Comparison of side effects of pentagastrin test and calcium stimulation test in patients with increased basal calcitonin concentration: the gender-specific differences.

The aim of this study was to compare the side effects of the pentagastrin test and the calcium stimulation test in patients with increased basal calcitonin concentration, especially the gender-specific differences of side effects. A total of 256 patients (123 females and 133 males, mean age of 56 ± 27 years, range 21-83 years) had both pentagastrin and calcium stimulation tests. All patients filled in a questionnaire regarding the side effects within 30 min after completion of the stimulation tests. The differences of side effects between female and male patients as well as between the pentagastrin stimulation test and the calcium stimulation test were evaluated. Warmth feeling was the most frequent occurring side effect in all patients who had both pentagastrin and calcium stimulation tests, followed by nausea, altered gustatory sensation, and dizziness. The incidences of urgency to micturate (p < 0.05) and dizziness (p < 0.05) were significantly increased in the female patients as compared to male patients by calcium stimulation test. Significant higher incidences of urgency to micturate (p < 0.05) and warmth feeling (p < 0.05) were found by calcium stimulation test as compared with those by pentagastrin test in female patients. The incidences of nausea (p < 0.05) and abdominal cramping (p < 0.05) in male patients were significantly higher by pentagastrin stimulation test than by calcium stimulation test. There is a significant gender-specific difference in side effects induced by calcium stimulation test. Female patients have fewer side effects by pentagastrin test than by calcium stimulation test. Male patients may tolerate the calcium stimulation test better than the pentagastrin test.

Pentagastrin-induced hemoconcentration in healthy volunteers and patients with panic disorder: effect of pretreatment with ethinyl estradiol.

Panic disorder has been associated with both an increased risk of coronary events as well as an increased risk of stroke. Hemoconcentration, with both a decrease in plasma volume and an increase in plasma viscosity, is a possible contributor to the risk of acute ischemic events. Our objectives were to demonstrate the process of hemoconcentration in response to induced panic symptoms and to assess the effect of pretreatment with ethinyl estradiol on panic-induced hemoconcentration. Fifteen male patients with panic disorder and 10 male healthy volunteers were included in a double-blind cross-over placebo-controlled design consisting of two injections of pentagastrin following randomized pretreatment with placebo and ethinyl estradiol. Plasma levels of hematocrit and hemoglobin were assessed at baseline and post-injections, and used to calculate an indirect estimation of the change in plasma volume. Pentagastrin-induced panic symptoms were associated with a mean decrease in plasma volume of 4.8% in the placebo pretreatment condition. Pretreatment with ethinyl estradiol attenuated this effect. The acute hemoconcentration observed in relation to pentagastrin-induced panic symptoms may be relevant to the increased risk of stroke and acute coronary events found in patients with panic disorder.

Effect of time of preparation on pentagastrin-induced symptom, endocrine and cardiovascular responses.

Pentagastrin is a cholecystokinin (CCK)-B agonist and laboratory panicogenic agent that produces endocrine (ACTH and cortisol), symptom (anxiety, panic) and cardiovascular (heart rate) responses. Although in vitro data have supported its chemical stability, preliminary data suggested that increasing time between drug preparation and drug infusion could reduce the magnitude of endocrine and symptom responses. The current study examined this possibility. Twenty-one healthy subjects presented at the University of Michigan General Clinical Research Center (GCRC) and had an intravenous catheter inserted. Heart rate, cortisol levels and subjective anxiety were measured before and after pentagastrin and placebo injections. Pentagastrin was prepared either within 60 min of IV infusion (Normal Preparation group) or at least 3.5 h prior to infusion (Early Preparation group). Relative to the Normal Preparation group, Early Preparation subjects had similar heart rate responses but significantly smaller cortisol and subjective anxiety responses. Early preparation of pentagastrin thus appears to weaken endocrine and subjective anxiety responses, highlighting the importance of attending to often overlooked procedural variables (e.g., time between preparation and administration) in studies of this type. The sensitivity of cortisol and anxiety responses to preparation time, but insensitivity of heart rate, is consistent with previous studies suggesting different thresholds of activation for the three response modalities. These differential sensitivities may suggest different and separable CCK-B stimulated pathways for each response, which combine to produce panic, rather than a single, unified CCK-B mediated panicogenic response.

Delayed increase in LDL cholesterol following pentagastrin-induced panic attacks.

