Histamine Type Research Articles

Discrepancies between home medications listed at hospital admission and reported medical conditions

Background: One of the Joint Commission on Accreditation of Healthcare Organization's National Patient Safety Goals is for hospitals to accurately and completely reconcile patients' medications. Unfortunately, medication histories in charts might bc inaccurate and incomplete. In a thorough medication history, each medication should match a particular reported medical condition. The use of medications without a clear reported indication is of particular concern and has bccn associated with inappropriate use and polypharmacy. Objectives: The purposes of this study were to evaluate the occurrence of discrepancies between home medications listed in hospital admission notes and patients' reported medical conditions and to describe the types of medications most often identified as not having a corresponding indication. Methods: In this retrospective observational study, data were included from adult patients (≥18 years of age) who were receiving ≥3 home medications on admission to medical wards at a university hospital during a 6-month period. Each home medication listed in the admission note, together with any preadmission paperwork, was matched with an indication listed in the note. Medications were deemed unspecified if an indicated disease state or condition for the medication was not reported. Results: Data from 121 patients were included. The majority (91.7%) of the patients were admitted to an internal medicine service. Eighty-four patients (69.4%) had ≥1 unspecified medication listed in the admission note. Patients with ≥1 unspecified home medication reported taking a signifcantly higher number of home medications (10.2 [4.5] vs 7.5 [3.5] in those without unspecified medications; P = 0.007). Thirty-two patients (26.4%) were receiving proton pump inhibitors or histamine type 2 antagonists without a reported indication. Seventeen patients (14.0%) were receiving selective scrotonin rcuptakc inhibitors without a reported indication. Conclusions: Nearly 70% of patients admitted to a medical ward had ≥1 unspecified medication listed in the admission note. Based on these results, health care professionals must bc careful to obtain and document complete medication histories with matching indications.

Body Mass Index and the Efficacy of Acid-Mediating Agents for GERD

In studies of the association between obesity and gastroesophageal reflux, one subject that has received very little attention is the effect excess body mass may have on the effectiveness of acid-mediating agents. The lack of systematic research may reflect the perceived high clinical efficacy of drugs like proton pump inhibitors. Both proton pump inhibitors and histamine type 2 receptor antagonists have low rates of significant adverse events; if there are differences in the side effect profiles based on BMI, it is unlikely such associations would be detected. Also, while the metabolism of many drugs can be affected by body mass, it is not clear that such a relationship exists with acid-mediating agents. Nevertheless, there is evidence that body mass index may indeed be associated with the efficacy of proton pump inhibitors and histamine type 2 receptor antagonists. This review will examine that evidence and consider some of the possible pharmacokinetic effects that might relate to body mass index.

W1720 Gastric Hypersecretion Related to Cholinergic Hypersensitivity in the Flinders Rat Model of Depression Contributes to Stress Induced Ulceration of the Stomach

G A A b st ra ct s that such gradient expression of Shh was disappeared by H. pylori colonization (J. Pathol. 206:186-197, 2005) or by hypochlorhydria due to immature parietal cells (J. Pathol. 213:161-169, 2007). The present study was designed to investigate the expression of AQP4 in the mouse stomach after acid suppression with a histamine type 2 receptor antagonist (H2RA) or proton pump inhibitor (PPI). Methods. Male 5-week-old C57B/6 mice were prepared for this study, and an H2RA (Famotidine: FAM, 15mg/kg, 2x/day, s.c.) or PPI (Lansoprasole: LPZ 30mg/kg, 1x/day, s.c.) was administered to the animals. A saline was administered as control. One, 4 or 8 weeks after the administration, the stomachs of the mice were removed and examined. The mRNA expression of AQP4 was evaluated by quantitative RT-PCR. The protein levels of AQP4 were examined by Western blotting and its localization was assessed by immunohistochemistry. Results. The LPZ group exhibited higher expression levels of the gastric AQP4 mRNA than the control or FAM group (AQP4/ β-actin: 1 week: cont. 0.77±0.05, FAM 0.75±0.05, LPZ 1.42±0.12; p<0.05; 4 weeks: cont. 0.72±0.06, FAM 0.72±0.05, LPZ 1.12±0.11; p<0.05; 8 weeks: cont. 0.73±0.05, FAM 0.65±0.03, LPZ 1.22±0.11; p<0.05). The protein level of AQP4 and Shh also exhibited higher level in LPZ group than the control or FAM group (AQP4/β-actin:% expression of control, 1 week: FAM 63.1±10.6, LPZ 203.1±22.5; p<0.01; 4 weeks: FAM 90.1±12.1, LPZ 148.9±7.9; p<0.01; 8 weeks: FAM 87.8±22.9, LPZ 134.3±18.8; p<0.01). AQP4 was specifically expressed in the basolateral membrane of the gastric parietal cells. A significant increase in the number of AQP4-positive parietal cells even in the neck of fundic glands was observed after acid suppression by LPZ. On the other hand, Shh expression was extensively reduced in LPZ group. Conclusion. Increase in the number of AQP4-positive parietal cells in the fundic glands was observed in the Shh faded area under the condition of potent acid suppression by PPI, not by H2RA. This observation suggests that the reduced proton pump activity paralleled with a faded Shh expression in basal parietal cells might determine the expression of its water channel, AQP4.

