Prolonged Use Of Proton Pump Inhibitors Research Articles

Proton Pump Inhibitors and Bone Health: What the Orthopaedic Surgeon Needs to Know.

* Proton pump inhibitors (PPIs) are widely prescribed medications that are utilized for the treatment of gastroesophageal reflux and similar gastrointestinal disorders in all patient populations.* There is evidence that prolonged use of PPIs can lead to osteoporosis and altered bone metabolism and can even affect developing bone in pediatric patients.* There is evidence that the use of these medications increases the risk of fractures in pediatric and adult patients, including fragility fractures of the hip and spine in elderly patients.* There is preclinical evidence that the use of PPIs can affect bone-healing after fracture, delaying callus formation and altering the biomechanics of healing bone.* Orthopaedic surgeons, primary-care managers, and gastroenterologists should consider these risks when their patients are receiving prolonged PPI therapy, and the risks and benefits of PPI use should be taken into account when tailoring PPI use to each individual patient.

Factors related to gastric neuroendocrine tumors

Introduction and aimsAn association between long-term use of proton pump inhibitors and the development of gastric neuroendocrine tumors has been reported, but it is still a subject of debate. The aims of the present study were to determine the presence of this association in a Mexican population and to identify the risk factors for developing gastric neuroendocrine tumors. Materials and methodsA case-control study was conducted, in which the cases were patients with a histopathologic diagnosis of gastric neuroendocrine tumor and the controls were patients evaluated through upper endoscopy. The controls were paired by age, sex, and endoscopic examination indication. Proton pump inhibitor use was considered prolonged when consumption was longer than 5 years. ResultsThirty-three patients with gastric neuroendocrine tumor and 66 controls were included in the study. Eighteen (54.5%) patients in the case group were women, as were 39 (59%) of the patients in the control group. The median age of the patients in the case group was 55 years (minimum-maximum range: 24-82) and it was 54 years (minimum-maximum range:18-85) in the control group. A greater number of patients in the gastric neuroendocrine tumor group presented with gastric atrophy (p<0.0001) and autoimmune atrophic gastritis (p=0.0002), compared with the control group. No association between gastric neuroendocrine tumor and prolonged proton pump inhibitor use, sex, smoking, gastroesophageal reflux disease, Helicobacter pylori infection, diabetes mellitus, or autoimmune diseases was found in the univariate analysis. ConclusionsThe results of our study showed no association between proton pump inhibitor use for more than 5 years and the development of gastric neuroendocrine tumor. The presence of gastric atrophy and autoimmune atrophic gastritis was associated with gastric neuroendocrine tumor development.

Antisecretory treatment: clear-cut benefit and potential risk

Proton pump inhibitors (PPI) remain a key element in the management of acid-dependent diseases. The antisecretory drug administration schedule should take into account the nature of the disease and the research data reflected in relevant international consensus. The patient’s adherence to the PPI intake has a significant impact on the results of management of acid-dependent diseases. The benefit of PPI intake significantly exceeds the potential harm that is low or very low. To date, there is no conclusive evidence of the adverse effects of the prolonged use of PPI, however, if there is no indication for the PPI intake, it is not recommended to use high doses of the drug. The pharmacodynamic effect of different PPIs doesn’t differ significantly, however, according to experts’ opinion based on meta-analysis, esomeprazole has some advantage over other drugs.

The relationship between proton pump inhibitors and renal disease.

ABSTRACTProton pump inhibitors (PPIs) bind to enzyme H+/K+-ATPase and inhibit its activity in the stomach, thus decreasing the secretion of gastric acid. PPIs may trigger acute interstitial nephritis, a potentially severe adverse event commonly associated with acute kidney injury. Studies have found that prolonged use of PPIs may increase the risk of chronic kidney disease (CKD). The increase in prescription and inadequate use of this class of medication calls for studies on the effects of prolonged PPI therapy on renal function. Therefore, this review aimed to analyze recent studies on the matter and discuss the possible consequences of the long-term use of PPIs on renal function.

The Case for Thoughtful Prescribing of Proton Pump Inhibitors in Infants.

