Hoek, J. van der

A Case Series of Proton Pump Inhibitor-Induced Hypomagnesemia (Article)

2010-07-01T00:00:00Z

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 receptor subtype 5 in neuroendocrine tumours (Article)

2010-03-01T00:00:00Z

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.

Severe hyponatremia with high urine sodium and osmolality (Article)

2009-11-01T00:00:00Z

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

2007-04-01T00:00:00Z

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 functional role of somatostatin receptor subtypes in pituitary adenomas (Doctoral Thesis)

2006-05-17T00:00:00Z

The main subject of the current thesis is the role of somatostatin (SRIF) receptors subtype 2 and 5 in the patho-physiological regulation of GH and ACTH release from human pituitary adenomas. The sst expression pattern in both types of pituitary adenomas is evaluated with respect to the inhibitory effects by SRIF-analogs on hormone secretion from the primary cultured tumor cells. The novel multiligand SOM230, compared with the current clinically available SRIF-analog OCT, is evaluated both for its clinical potential in the medical treatment of acromegaly, as well for in vitro for its potential in the medical treatment in patients with Cushing’s disease. SOM230, together with sst-selective analogs and chimeric molecules, targeting the sst2, sst5 and Dopamine D2 Receptor, are used as tools to retrieve insights with respect to the functional interplay between sst2, sst5 and D2R in the regulation of adenylyl cyclase activity as well the susceptibility of sst receptors to undergo ligand-induced adaptation, i.e. tachyphylaxis, of inhibition of adenylyl cyclase activity by SRIF-analogs.

Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. (Article)

2005-08-01T00:00:00Z

In a series of human corticotroph adenomas, we recently found predominant mRNA expression of somatostatin (SS) receptor subtype 5 (sst5). After 72 h, the multiligand SS analog SOM230, which has a very high sst5 binding affinity, but not Octreotide (OCT), significantly inhibited basal ACTH release. To further explore the role of sst5 in the regulation of ACTH release, we conducted additional studies with mouse AtT-20 cells. SOM230 showed a 7-fold higher ligand binding affinity and a 19-fold higher potency in stimulating guanosine 5'-O-(3-thiotriphosphate) binding in AtT-20 cell membranes compared with OCT. SOM230 potently suppressed CRH-induced ACTH release, which was not affected by 48-h dexamethasone (DEX) pretreatment. However, DEX attenuated the inhibitory effects of OCT on ACTH release, whereas it increased the inhibitory potency of BIM-23268, an sst5-specific analog, on ACTH release. Quantitative PCR analysis showed that DEX lowered sst(2A+2B) mRNA expression significantly after 24 and 48 h, whereas sst5 mRNA levels were not significantly affected by DEX treatment. Moreover, Scatchard analyses showed that DEX suppressed maximum binding capacity (B(max)) by 72% when 125I-Tyr3-labeled OCT was used as radioligand, whereas B(max) declined only by 17% when AtT-20 cells were treated with [125I-Tyr11]SS-14. These data suggest that the sst5 protein, compared with sst2, is more resistant to glucocorticoids. Finally, after SS analog preincubation, compared with OCT both SOM230 and BIM-23268 showed a significantly higher inhibitory effect on CRH-induced ACTH release. In conclusion, our data support the concept that the sst5 receptor might be a target for new therapeutic agents to treat Cushing's disease.

The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. (Article)

2005-04-01T00:00:00Z

OBJECTIVE: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing's disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst(1), sst(2), sst(3) and sst(5) was recently introduced. We compared the in vitro effects of the sst(2)-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells. METHODS: By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied. RESULTS: Corticotroph adenomas expressed predominantly sst(5) mRNA (six out of six adenomas), whereas sst(2) mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range -30 to -40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (- 28%). In AtT20 cells, expressing sst(2), sst(3) and sst(5), SOM230 inhibited ACTH secretion with high potency (IC(50) 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst(5) is relatively resistant to negative control by glucocorticoids. CONCLUSIONS: The selective expression of sst(5) receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing's disease.

A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients (Article)

2004-01-01T00:00:00Z

Treatment with the somatostatin receptor (sst) subtype 2 predominant analogs octreotide and lanreotide induces clinical and biochemical cure in approximately 65% of acromegalic patients. GH-secreting pituitary adenomas, which are not controlled, also express sst(5). We compared the acute effects of octreotide and SOM230, a new somatostatin analog with high affinity for sst(1,2,3,5) on hormone release in acromegalic patients. In a single-dose, proof-of-concept study, 100 microg octreotide and 100 and 250 microg SOM230 were given s.c. to 12 patients with active acromegaly. Doses of 100 and 250 microg SOM230 dose-dependently suppressed GH levels from 2-8 h after administration (-38 +/- 7.7 vs. -61 +/- 6.7%, respectively; P < 0.01). A comparable suppression of GH levels by octreotide and 250 microg SOM230 was observed in eight patients (-65 +/- 7 vs. -72 +/- 7%, respectively). In three patients, the acute GH-lowering effect of 250 microg SOM230 was significantly superior to that of octreotide (-70 +/- 2 vs. -17 +/- 15%, respectively; P < 0.01). In one patient, the GH-lowering effect of octreotide was better than that of SOM230. Tolerability for SOM230 was good. Glucose levels were initially slightly elevated after octreotide and SOM230, compared with control day, whereas insulin levels were only significantly suppressed by octreotide. We conclude that SOM230 is an effective GH-lowering drug in acromegalic patients with the potential to increase the number of patients controlled during long-term medical treatment.

The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro (Article)

2004-01-01T00:00:00Z

To determine the inhibitory profile of the novel somatostatin (SRIF) analog SOM230 with broad SRIF receptor binding, we compared the in vitro effects of SOM230, octreotide (OCT), and SRIF-14 on hormone release by cultures of different types of secreting pituitary adenomas. OCT (10 nM) significantly inhibited GH release in seven of nine GH-secreting pituitary adenoma cultures (range, -26 to -73%), SOM230 (10 nM) in eight of nine cultures (range, -22 to -68%), and SRIF-14 (10 nM) in six of six cultures (range, -30 to -75%). The sst analysis showed predominant but variable levels of somatostatin receptor (sst)(2) and sst(5) mRNA expression. In one culture completely resistant to OCT, SOM230 and SRIF-14 significantly inhibited GH release in a dose-dependent manner with an IC(50) value in the low nanomolar range. In the other cultures, SOM230 showed a lower potency of GH release inhibition (IC(50), 0.5 nM), compared with OCT (IC(50), 0.02 nM) and SRIF-14 (IC(50), 0.02 nM). A positive correlation was found between sst(2) but not sst(5) mRNA levels in the adenoma cells and the inhibitory potency of OCT on GH release in vivo and in vitro, and the effects of SOM230 and SRIF-14 in vitro. In three prolactinoma cultures, 10 nM OCT weakly inhibited prolactin (PRL) release in only one (-28%), whereas 10 nM SOM230 significantly inhibited PRL release in three of three cultures (-23, -51, and -64.0%). The inhibition of PRL release by SOM230 was related to the expression level of sst(5) but not sst(2) mRNA. Several conclusions were reached. First, SOM230 has a broad profile of inhibition of tumoral pituitary hormone release in the low nanomolar range, probably mediated via both sst(2) and sst(5) receptors. The higher number of responders of GH-secreting pituitary adenoma cultures to SOM230, compared with OCT, suggest that SOM230 has the potency to increase the number of acromegalic patients which can be biochemically controlled. Second, compared with OCT, SOM230 is more potent in inhibiting PRL release by mixed GH/PRL-secreting adenoma and prolactinoma cells.