Design of histidine containing peptides for better understanding of their coordination mode toward copper(II) by CD spectroscopy

The systematic investigation of the copper(II) complexes of tripeptides Xaa–Xaa–His, Xaa–His–Xaa and His–Xaa–Xaa, where Xaa = Gly or Ala was performed by combined pH-metry, spectrophotometry, CD and in part EPR spectroscopy. The matrix rank analysis of the spectral data revealed the number of the coloured and optically active species as a basis for the solution speciation. A critical evaluation on the speciation and solution structure of the complexes formed is presented on the basis of their d–d band optical activity. The replacement of a Gly residue with the chiral Ala amino acid allowed us to gain decisive information on the solution structure of the complexes by CD spectroscopy. It was shown that the tripeptides with histidine in the third position formed CuH −2L species with (NH 2, 2N −, ImN – where Im stands for imidazole) coordination sphere as a major species, and only the macrochelated CuL complexes as minor species around pH 5.0. In copper(II)–Xaa–His–Xaa tripeptide systems the CuH −1L (NH 2, N −, ImN) is the most stable species at physiological pH, but the vacant fourth site around copper(II)ions is offered for further deprotonation, most probably resulting in mixed hydroxo species at low (<5 × 10 −4 M) metal ion concentrations, while a tetrameric complex is dominant when the copper concentration exceeds 3 × 10 −3 M. The histamine type coordination mode in CuL and CuL 2 complexes of His–Xaa–Xaa ligands predominates at low pH. The structural consequences drawn from the CD spectra for the mono and bis parent complexes were supported by theoretical calculations. CD spectra strongly suggest the participation of the imidazole nitrogen both in the Cu 2H −2L 2 and CuH −2L complexes.

Gastroesophageal Reflux Disease, Acid Suppression, and Mycobacterium avium Complex Pulmonary Disease

Weekly symptoms of gastroesophageal reflux disease (GERD) occur in 20% of the population, and GERD has been implicated in the pathophysiology of many respiratory diseases. Microaspiration of contaminated water is a potential portal of entry for Mycobacterium avium complex (MAC) organisms into the respiratory tract, and acid-suppression therapy may enhance the survival of mycobacteria in the stomach. This study aimed to assess the prevalence of GERD, swallowing disorders, reflux symptoms, and acid-suppression therapy in patients with MAC lung disease (MAC positive [MAC+]), and to compare these patients to control subjects without MAC lung disease (MAC negative [MAC-]). Clinical information was collected on 58 MAC+ patients and 58 age- and sex-matched MAC- patients who were asked to complete a DeMeester questionnaire of reflux symptoms and to identify any acid-suppressive medication consumed. A clinical diagnosis of GERD was documented in 23 of 52 MAC+ patients (44.2%), compared to 16 MAC- patients (27.6%) [p = 0.019]. MAC+ patients consumed significantly more histamine type 2 receptor antagonists and prokinetic agents, and MAC- patients consumed more antacids. The mean DeMeester questionnaire score (+/- SD) for MAC+ patients was 1.39 +/- 1.8, and for MAC- patients was 0.88 +/- 1.4. (p = 0.098). Aspiration was suspected in nine MAC+ patients (15.5%), compared to three MAC- patients (5.2%) [p = 0.032]. There was no association between GERD and radiologic presentation of MAC disease. Consolidation and nodules > 5 mm were more common in those receiving acid suppression than those who were not. GERD, acid suppression, and clinically suspected aspiration are more common in patients with MAC lung disease than in similar patients without MAC disease.