Reply: We appreciate the comments discussed in the letter by Drs Gunasekaran, Kakodkar, and Berman. Although the authors lay out the case for the differential pharmacokinetics of proton pump inhibitors in infants as a reason for cautious prescribing, we wanted to highlight that the main reason not to prescribe these medications in infants is because they are not efficacious in treating symptoms in otherwise healthy infants. Despite the fact that between 23% and 71% of infants are prescribed either an H2 antagonist or a proton pump inhibitor worldwide, there are multiple studies including placebo-controlled trials showing a lack of benefit of acid suppression in improving symptoms of fussing, crying, arching, apnea, cough, hoarseness, wheezing, or feeding intolerance (1–4). The lack of efficacy may be multifactorial; symptoms may not be reflux related or the reflux is a result of nonacidic gastric contents getting refluxed (ie, formula or breast milk) upon which acid suppression has no effect. So, although consideration of pharmacokinetics and side effects are important when prescribing, the biggest deterrent should be that these medications have consistently been shown not to improve symptoms. There are 2 notable populations in whom acid suppression is warranted, those patients at high risk for esophagitis and those with confirmed histologic esophagitis with eosinophilic infiltrates. Children with esophageal motility disorders such as treated achalasia or esophageal atresia fall into this first category; any reflux that enters the esophagus is poorly cleared because of profound disturbances of peristalsis. Recognizing the impact of dysmotility on poor reflux clearance is critical and, this population, we feel, merits aggressive acid suppression therapy with proton pump inhibitors to prevent long-term reflux complications including erosive esophagitis, metaplasia of esophageal epithelium, and stricturing (5). Apart from patients with dysmotility, a second population meriting therapy includes symptomatic infants with eosinophilic infiltration of the esophagus in whom proton pump inhibitor (PPI) therapy may help to narrow the differential diagnosis including eosinophilic esophagitis, proton pump inhibitor responsive eosinophilic esophagitis, and reflux esophagitis. As with all medications, prescribing needs to be done thoughtfully and the pathophysiology of the signs and symptoms needs to be considered. We whole heartedly agree that there is a limited role for proton pump inhibitors in infants. Those infants with motility disorders and confirmed esophagitis do, however, merit therapy. Again, we assert that once prescribed, the benefit/risk ratio of long-term PPI treatment should be balanced, and the need of prolonged use of PPIs should be reassessed on a regular basis.

Proton Pump Inhibitors Increase Risk for Hepatic Encephalopathy in Patients With Cirrhosis in A Population Study

Hepatic encephalopathy (HE) is a serious complication of cirrhosis and is associated with gut dysbiosis. Proton pump inhibitors (PPIs), frequently prescribed to patients with cirrhosis, can contribute to small-bowel bacterial overgrowth. We investigated whether PPI predisposes patients with cirrhosis to HE using a large database of patients. We performed a case-control study nested within a sample of Taiwan National Health Insurance beneficiaries (n=1,000,000), followed up longitudinally from 1998 through 2011. Patients with cirrhosis and an occurrence of HE (n=1166) were selected as the case cohort and matched to patients without HE (1:1, controls) for sex, enrollment time, end point time, follow-up period, and advanced cirrhosis. Information on prescribed drugs, drug dosage, supply days, and numbers of dispensed pills was extracted from the Taiwan National Health Insurance database. PPI use was defined as more than 30 cumulative defined daily doses (cDDDs); PPI nonuse was defined as 30 cDDDs or fewer. We performed logistic regression analyses to estimate the association between PPI use and the occurrence of HE. Among patients with cirrhosis and an occurrence of HE, 38% (n= 445) had a history of PPI use before HE occurrence. We observed a relationship between dose of PPI taken and HE risk. The confounder-adjusted odd ratios were 1.41 (95% confidence interval [CI], 1.09-1.84), 1.51 (95% CI, 1.11-2.06), and 3.01 (95% CI, 1.78-5.10) for patients with 30-120 cDDDs, 120-365 cDDDs, and more than 365 cDDDs, respectively, compared with PPI nonusers. All categories of PPIs, except rabeprazole, were associated with an increased risk of HE. Based on an analysis of data from Taiwan National Health Insurance beneficiaries, we found that use of PPIs in patients with cirrhosis increases the risk for HE; risk increases with dose. It therefore is important for health care providers to carefully consider prolonged PPI use by patients with cirrhosis.