OBJECTIVE: Panic disorder (PD) has been associated with an increased risk for cardiovascular (CV) morbidity and mortality. There are inconsistent reports of increased low-density lipoprotein cholesterol (LDL-C) in patients with PD. Studies have reported a correlation between cholesterol levels and the intensity and frequency of panic attacks (PAs), suggesting that an elevation in cholesterol could be due to physiological and neurochemical changes that occur during and after a PA. The objective of our study was to show that the occurrence of a PA is associated with an increase in LDL-C. MATERIALS AND METHODS: We used a double-blind, placebo-controlled crossover design with randomized injections of placebo and pentagastrin in 18 patients with PD (11 men, 7 women) and 33 healthy-control subjects (24 men, 9 women). RESULTS: Pentagastrin-induced PAs were associated with a statistically significant 10.4% delayed (24 h) increase in LDL-C levels in male subjects. Such an effect was not observed in female subjects. CONCLUSION: LDL-C levels are directly affected by the occurrence of a PA in males. These findings, in association with previous reports of increased cholesterol levels in PD patients, suggest that a chronic increase in LDL-C as a result of frequent PAs may be one of the mechanisms that contributes, at least in male patients, to previously reported increased CV risk in patients with PD. The gender difference and the temporal association between PAs and increased LDL-C may explain the inconsistency in the findings of previous investigations of cholesterol levels in PD patients.

Effects of cyclooxygenase-1 and -2 inhibition on gastric acid secretion and cardiovascular functions in rats.

The discovery of a second isoform of cyclooxygenase has led to a re-evaluation of the mechanisms underlying the adverse effects of nonsteroidal anti-inflammatory drugs, focusing in particular on the gastrointestinal system. We investigated the involvement of cyclooxygenase-1 and -2 in the regulation of gastric acid secretion and cardiovascular functions in anesthetized rats, after acute intravenous administration of the selective cyclooxygenase-1 inhibitor SC-560, the selective cyclooxygenase-2 inhibitor celecoxib and the nonselective inhibitor indomethacin. Indomethacin, celecoxib and SC-560 did not significantly modify basal acid secretion. Indomethacin and celecoxib were also ineffective on the acid secretion stimulated by pentagastrin; by contrast, SC-560 significantly enhanced the acid secretion stimulated by pentagastrin, electrical vagal stimulation or histamine. The stimulatory effects of SC-560 were prevented by cervical vagotomy, atropine and famotidine. Indomethacin caused either no change, increasing or decreasing effects on mean arterial pressure and heart rate. By contrast, SC-560 was unable to change cardiovascular parameters at 5 mg/kg, while inducing a marked bradycardia at 10 mg/kg. Celecoxib was ineffective. Our findings indicate that cyclooxygenase-1-derived prostaglandins are involved in the regulation of stimulated acid secretion and of basal heart rate; the role of prostaglandins in the acute control of systemic blood pressure under resting conditions seems to be negligible.

Anxiogenic effects of the CCK(B) agonist pentagastrin in humans and dose-dependent increase in plasma C-peptide levels.

RATIONALE: Cholecystokinin type B (CCK(B)) receptor agonists such as pentagastrin or CCK-4 have panic-like anxiogenic effects in humans. It has also been shown that CCK-4 can stimulate insulin release and thus C-peptide release from pancreatic islet cells. Combined, these mechanisms may provide a basis for a bioassay. OBJECTIVES: Our aim was to study if a pentagastrin bolus injection evokes insulin release (as measured by C-peptide) and if the levels of C-peptide correlate to the anxiogenic effect of pentagastrin. METHODS: Pentagastrin was given in bolus IV injections to healthy volunteers at increasing doses (0.003, 0.012, 0.05 and 0.2 microg/kg). RESULTS: A significant increase in the plasma level of C-peptide was observed 2-4 min after the highest dose of pentagastrin. This increase was accompanied by a transient panic-like anxiety within 2 min following pentagastrin, measured using a state anxiety scale. Also, 0.05 microg/kg pentagastrin gave a minor but significant subjective discomfort at the same time interval. The basal plasma level of C-peptide preceding the pentagastrin injection showed a positive correlation to the intensity of the subsequent pentagastrin-induced panic-like anxiety as rated on the state anxiety scale. In addition, basal plasma levels of cortisol were positively correlated to the subsequent pentagastrin-induced increase in plasma C-peptide levels. CONCLUSIONS: Our results imply a possible relationship between insulin/C-peptide release and sensitivity to psychotropic activation by CCK(B) receptor stimulation. Furthermore, we postulate that both basal and pentagastrin-induced plasma levels of C-peptide may possess characteristic phenotype properties for anxiety related traits.