Pharmacological Prophylaxis and Management of Adult Postoperative/Postdischarge Nausea and Vomiting

Postoperative nausea and vomiting (PONV) is a relatively common complication that can adversely affect the quality of a patient's postoperative recovery. Factors to consider when determining a patient's risk for developing PONV include female gender, history of PONV, history of motion sickness, nonsmoking status, postoperative use of opioids, use of inhaled anesthetic agents, and use of nitrous oxide. Receptors that, when activated, can cause PONV include dopamine type-2, serotonin type-3, histamine type-1, muscarinic cholinergic type-1, and neurokinin type-1. Patients with a moderate-to-high risk of developing PONV will benefit from the administration of a prophylactic antiemetic agent that blocks one or more of these receptors. Effective agents for prophylaxis include transdermal scopolamine, prochlorperazine, promethazine, droperidol, ondansetron, dolasetron, granisetron, dexamethasone, and aprepitant. In the highest-risk patients, combining two or more prophylactic antiemetics with different mechanisms of action has been shown to be more effective than a single agent. In addition, the patient's risk could be reduced by considering the use of regional anesthesia, maintaining general anesthesia with propofol rather than with inhaled anesthetic agents, ensuring good intravenous hydration, and providing effective pain management using a multimodal approach (eg, minimizing the use of opioids). If PONV does occur in the immediate postoperative period, it is best treated with an antiemetic agent from a different pharmacologic class than the agent that was administered for prophylaxis. Once a patient is discharged, alternative formulations of antiemetics such as ondansetron oral or dissolving tablets or promethazine tablets or suppositories can be used.

Lack of histamine type-1 receptors impairs the thermal response of respiration during hypoxia in mice (Mus musculus)

Thermoregulation and the hypoxic ventilatory response are modulated by histamine type-1 (H1) receptors in the brain. In this study, we tested the hypothesis that activation of H1 receptors is required for the thermal control of ventilation during normoxia and hypoxia, using conscious male wild-type and H1 receptor-knockout (H1RKO) mice (Mus musculus). Under normoxic conditions, hyperthermia (39 degrees C) decreased minute ventilation (V (E)) and oxygen consumption [Formula: see text] in both genotypes, suggesting that H1 receptors are not involved in thermal ventilatory control during normoxia. Pa(CO2) was unchanged in both hyperthermia and normothermia, suggesting that the thermal decrease in V (E) is optimized by metabolic demand. Acute hypoxic gas exposure (7% O(2)+3% CO(2) in N(2)) increased, and then decreased, V (E) in wild-type mice; this increase was augmented and sustained by hyperthermia. Hypoxic gas exposure reduced [Formula: see text] and [Formula: see text] in wild-type mice at both body temperatures; the reduced [Formula: see text] during combined hyperthermia and hypoxia was higher than during normothermia and hypoxia. In H1RKO mice, hyperthermia did not augment the V (E) response to hypoxia, and did not affect [Formula: see text] and [Formula: see text] during hypoxia. In conclusion, histamine participates in the thermal increase of ventilation during hypoxia by activating H1 receptors.

Ranitidine in Acute High‐Dose Organophosphate Exposure in Rats: Effect of the Time‐Point of Administration and Comparison with Pyridostigmine