Proton Pump Inhibitors and Hypomagnesemia in the General Population: A Population-Based Cohort Study

Proton pump inhibitor (PPI) use has been associated with hypomagnesemia in case reports and hospital-based cohort studies. Our objective was to determine whether PPI use is associated with hypomagnesemia in the general population and whether this is also found in histamine 2 receptor antagonist (H2RA) users. Prospective cohort study. 9,818 individuals from the general population (Rotterdam Study). PPI use and H2RA use compared to no use. Serum magnesium and hypomagnesemia (serum magnesium≤ 1.44 mEq/L).Analyses were adjusted for age, sex, body mass index, kidney function, comorbid conditions, and alcohol and diuretic use. Serum magnesium level was 0.022 mEq/L lower in PPI users (n=724; 95% CI,-0.032 to-0.014 mEq/L) versus those with no use. PPI use was associated with increased risk of hypomagnesemia (n=36; OR, 2.00; 95% CI, 1.36-2.93) compared to no use. Effect modification was found between the use of PPIs and loop diuretics; in participants using loop diuretics (n=270), PPI use was associated with a further increased risk of hypomagnesemia (n=5; OR, 7.22; 95% CI, 1.69-30.83) compared to no use. The increased risk with PPIs was only seen after prolonged use (range, 182-2,618 days; OR, 2.99; 95% CI, 1.73-5.15). Including dietary magnesium intake into the model did not alter results (available for 2,504 participants, including 231 PPI users). H2RA users (n=250) also had a lower serum magnesium level (-0.016 [95% CI,-0.032 to-0.002] mEq/L) and increased risk of hypomagnesemia (n=12; OR, 2.00; 95% CI, 1.08-3.72) compared to those with no use, but no interaction with loop diuretics. Cross-sectional analysis with single serum magnesium measurement. PPI use is associated with hypomagnesemia in the general population. Prolonged PPI use and concomitant loop diuretic use are associated with a stronger risk increase. Similar but weaker associations were found in H2RA users, except for interaction with loop diuretics.

Pharmacogenomic testing: the case for CYP2C19 proton pump inhibitor gene-drug pairs.

The use of proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux and related diseases is increasing, especially in the pediatric population. Prolonged use of PPIs has been associated with several adverse effects, including potentially life-threatening gastric and respiratory infections, which are related to dose or to the degree of gastric acid suppression. Genetic variation in the CYP2C19 gene gives rise to poor and extensive metabolizer phenotypes, which influence PPI clearance, efficacy and exposure. A recent paper linked lansoprazole-associated respiratory infections in children with the poor metabolizer phenotype. The case is made for implementing pharmacogenomic testing for the CYP2C19-PPI gene-drug pair and to dose accordingly in order to minimize PPI-associated infections.

Aspirin and Proton Pump Inhibitor Combination Therapy for Prevention of Cardiovascular Disease and Barrett's Esophagus

Aspirin, used at low doses (75–325 mg daily), prevents aggregation of platelets and is prescribed for patients as pharmacologic prevention of cardiovascular disease. Despite the well–documented beneficial effects of aspirin, prolonged use is associated with damage to the gastrointestinal (GI) mucosa in the upper and lower GI tract. Patient risk of hemorrhage and peptic ulcer formation is increased with older age, previous ulcer history, Helicobacter pylori infection, and concomitant use of nonsteroidal anti–inflammatory drugs, corticosteroids, or antithrombotic agents. As termination of aspirin therapy can precipitate a cardiovascular event, patients at risk need co–therapy with gastroprotective agents, such as proton pump inhibitors (PPIs), to reduce the GI side effects of aspirin treatment. Fixed–dose combinations of low–dose aspirin and gastroprotective agents have been designed to increase medication compliance, improve clinical outcomes, and reduce the overall cost of therapy. Prolonged use of PPIs may, however, lead to serious adverse effects or, in some cases, reduce the cardioprotective effects of aspirin. Hence, physicians need to carefully consider the benefits and risks associated with the condition of each patient to optimize clinical outcomes of combination therapy. A growing body of clinical evidence indicates that aspirin may decrease the risk of colorectal and other GI cancers, as well as reduce progression from Barrett's esophagus (BE) to esophageal adenocarcinoma. Furthermore, PPIs have recently been shown to reduce neoplastic transformation in patients with BE. Thus, the use of a fixed–dose aspirin/PPI combination could potentially provide chemopreventive benefit to patients with BE, and, at the same time, treat the underlying gastroesophageal reflux responsible for the condition.

Thickened Gastric Folds Secondary to Prolonged Proton Pump Inhibitor Use: Clinically Relevant?