The quest for biological correlates of social phobia: an interim assessment.

OBJECTIVE: The primary goal of this review was to assess critically the literature concerning the ongoing search for possible biological correlates of social phobia. METHODS: In addition to manual searches, Medline, Current Contents and Psych Info databases were searched for relevant publications. RESULTS: On the evidence of an extensive body of research, so far biological correlates of social phobia remain elusive. Furthermore, the majority of studies reveal by default that the neurobiological functioning of social phobics is very much like that of normal control subjects. CONCLUSION: The conceptual and methodological foundations underpinning the current research programme are discussed critically. Its main weaknesses were found to be: lack of theory to guide research and aid the interpretation of results, static comparisons between subject groups and analysis oblivious to great individual variations. Possibilities of alternative approaches to study the neurobiology of social phobia are raised. Among others, continuous and situation-specific measurement, subjects used as their own controls and neurobiological correlates of clinical improvement following psychotherapy are considered.

Dose response of adrenocorticotropin and cortisol to the CCK-B agonist pentagastrin.

Cholecystokinin (CCK) is an abundant neurotransmitter in brain. Its functional significance in humans is incompletely understood, but it may modulate activity in the hypothalamic-pituitary-adrenal (HPA) axis. To explore this hypothesis, we examined the effects of varying doses (0 to 0.8 microgram/kg) of the CCK-B agonist pentagastrin on adrenocorticotropin (ACTH) and cortisol release in healthy human subjects. We also examined anxiety, heart rate (HR), and blood pressure (BP) responses. Pentagastrin induced large (up to 520% increase over baseline), significant and very rapid, dose-dependent elevations in ACTH and cortisol levels. Significant elevations in HR and BP were seen at all doses, without clear dose-response relationships. Anxious distress and symptom responses were also somewhat dose dependent; but hormonal responses were more robustly linked to pentagastrin dose than to these subjective measures. The HPA axis response to the CCK-B agonist pentagastrin may be a direct pharmacological effect. Further work is needed to determine the mechanisms and the physiological significance of CCK-mediated modulation of the human neuroendocrine stress axis.

A comparison of the effects of intravenous pentagastrin on patients with social phobia, panic disorder and healthy controls.

The present study sought to determine whether social phobics, like patients with panic disorder, have increased sensitivity to the panicogenic effects of pentagastrin. Intravenous pentagastrin and placebo were administered in a double-blind fashion to 19 social phobics, 11 patients with panic disorder, and 19 healthy controls while they participated in a structured social interaction task. Behavioral, cardiovascular, and neuroendocrine responses were obtained. Pentagastrin led to panic attacks in 47% of the social phobics, 64% of the panic disorder patients, and 11% of the healthy controls. The social interaction itself increased anxiety, blood pressure, and pulse in all three groups. These findings suggest that the panicogenic effects of pentagastrin are not limited to patients with panic disorder and provide further evidence for shared neurobiology in social phobia and panic disorder.

Early and late effects of low-dose famotidine, ranitidine or placebo on pentagastrin-stimulated gastric acid secretion in man.