Weak and reversible inhibitors of cholinesterase, when co-administered in large doses, can act in a protective manner against more potent inhibitors such as organophosphates. The clinically widely used histamine type 2 (H2) receptor blocker ranitidine is among H2 blockers the most potent inhibitor of acetylcholinesterase but roughly three to four orders of magnitude less potent than paraoxon (an irreversible organophosphate esterase inhibitor) or pyridostigmine (a reversible carbamate esterase inhibitor). We have previously shown that in vitro ranitidine confers some protection against inhibition of cholinesterases by paraoxon and that in vivo it both increases the number of rats surviving an acute paraoxon exposure and also protects to some degree the cholinesterases from organophosphate inhibition. The purpose of the study was to compare in a prospective non-blinded study, in a rat model of acute high-dose paraoxon exposure, ranitidine with pyridostigmine either administered simultaneously or 30 min. before exposure. There were 36 rats in each of the 5 groups. All substances were applied intraperitoneally. Additional analysis included data from a similar experiment carried out in 2005, in which 54 rats were exposed to paraoxon only (G1) and 54 to paraoxon+ranitidine simultaneously (G2). All groups (except controls; G6 & G7) received 1 micro Mol paraoxon (approximately LD75); groups 2-5 received in addition to paraoxon: G2: 50 micro Mol ranitidine within 1 min. of paraoxon, G3: 1 micro Mol pyridostigmine within 1 min. of paraoxon, G4: 50 micro Mol ranitidine 30 min. before paraoxon, G5: 1 micro Mol pyridostigmine 30 min. before paraoxon. Groups 6 & 7 received only ranitidine and pyridostigmine respectively, group G1 received only paraoxon. Mortality was recorded at 30 min., 1, 2, 3, 4, 24 and 48 hr. Mortality data were compared using Kaplan-Meier plots and logrank tests. No Bonferroni correction for multiple comparisons was applied and an alpha < or = 0.05 was considered significant. All statistical analysis was performed by using SPSS 12.0 statistical software (SPSS Inc., Chicago, IL, USA). Simultaneous administration of ranitidine or pyridostigmine with paraoxon does not significantly affect mortality. Pretreatment (30 min. before) with both ranitidine or pyridostigmine statistically and significantly reduced mortality. When administered before paraoxon, pyridostigmine is statistically significantly superior to ranitidine. Both ranitidine and pyridostigmine are protective against acute paraoxon toxicity provided they are administered before paraoxon. Pyridostigmine results are statistically significantly superior to ranitidine (< or =0.05).

Histamine Type 1 Receptor Deficiency Reduces Airway Inflammation in a Murine Asthma Model

Background: Histamine plays an important role in immediate and late immune responses. The histamine type 1 (H1) receptor is expressed on several immune cell populations, but its role in a murine model of asthma remains unclear. The present study evaluated the role of histamine H1 receptors in airway allergic inflammation by comparing the development of bronchial asthma in histamine H1 receptor gene knockout (H1RKO) and wild-type mice. Methods: H1RKO and wild-type mice were sensitized by intraperitoneal injection of ovalbumin (OVA) or saline, and then challenged with aerosolized OVA or saline. Ventilatory timing in response to inhaled methacholine was measured, and samples of blood, bronchoalveolar lavage, and lung tissues were taken 24 h after the last OVA challenge. Results: OVA-treatedwild-type mice showed significantly increased airway eosinophilic infiltration, and airway response to methacholine compared to OVA-treated H1RKO mice. The serum level of immunoglobulin E and levels of interleukin (IL)-4, IL-5, IL-13, and TGF-β1 in bronchoalveolar lavage fluid were lower in OVA-treated H1RKO mice than in OVA-treated wild-type mice, but there was no significant difference in interferon-γ expression. Overall, deletion of histamine H1 receptors reduced allergic responses in a murine model of bronchial asthma. Conclusion: Histamine plays an important role via H1 receptors in the development of T helper type 2 responses to enhance airway inflammation.

Impaired ventilation and metabolism response to hypoxia in histamine H1 receptor-knockout mice

The role of central histamine in the hypoxic ventilatory response was examined in conscious wild-type (WT) and histamine type1 receptor-knockout (H1RKO) mice. Hypoxic gas (7% O(2) and 3% CO(2) in N(2)) exposure initially increased and then decreased ventilation, referred to as hypoxic ventilatory decline (HVD). The initial increase in ventilation did not differ between genotypes. However, H1RKO mice showed a blunted HVD, in which mean inspiratory flow was greater than that in WT mice. O(2) consumption (V(O2)) and CO(2) excretion were reduced 10min after hypoxic gas exposure in both genotypes, but (V(O2)) was greater in H1RKO mice than in WT mice. The ratio of minute ventilation to (V(O2)) during HVD did not differ between genotypes, indicating that ventilation is adequately controlled according to metabolic demand in both mice. Peripheral chemoreceptor sensitivity did not differ between genotypes. We conclude that central histamine contributes via the H1 receptor to changes in metabolic rate during hypoxia to increase HVD in conscious mice.