Purpose: A 60-year-old Caucasian woman was referred for an endoscopic ultrasound after a thorough evaluation for intermittent epigastric and right hypochondriac abdominal pains revealed markedly thickened gastric folds. Of note, she had been on a proton pump inhibitor (PPI) on a daily basis for many years. Her work-up included ultrasonography of the abdomen, biliary scintigraphy, upper GI scintigraphy, CT and MRI of the abdomen, a colonoscopy, and an EGD at another facility. The only abnormal findings were those of thickened gastric folds in the body and fundus on radiological and endoscopic imaging (Image 1). Helicobacter pylori infection was ruled out on antral biopsies. Due to a concern for an infiltrative or inflammatory gastric disorder, she underwent an endoscopic ultrasound at our tertiary referral center for further evaluation. There was thickening of the mucosa and submucosa but not the muscularis layer (Image 2), with a 2.1-cm wall thickness and no perigastric lymphadenopathy. A cold snare biopsy was obtained revealing benign oxyntic mucosa with focal cystic dilatation and cytoplasmic vacuolization, consistent with PPI therapy and no other abnormality. It has been well described that long-term PPI use can result in reversible, duration dependent, parietal cell hypertrophy and hyperplasia secondary to the resultant hypergastrinemia and its trophic effects. However, macroscopic findings suggestive of hypertrophied gastric folds have not been well described in this setting. Hence, we postulate, that the trophic effect of excessive gastrin in the setting of prolonged PPI therapy could potentially lead to gastric hypertrophy, the long term effects and malignant potential of which are yet unknown and merit further investigation.FigureFigure

Su2026 PPI Use and Small Intestinal Bacterial Overgrowth Detected on Lactulose Breath Testing: Results of a Prospective Cross Sectional Study Among U.S. Veterans With Irritable Bowel Syndrome

Background/Aims: Proton Pump Inhibitors (PPIs) have been proposed to be the missing link in the controversy surrounding Small Intestinal Bacterial Overgrowth (SIBO) and Irritable Bowel Syndrome (IBS). Recent studies examining the relationship between PPIs and SIBO have been limited by retrospective analysis and failure to control for confounding factors such as somatization which may be common to both PPI use and SIBO. Consequently, the aims of this prospective cross sectional study were: 1) To calculate adjusted Odds Ratios (ORs) for hydrogen (H2) and methane (CH4) SIBO based upon PPI use 2) To determine the impact of PPI use on Lactulose Breath Testing (LBT) parameters. Methods: 149 nondiabetic veterans (67 PPI users, 82 non-users, 82% male, mean age 45) meeting Rome III IBS criteria undergoing LBT were recruited. Data on IBS subtype and severity (IBS Severity Scoring System), bloating, depression/anxiety (Hospital Anxiety Depression Score) and somatization (Psychosomatic Symptom Checklist) were obtained by questionnaire. Use of PPIs, fiber, laxatives, probiotics, H2-Blockers, anti-cholinergics, diagnoses of GERD and BMI were obtained from the medical record. LBT's were defined as positive using different criteria: 1) Two H2 Peaks (Increase .20 ppm over the baseline by 90 min with a single peak occurring at least 15 min prior to the second peak with a trough after the first peak of . 5ppm) 2) Increase in H2 by . 20 ppm by 90 min. 3) Any CH4 . 5 ppm 4) Rise in CH4 by. 20 ppm by 90 min. Adjusting for confounding factors using logistic regression, adjusted ORs for PPI use and SIBO were calculated. LBT parameters including baseline H2 and CH4, amplitude of rise to first H2 peak (P1), and time to P1 were compared between PPI and non-PPI groups using Wilcoxon rank sum and t-tests. Results: The prevalence of H2-SIBO using Two H2 Peak criteria was 36.9% in PPI vs. 17.9% in Non-PPI groups (p=0.01). Adjusted OR for PPI Use and Two Peak H2-SIBO was 4.3 (95% CI 1.4-12.9, p=0.01). PPI use of . 180 days was found to be associated with Two Peak H2-SIBO with OR 3.2 (95% CI 1.2-8.9, p=0.02). ORs for PPI use and SIBO were not statistically significant using the other H2 or CH4 criteria (Table). Among LBT parameters, there was a trend towards a shorter time to P1 in the PPI group (Fig 1). However, a statistically significant difference was found in time to P1 when comparing PPI use of .180 days vs. , 180 days (58.7 vs. 75.7 min, p=0.02) (Fig 1). Comparisons between PPI vs. Non-PPI groups did not find differences in baseline H2 (0 vs. 0 ppm, p=0.45), CH4 (1 vs.1.2 ppm, p=0.70) or amplitude to P1 (50 vs. 45 ppm, p=0.55). Conclusions: PPI use is associated with an increased prevalence of H2-SIBO on LBT but only when using the Two H2 Peak criteria. This may be caused by an earlier rise in H2 in the proximal small bowel seen with prolonged PPI use. (Table) Adjusted Odds Ratios for PPI Use and SIBO Using Different H2 and CH4 Criteria