BACKGROUND: There are no published comparative studies on the effect of low-dose H2-antagonists on pentagastrin-stimulated gastric acid secretion. METHODS: Twenty-four healthy subjects were dosed with either famotidine 10 mg, ranitidine 75 mg or placebo in a balanced three-period cross-over design. The subjects were studied in groups of 12, simultaneously, under identical controlled environmental conditions. Gastric juice was aspirated in 15-min aliquots during sub-maximal (0.6 microgram.h/kg) intravenous pentagastrin stimulation in the third and fourth hours (early period) and the eighth and ninth hours (late period) after oral dosing. The hydrogen ion (H+) content of gastric juice was measured ex vivo, by titrating to pH7 known volumes of gastric aspirate against 0.1 M sodium hydroxide, using a versatile microprocessor-controlled auto-titration unit. Gastric acid output during the period of interest was calculated by adding the hydrogen ion content of 15-min aliquots collected during that period. The geometric mean of the cumulative pentagastrin-stimulated gastric acid output during the early and late periods was determined for the subjects dosed with either famotidine, ranitidine or placebo. Comparisons were performed by ANOVA. RESULTS: During the early period (2-4 h post-dose), When the subjects were given placebo, mean gastric acid output was 46.6 mmol, decreasing by 76% to 11.3 mmol (P < 0.001) when treated with famotidine and by 76% to 11.1 mmol (P < 0.001) when treated with ranitidine. During the late period (7-9 h post-dose), when the subjects were dosed with placebo, mean gastric acid output was 41.2 mmol, decreasing by 38% to 25.7 mmol (P < 0.001) when treated with famotidine and by 27% to 30.0 mmol (P = 0.007) when treated with ranitidine. The difference between the inhibitory effects of famotidine and ranitidine on gastric acid output were non-significant during either period. CONCLUSIONS: Low-dose famotidine and ranitidine, intended for over-the-counter use, inhibit stimulated gastric acid secretion profoundly in the third and fourth hours after an oral dose. Modest effects are still detectable up to 9 h after dosing.

Pentagastrin has panic-inducing properties in obsessive compulsive disorder.

The effects of the CCKB-receptor agonist pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK-4), were studied in seven patients suffering from obsessive compulsive disorder (OCD) and seven healthy controls. All subjects were challenged with an IV dose of 0.6 micrograms/kg pentagastrin or placebo under double blind placebo controlled conditions, on two separate occasions, with a minimum interval of 1 week. Six (86%) out of seven OCD patients experienced a panic-like reaction after pentagastrin administration, against only two (29%) in the control group. These differences failed to reach statistical significance, probably due to the small sample size. No increases were observed in obsessions or compulsive behaviors as assessed with the Yale-Brown Obsessive Compulsive Challenge Scale, neither in the pentagastrin, nor in the placebo condition. These findings suggest that pentagastrin has panic-inducing properties in OCD patients, without affecting the core symptoms. The panic-inducing properties of pentagastrin are not specific for panic disorder patients, which might be indicative of a common neurobiological dysfunction in panic disorder and OCD at the level of CCK-B receptors.

Cholecystokinin and anxiety in normal volunteers: an investigation of the anxiogenic properties of pentagastrin and reversal by the cholecystokinin receptor subtype B antagonist L-365,260.

1. Two studies were undertaken to develop a model of experimentally induced anxiety in normal volunteers based on cholecystokinin (CCK) receptor agonism/antagonism. 2. In Study 1 rapid intravenous injections of the CCK receptor subtype B (CCKB) agonist pentagastrin (0.15, 0.3 and 0.6 micrograms kg-1) were found to produce dose-related increases in subjective ratings of anxiety compared with placebo. 3. In Study 2 the effects of pre-treatment with two doses of the CCKB receptor antagonist L-365,260 (10 mg, 50 mg p.o.) on the anxiety induced by pentagastrin 0.3 micrograms kg-1 i.v. were investigated. Detailed measurements of blood pressure and pulse rate were also undertaken. Pentagastrin produced changes in blood pressure and pulse rate which had a similar time course to that observed for subjective anxiety ratings. L-365,260 reversed both the autonomic and anxiogenic effects of pentagastrin. 4. The pentagastrin model would appear to be a useful tool for investigating potential anxiolytics in normal volunteers.

The effect of tripotassium dicitrato bismuthate on the rat stomach.

BACKGROUND: Bismuth has been used as symptomatic treatment of dyspepsia for many years. It promotes healing of peptic ulcers and reduces their recurrence. The beneficial effect of bismuth on duodenal ulcer disease is thought to be due to an effect on Helicobacter pylori, although it has a rather weak bactericidal effect on H. pylori in vitro. Eradication of H. pylori in duodenal ulcer patients by a combination of bismuth, tetracycline and metronidazole has been reported to increase the density of somatostatin-producing D cells in the antrum. A reduced D cell density in the antral mucosa of duodenal ulcer patients could explain their exaggerated gastrin release. AIMS/METHODS: To test the possibility that bismuth could affect the neuroendocrine cells independently of the presence of H. pylori or not, we gave rats a diluted tripotassium dicitrato bismuthate solution by gastric gavage for 14 days. RESULTS: Tripotassium dicitrato bismuthate treatment did not affect maximal pentagastrin-stimulated acid secretion or histamine release in isolated rat stomachs or the density of argyrophil cells in the oxyntic and antral mucosa. However, it significantly reduced the duodenal concentration of gastrin and calcitonin gene-related peptide, and the density of G cells in the antrum and duodenum. CONCLUSION: The effect of tripotassium dicitrato bismuthate on the G cell may be of significance for its beneficial effect on duodenal ulcer disease.

