack of response to therapy for SIADH, the diagnosis was reconsidered and hypothyroidism and/or adrenal insufficiency were suspected, especially because serum glucose was also low. Serum thyroid-stimulating hormone was 63 mU/L (reference interval 0.4–4.0 mU/L) with free thyroxine of 5 pmol/L (reference interval 9–24 pmol/L; to convert pmol/L of free thyroxine to ng/dL, divide by 13). Random cortisol was 151 nmol/L (reference interval 150–700 nmol/L; to convert nmol/L of cortisol to μg/L, divide by 0.0157), and a stimulation test with the 1–24 fragment of adrenocorticotropic hormone (ACTH) showed a baseline cortisol of 56 nmol/L, which increased only to 57 nmol/L (normal response >500 nmol/L). Plasma ACTH was …

The somatostatin receptor subtype 5 in neuroendocrine tumours

Importance of the field: In recent years, scientific work has been intensified to unravel new (patho-) physiological insights, particularly regarding the functional role of somatostatin (SRIF) receptor subtype 5 (sst) and the development of novel sst5-targeted SRIF analogues, in order to broaden medical therapeutic opportunities in patients suffering from neuroendocrine diseases. Areas covered in this review: The scope of this review is primarily focused upon recent insights in sst5-receptor physiology, novel sst5-targeted treatment options predominantly directed towards pituitary adenomas, and gastroenteropancreatic neuroendocrine tumours. What the reader will gain: An understanding of the potential that novel sst5-targeted SRIF analogues might have in the medical treatment of Cushing’s disease and acromegaly, as demonstrated by translational research, based on pathophysiological data combined with results from clinical trials. Take home message: The role of targeting sst5 in gastroenteropancreatic neuroendocrine tumours remains to be established. The sst5 subtype might function as sst2 modulator in terms of receptor internalization and desensitization, and seems less important compared with sst2-preferring SRIF analogues in the regulation of human insulin secretion by the pancreas. Finally, absence of sst5 in corticotroph adenomas could be related to tumour aggressiveness in Cushing’s disease.

The Superior Therapeutic Properties of SOM230 Originate from Unique Structural Elements

A rational drug design approach involving transposition of functional groups from SRIF into a reduced size cyclohexapeptide template has led to the discovery of SOM230, a novel, stable cyclohexapeptide somatostatin mimic which exhibits unique high affinity binding to human somatostatin receptors (sst1-5). SOM230 has potent, long lasting inhibitory effects on growth hormone and insulin-like growth factor-1 release and is a promising development candidate currently under evaluation in phase II clinical trials.