Proton Pump Inhibitors Reduce the Risk of Neoplastic Progression in Patients With Barrett's Esophagus

Acid exposure contributes to the development of Barrett's esophagus (BE) and its progression toward esophageal adenocarcinoma. Patients with BE are frequently treated with acid suppressants, but it is unclear whether these prevent the development of BE-related cancer. We investigated whether acid suppression reduces the risk of neoplastic progression in patients with BE. We performed a multicenter prospective cohort study of 540 patients with BE. We collected information on medication use at each surveillance visit, which was cross-checked with pharmacy records. Patients also completed a questionnaire about their use of over-the-counter medication. Incident cases of high-grade dysplasia and esophageal adenocarcinoma were identified during a median follow-up period of 5.2 years. Time-dependent Cox regression models were used to investigate the effect of acid suppression on the risk of neoplastic progression. Forty patients (7%) developed high-grade dysplasia or esophageal adenocarcinoma during the follow-up period. Use of histamine-2 receptor antagonists did not affect the incidence of neoplastic progression. However, use of proton pump inhibitors (PPIs) at inclusion in the study or during the follow-up period reduced the risk of neoplastic progression (hazard ratio, 0.41; 95% confidence interval, 0.18-0.93 and hazard ratio, 0.21; 95% confidence interval, 0.07-0.66). Prolonged use of PPIs and good adherence were associated with an additional protective effect. The prevalence of esophagitis decreased during PPI use, but length of BE was not affected. In a multicenter prospective cohort study, PPI use was associated with a reduced risk of neoplastic progression in patients with BE.

No Evidence of Cancer Risk from Long-Term PPI Therapy

Prolonged use of proton-pump inhibitors (PPIs) has been associated with an increase in serum gastrin levels, which could drive proliferation of

Effect of Proton Pump Inhibitors and H2 Antagonists on the Stomach Wall in 99mTc-Sestamibi Cardiac Imaging

On the basis of previously unpublished observations, we hypothesized that prolonged use of proton pump inhibitors (PPIs) causes an increase in (99m)Tc-sestamibi uptake in the stomach wall, manifested as curvilinear activity surrounding the photopenic fundus of the stomach cavity. We prospectively evaluated the frequency of stomach wall uptake in patients undergoing myocardial perfusion SPECT who were taking PPIs or H(2) antagonists. Patients (n = 138) who were scheduled for single-day rest/stress (99m)Tc-sestamibi SPECT were randomly selected. Poststress SPECT was performed 30 min after treadmill exercise or 45 min after dipyridamole infusion. The rest scan was obtained 45 min after tracer injection. All patients drank 473 mL of water 5-10 min after both the rest and the stress radiotracer injections. Patients were questioned regarding their use of PPIs and H(2) antagonists. The significant use of either was defined as more than 2 wk of continuous therapy before cardiac SPECT. Masked observers assessed poststress planar projection images in endless-loop cinematic format for the following 3 patterns: stomach cavity uptake, attributable to duodenogastric reflux of tracer; stomach wall uptake; and no stomach uptake. A 2-tailed chi(2) test with Yates correction was used to calculate statistically significant associations among variables. Only patients with observed patterns of stomach wall uptake (n = 30) and no stomach wall uptake (n = 91) were included. Patients with stomach cavity uptake (n = 17) were excluded because the assessment of the adjacent stomach wall uptake was not possible. Of the patients included (n = 121), 30 were men and 91 were women. Sixty-seven patients were older than 60 y; 26 patients were taking PPIs. Of the 95 patients not taking PPIs, 14 were taking H(2) antagonists. No patients were taking both medications. Stomach wall uptake was strongly associated with prolonged use of PPIs (chi(2) = 51.9, P < 0.0001). No statistically significant association was noted among age, sex, or use of H(2) antagonists (P = NS). Prolonged PPI therapy, but not H(2) antagonist therapy, contributes to a significant increase in stomach wall activity, potentially resulting in Compton scatter or ramp filter artifacts affecting the inferior wall of the left ventricle. Stomach wall activity, unlike the stomach cavity activity, cannot be prevented by the ingestion of water before imaging. Therefore, it is important to elicit a history of prolonged PPI use to better anticipate the possibility of increased stomach wall activity, which can confound the image quality and interpretation.

Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo

BackgroundBarrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in...

Do Acid-Lowering Agents Affect Vitamin B12 Status in Older Adults?

To examine the relationship between serum vitamin B12 levels in older adults on histamine(2) receptor antagonists (H2 blockers) or proton-pump inhibitors (PPI) over 6 years. A cross-sectional sample of 659 adults, 60 to 102 years, from long-term care facilities and community ambulatory care (C) in the Bronx. Patient demographics, serum B12 levels, use and duration of use of H2 blockers, PPIs, antacids, multivitamin/minerals, liquid dietary supplements, oral vitamin B12 supplementation, oral or intramuscular B12 therapy, and recent lab chemistries. Acid-lowering agents (ALA) were used by 54% (PPIs by 26% and H2 blockers by 28%), duration averaged 18.2 +/- 16.0 (SD) months. NH and C subjects had similar ages (P = .9971), gender distributions (P = .625), durations of ALA use (P = .1227), and rates of PPI use (P = .130); NH subjects used more H2 blockers (P < .0005) and had less low B12 status (P = .037). H2 blocker use did not influence serum B12 status (P = .1036) while PPI use was associated with diminished serum B12 levels (P < .00005). Concomitant oral B12 supplementation slowed but did not prevent the decline in B12 status during prolonged PPI use (P = .0125). B12 status declines during prolonged PPI use in older adults, but not with prolonged H2 blocker use; supplementation with RDA amounts of B12 do not prevent this decline. This report reinforces that B12 deficiency is common in the elderly and suggests that it appears prudent to monitor periodically B12 status while on prolonged PPI use, to enable correction before complications ensue.

P-5: TCAP-1 administration in rats modulates the anxiogenic effects of CRF in three tests of anxiety