Evaluation of alternative proximal gastric vagotomy techniques after a 9-month interval in a rat model.

Proximal gastric vagotomy (PGV) is an accepted operation for patients with ulcers that are refractory to medical management. Results comparable to those of standard, operative PGV have previously been demonstrated using endoscopic chemoneurolytic injection or laparoscopic laser seromyotomy in a porcine model. In this study, we evaluated several PGV techniques in regard to long-term effects on acid secretion, ulcer prophylaxis, and permanent vagal denervation in a rat model. Trans-mucosal injection of chemoneurolytic agents (cobaltous chloride, benzalkonium chloride, and phenol) and seromyotomy by CO2 laser were performed. After 9 months, all rats received sub-serosal gastric injections of horseradish peroxidase (HRP) during laparotomy. Twenty-four hours later, an ulcerogenic dose of pentagastrin was administered sub-cutaneously. Three days after administration of HRP (to allow time for retrograde axonal transport and labeling of cells of the dorsal vagal nucleus with HRP), necropsy was performed. The pre-pyloric gastric mucosa was inspected for ulcerogenic changes, and a Congo red solution was applied to the gastric mucosa to map the acid-secreting areas. All PGV methods significantly diminished pentagastrin-induced ulceration when compared to sham controls. Benzalkonium chloride chemoneurolytic and laser methods were most effective for decreasing the size of acid-secreting areas. A reduced number of HRP-stained cells in the dorsal vagal nucleus indicated permanent denervation of vagal-gastric connections by operative and laser techniques.

Normal calcitonin response to pentagastrin stimulation in patients with chronic renal failure.

High calcitonin levels have been reported in chronic renal failure. To study the C cell response in patients with chronic renal failure, an intravenous bolus of pentagastrin was administered to 11 patients and 11 healthy subjects. Samples were obtained at 0, 1, 2, 3, 5 and 10 min for calcitonin assay. In order to detect only the active monomeric calcitonin, an immunoradiometric assay method was used. The influence of calcium, phosphate, alkaline phosphatase and intact parathyroid hormone was also evaluated. Although basal calcitonin levels were higher (p < 0.01) in chronic renal failure (mean +/- SEM: 10.1 +/- 2.9 pmol/l) versus healthy subjects (1.1 +/- 0.3 pmol/l), the area under the curve showed there to be no differences between the two groups. The rising branch of the area under the curve, employed as an expression of the C cell response capacity, showed no differences either (chronic renal failure vs healthy subjects: 5.6 +/- 2 vs 2.6 +/- 0.7 pmol l-1 min-1, p = 0.28). In the chronic renal failure group, a positive correlation was found (r = 0.625, p < 0.05) between the rising branch of the area under the curve and parathyroid hormone. We conclude that monomeric calcitonin is increased in chronic renal failure, but C cells of the thyroid respond to pentagastrin, as they do in normal subjects. This finding is of great clinical importance when a patient with renal impairment is evaluated for medullary thyroid carcinoma. The calcitonin response to pentagastrin seems to be related directly to the degree of secondary hyperparathyroidism in chronic renal failure.

[Sucralfate (Ulcogant). The mechanism of action of a cytoprotective agent]. / Sucralfat (Ulcogant) Der Wirkmechanismus eines Zytoprotektivums.

The new antiulcer drug sucralfate is characterized by a multiple mode of action. Its predominant feature is a protection of the mucosa from endogenous and exogenous noxious agents. These cytoprotective properties result from a locally formed layer covering ulcers and erosions which inhibits the diffusion of H-ions and pepsin to the damaged mucosa. This layer is also stable against exogenous substances with deleterious effects on the mucosa like alcohol and salicylates. Furthermore, sucralfate binds pepsin and bile acids. Recently, a stimulating effect of sucralfate on the release of prostaglandins and the regeneration of epithelial cells in the gastric mucosa was demonstrated. There is no influence of sucralfate on the production of gastric juice and pH. Since sucralfate is minimally absorbed it is a safe and well tolerated drug.