Contribution of Histamine Type-1 Receptor to Metabolic and Behavioral Control of Ventilation

Histaminergic neurons in the hypothalamus are well documented as being involved in the control of autonomic functions, such as the balance of energy metabolism and circadian rhythm. We tested the hypothesis that an activation of the histamine type-1 (H1) receptor is required for the control of ventilation during the course of a day in free-moving mice. Ventilation, aerobic metabolism, and electroencephalogram were measured by a whole-body-plethysmograph, a magnetic-type mass spectrometry system, and a telemetry system, respectively, in H1 receptor-knockout (H1RKO) and wild-type mice. Both genotypes showed daily oscillations in minute ventilation (V(E)) and oxygen consumption (VO(2)), with greater values during the dark period compared to the light period. In the latter, H1RKO mice showed increased V(E) and CO(2) excretion (VCO(2)) relative to wild-type mice, and V(E) was comparable to the VCO(2) increase. However, there was no change in VO(2) in H1RKO mice, suggesting that differences in VCO(2) between genotypes are responsible for differences in V(E) during the light period. During the dark period, VCO(2) was elevated in H1RKO mice compared with WT mice. Because there was no difference in V(E), the ratio of V(E) to VCO(2) was reduced in H1RKO mice. Electroencephalogram results suggested that this might be due to a depressed arousal state in H1RKO mice because the ratio of delta to theta band power spectrum densities was greater in H1RKO mice than in wild-type mice. We concluded that histamine modulates ventilation by affecting metabolism and arousal state via H1 receptors.

Inlet patch of gastric mucosa in upper esophagus causing chronic cough and vocal cord dysfunction

An inlet patch of gastric mucosa in the upper esophagus is usually an incidental, congenital finding found during upper gastrointestinal tract endoscopy. Although it has been reported to cause dysphagia, strictures, adenocarcinoma, and webs, it has never been associated with cough and vocal cord dysfunction. To report the first case of a patient with an inlet patch of gastric mucosa in the upper esophagus as the cause of a particularly troublesome, chronic cough that was initially missed on 2 upper endoscopies. The patient is a 50-year-old man with a 7-year history of chronic cough associated with hoarseness, shortness of breath, and globus sensation. For diagnostic evaluation, pulmonary function tests, chest computed tomography, rhinolaryngoscopy, upper gastrointestinal tract endoscopy, and histologic examinations were performed. A multidisciplinary approach revealed several possible causes for the chronic cough, including vocal cord dysfunction, postnasal drip syndrome, allergic rhinitis, and mild gastroesophageal reflux disease that was only partially responsive to therapy. The results of 2 initial upper gastrointestinal tract endoscopies were interpreted as normal. A third endoscopy detected an inlet patch of gastric mucosa in the upper esophagus. Treatment with a high-dose histamine type 2 receptor antagonist and a proton pump inhibitor alleviated the patient's symptoms. An inlet patch of gastric mucosa in the upper esophagus is not uncommon, but it is often overlooked or believed to be an incidental, congenital finding. This is the first report, to our knowledge, of an inlet patch resulting in a troublesome, chronic cough.

The Novel Acid Pump Antagonists for Anti-secretory Actions with Their Peculiar Applications Beyond Acid Suppression

The H+/K+-ATPase of gastric parietal cell exchanges luminal K+ for cytoplasmic H+, of which outcome is gastric acidification with outflux of hydronium ion (H3O+). Secretion of gastric acid from the H+/K+-ATPase is stimulated by neuronal sensing and elaborately regulated various neuronal transmitters and hormones, consequently resulting in anchoring of the H+/K+-ATPase in canaliculi membrane of gastric parietal cell. Since hypersecretion of gastric acid or a defect of its barrier function is considered as a principal casual factor in the acid-related diseases such as duodenal and gastric ulcer, reflux esophagitis, and some types of gastritis, the development of anti-secretory agents including PPIs (proton pump inhibitors) and H2-RAs (histamine type 2 receptor antagonists) has revolutionized during the second millennium. Similar considerations applying to design of compounds substituting K+ led to the development of acid pump antagonists (APAs), of which advantages are independent of secretory status, no lag time required, reversible in actions allowing “on-demand dosage”. Our recent studies revealed that these inhibitors of H+/K+-ATPase could be extensively applied for the selective induction of cancer cell apoptosis, a significant anti-inflammatory and gastroprotective action far beyond acid suppression. In the current review, we described the mechanistic regulation of gastric acid secretion with pump inhibitor, the difference and characteristics between PPI and APA based on the molecular mechanism, and their new applications beyond acid suppression.