s / Neuropeptides 40 (2006) 417–445 443 are known to correlate negatively with body mass index (BMI) so that ghrelin is elevated in anorexia nervosa and decreased in obesity. In patients with cancer cachexia, it has been postulated that lack of appetite and weight loss, despite elevated ghrelin levels, results from partial ghrelin resistance. Exogenous ghrelin administered to these patients has been shown to increase caloric intake by 31%. In this study, we have shown that increased endogenous release of ghrelin from neuroendocrine tumors (NETs) can overcome the partial ghrelin resistance seen in cancer cachexia. Methods: The study was conducted as a single-center, prospective trial enrolling 35 patients with NETs. Total ghrelin levels and chromogranin A (CgA) values were measured and analyzed for differences by t test (p < 0.05). Subgroups examined included patients with and without hepatic metastases, carcinoid versus pancreatic NETs, and patients with and without hypergastrinemia due either to prolonged proton pump inhibitor use or due to Zollinger-Ellison Syndrome (ZES). Results: Mean total ghrelin levels in patients with NET and hepatic metastases (589 pg/ml) were significantly elevated compared to the group of NET patients without hepatic metastases (411 pg/ml). The former had a mean BMI of 27.2 compared to a mean of 26.3 for the latter. These higher ghrelin levels correlated with higher serum chromogranin A levels. Mean total ghrelin in patients with hypergastrinemia due to prolonged proton pump inhibitor therapy (591 pg/ml) differed significantly from untreated patients (418 pg/ml). No significant differences in ghrelin levels were seen in patients with carcinoid tumors compared to those with pancreatic neuroendocrine tumors nor between patients with Zollinger-Ellison syndrome versus those without. All patients with neuroendocrine tumors had elevated levels of ghrelin compared to the standard reference range. Conclusions: We report that in all subgroups analyzed, patients with NETs had levels of ghrelin that positively correlated with BMI suggesting that any partial ghrelin resistance may be overcome with increased endogenous ghrelin. This data supports the possibility that ghrelin is co-released from NETs and exerts an orexigenic effect in these patients, helping to maintain weight preservation despite widely disseminated disease. doi:10.1016/j.npep.2006.09.044 P-8: INVOLVEMENT OF PROTEOGLYCANCONTAINING CELLS AND/OR THE PROTEOGLYCAN EXTRACELLULAR MATRIX IN SYNAPTIC TRANSMISSION Yu.S. Garkun , A.A. Denisov , P.G. Molchanov , N.V. Yakubovich , V.A. Kulchitsky ; a Institute of Physiology, National Academy of Sciences, 28 Akademicheskaya Str., 220072, Minsk, Belarus; b Belarus State University, 4 Nezavisemosty Ave., 220050, Minsk, Belarus In many respects cell-to-cell communications are determined by interaction between cells and extracellular matrix. We attempted to change the functional state of the extracellular matrix by applying chondroitin sulfate to test the hypothesis that proteoglycans can influence synaptic transmission in brain slices by transforming extracellular matrix. Experimental series were performed on 400 lm-thick hippocampal slices from 3–4-week old rats. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSPs) in the CA1 area were recorded under electrical stimulation of the Schaffer collaterals in a series of 48 hippocampal slices taken from 16 young rats under perfusion with 0.001– 1.0% chondroitin sulfate. Beginning at 60s after application of 0.01% chondroitin sulfate, an increase in the amplitude of the fEPSPs in response to both paired pulse stimuli was induced and persisted until 90s. Following this, the fEPSPs in response to both pulses declined rapidly over 60s, to an extent whereby fEPSPs were almost abolished. The initial facilitation of fEPSPs and PSs amplitudes following chondroitin sulfate may result from either an increase in net excitatory post-synaptic current or an increase in post-synaptic impedance. Similarly, the subsequent impairment of fEPSPs and PSs amplitude in the period 90 to 150s after chondroitin application presumably reflects a reduction in excitatory post-synaptic current or a large fall in postsynaptic impedance. All these processes can be initiated by structural shifts in perineuronal nets including changes of a configuration of active zones and receptor ratio. Thus, proteoglycans may influence interneuronal communications in the CA1 region of the hippocampus. doi:10.1016/j.npep.2006.09.045 P-9: VASOACTIVE INTESTINAL PEPTIDE MODULATES PLASMACYTOID DENDRITIC CELL FUNCTION BY ALTERATION OF THE IMMUNE PHENOTYPE AND INHIBITION OF IFNA SECRETION D. Fabricius , M. Sue O’Dorisio , Sue Blackwell , Bernd Jahrsdoerfer ; a Department of Pediatrics, University of Iowa, Iowa City, IA, USA; b Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; c Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA Plasmacytoid dendritic cells (pDC) are thought to be the main sentinels for viral infections, to which they

P-8: Involvement of proteoglycan-containing cells and/or the proteoglycan extracellular matrix in synaptic transmission

s / Neuropeptides 40 (2006) 417–445 443 are known to correlate negatively with body mass index (BMI) so that ghrelin is elevated in anorexia nervosa and decreased in obesity. In patients with cancer cachexia, it has been postulated that lack of appetite and weight loss, despite elevated ghrelin levels, results from partial ghrelin resistance. Exogenous ghrelin administered to these patients has been shown to increase caloric intake by 31%. In this study, we have shown that increased endogenous release of ghrelin from neuroendocrine tumors (NETs) can overcome the partial ghrelin resistance seen in cancer cachexia. Methods: The study was conducted as a single-center, prospective trial enrolling 35 patients with NETs. Total ghrelin levels and chromogranin A (CgA) values were measured and analyzed for differences by t test (p < 0.05). Subgroups examined included patients with and without hepatic metastases, carcinoid versus pancreatic NETs, and patients with and without hypergastrinemia due either to prolonged proton pump inhibitor use or due to Zollinger-Ellison Syndrome (ZES). Results: Mean total ghrelin levels in patients with NET and hepatic metastases (589 pg/ml) were significantly elevated compared to the group of NET patients without hepatic metastases (411 pg/ml). The former had a mean BMI of 27.2 compared to a mean of 26.3 for the latter. These higher ghrelin levels correlated with higher serum chromogranin A levels. Mean total ghrelin in patients with hypergastrinemia due to prolonged proton pump inhibitor therapy (591 pg/ml) differed significantly from untreated patients (418 pg/ml). No significant differences in ghrelin levels were seen in patients with carcinoid tumors compared to those with pancreatic neuroendocrine tumors nor between patients with Zollinger-Ellison syndrome versus those without. All patients with neuroendocrine tumors had elevated levels of ghrelin compared to the standard reference range. Conclusions: We report that in all subgroups analyzed, patients with NETs had levels of ghrelin that positively correlated with BMI suggesting that any partial ghrelin resistance may be overcome with increased endogenous ghrelin. This data supports the possibility that ghrelin is co-released from NETs and exerts an orexigenic effect in these patients, helping to maintain weight preservation despite widely disseminated disease. doi:10.1016/j.npep.2006.09.044 P-8: INVOLVEMENT OF PROTEOGLYCANCONTAINING CELLS AND/OR THE PROTEOGLYCAN EXTRACELLULAR MATRIX IN SYNAPTIC TRANSMISSION Yu.S. Garkun , A.A. Denisov , P.G. Molchanov , N.V. Yakubovich , V.A. Kulchitsky ; a Institute of Physiology, National Academy of Sciences, 28 Akademicheskaya Str., 220072, Minsk, Belarus; b Belarus State University, 4 Nezavisemosty Ave., 220050, Minsk, Belarus In many respects cell-to-cell communications are determined by interaction between cells and extracellular matrix. We attempted to change the functional state of the extracellular matrix by applying chondroitin sulfate to test the hypothesis that proteoglycans can influence synaptic transmission in brain slices by transforming extracellular matrix. Experimental series were performed on 400 lm-thick hippocampal slices from 3–4-week old rats. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSPs) in the CA1 area were recorded under electrical stimulation of the Schaffer collaterals in a series of 48 hippocampal slices taken from 16 young rats under perfusion with 0.001– 1.0% chondroitin sulfate. Beginning at 60s after application of 0.01% chondroitin sulfate, an increase in the amplitude of the fEPSPs in response to both paired pulse stimuli was induced and persisted until 90s. Following this, the fEPSPs in response to both pulses declined rapidly over 60s, to an extent whereby fEPSPs were almost abolished. The initial facilitation of fEPSPs and PSs amplitudes following chondroitin sulfate may result from either an increase in net excitatory post-synaptic current or an increase in post-synaptic impedance. Similarly, the subsequent impairment of fEPSPs and PSs amplitude in the period 90 to 150s after chondroitin application presumably reflects a reduction in excitatory post-synaptic current or a large fall in postsynaptic impedance. All these processes can be initiated by structural shifts in perineuronal nets including changes of a configuration of active zones and receptor ratio. Thus, proteoglycans may influence interneuronal communications in the CA1 region of the hippocampus. doi:10.1016/j.npep.2006.09.045 P-9: VASOACTIVE INTESTINAL PEPTIDE MODULATES PLASMACYTOID DENDRITIC CELL FUNCTION BY ALTERATION OF THE IMMUNE PHENOTYPE AND INHIBITION OF IFNA SECRETION D. Fabricius , M. Sue O’Dorisio , Sue Blackwell , Bernd Jahrsdoerfer ; a Department of Pediatrics, University of Iowa, Iowa City, IA, USA; b Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; c Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA Plasmacytoid dendritic cells (pDC) are thought to be the main sentinels for viral infections, to which they

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Are Children with Cystic Fibrosis Who Are Treated With a Proton‐Pump Inhibitor at Risk for Vitamin B 12 Deficiency?

ABSTRACTBackgroundIn a recent study, the authors demonstrated the beneficial effect of proton‐pump inhibitors (PPI) on fat malabsorption and bone mineral content in children with cystic fibrosis (CF). Prolonged use of PPI could result in vitamin B 12 deficiency as a consequence of impaired release of vitamin B 12 from food in a nonacid environment. The aim of this study was to evaluate the vitamin B 12 status of CF patients either treated with a PPI or not by measuring vitamin B 12 and homocysteine blood levels, the latter being a sensitive indicator of vitamin B 12 deficiency.MethodsThe study population consisted of 20 CF patients, 11 patients treated with a PPI for at least 2 years and 9 patients not treated with a PPI, and 10 healthy, age‐matched control participants. Homocysteine blood levels were measured by high‐performance liquid chromatography, and vitamin B 12 levels were measured by a competitive protein‐binding assay.ResultsVitamin B 12 levels were significantly higher in both CF groups compared with the control participants (PPI+, P = 0.02; PPI−, P = 0.009). There was no significant difference in vitamin B 12 levels between both CF groups. Homocysteine levels were normal and similar in all groups.ConclusionsCystic fibrosis patients treated with a PPI for at least 2 years show no signs of vitamin B 12 deficiency.