Prevention and treatment of postoperative nausea and vomiting

The physiology, risk factors, and prevention and treatment of postoperative nausea and vomiting (PONV) are discussed. Factors to consider when determining a patient's risk for PONV include sex, history of PONV, history of motion sickness, smoking status, duration of anesthesia, use of opioids, and type of surgery. Receptors that, when activated, can cause nausea or vomiting or both include dopamine type 2, serotonin type 3, histamine type 1, and muscarinic cholinergic type 1 receptors. Patients at moderate to high risk for PONV benefit from the administration of a prophylactic antiemetic agent that blocks one or more of these receptors. Effective agents include transdermal scopolamine, prochlorperazine, promethazine, droperidol, ondansetron, dolasetron, granisetron, and dexamethasone. In high-risk patients, combining two or more antiemetics with different mechanisms of action has been shown to be more effective than using a single agent. In addition to administering a prophylactic antiemetic, it is important to reduce the patient's risk by considering regional anesthesia, considering inducing and maintaining general anesthesia with propofol, ensuring good intravenous hydration, avoiding hypotension, and providing effective analgesia. If PONV occurs in the immediate postoperative period, it is best treated with an antiemetic agent from a pharmacologic class different from that of the prophylactic agent. Prophylactic antiemetic therapy for PONV is effective, but combinations of agents may be necessary for high-risk patients. Nonpharmacologic strategies are also important.

Protective agents in acute high‐dose organophosphate exposure: comparison of ranitidine with pralidoxime in rats

Weak and reversible inhibitors of cholinesterase, when coadministred in excess with a more potent inhibitor such as organophosphates, can act in a protective manner. Ranitidine (RAN) is a clinically widely used histamine type 2 (H2) receptor blocker. Ranitidine is also the most potent inhibitor of acetylcholinesterase among H2 blockers (inhibitory constant K in the low micromolar range) but roughly three orders of magnitude less potent than paraoxon. This study evaluates RAN-conferred protection in acute high-dose organophosphate (paraoxon, POX) exposure in rats in direct comparison with the therapeutic gold-standard pralidoxime (PRX). Group 1 received 1 microM POX, group 2 received 50 microM RAN, group 3 received 50 microM PRX, group 4 received 1 microM POX + 50 microM RAN and group 5 received 1 microM POX + 50 microM PRX. All substances were applied intraperitoneally. The animals were monitored for 48 h and mortality was recorded at 30 min and 1, 2, 3, 4, 24 and 48 h. Blood was taken for red blood cell acetylcholinesterase (RBC-AChE) measurements at baseline, 30 min and 24 and 48 h. Mortality occurred mainly in the fi rst 30 min after POX administration, with minimal changes occurring thereafter. Mortality (in %) at 30 min in groups 1, 4 and 5 was 52 +/- 18, 37 +/- 20 and 17 +/- 18, respectively, and mortality at 48 h was 59 +/- 12, 39 +/- 20 and 28 +/- 20, respectively. The RBC-AChE activities (in % of baseline values) at 30 min in groups 1, 4 and 5 were 18 +/- 16, 47 +/- 23 and 48 +/- 20, respectively. At 24 h the values were 46 +/- 16, 65 +/- 24 and 86 +/- 17, respectively, and at 48 h the values were 71 +/- 19, 78 +/- 21 and 110 +/- 27, respectively. Coadministration of PRX significantly decreases mortality in the described model at all points in time. Coadministration of RAN statistically significantly decreases mortality at 24 and 48 h. The extent of protection conferred by RAN is less (but not statistically significantly so) than that conferred by the gold-standard PRX. Coadministration of PRX statistically significantly increases RBC-AChE activities in the described model at all points in time. Ranitidine confers a statistically significant protection for the enzyme at 30 min only. We conclude that RAN is potentially of clinical use in reducing mortality in acute high-dose organophosphate exposure. Further studies involving different organophosphates and dosages, as well as different animal species, will be needed both to con fi rm these initial findings and to address the issue of the optimal timing for RAN preadministration.

Global expression analysis of ECL cells in Mastomys natalensis gastric mucosa identifies alterations in the AP-1 pathway induced by gastrin-mediated transformation

Enterochromaffin-like (ECL) cell hyperplasia and then irreversible neoplasia can be generated in the African rodent Mastomys natalensis using the H2 receptor blocker, loxtidine, for 8-16 wk. We used a GeneChip approach complemented by standard technologies to identify gene expression alterations in the gastric mucosa during gastrin-mediated ECL cell transformation. Gastric mucosa (mucosal scrapping) and ECL cell-enriched fractions were obtained from untreated Mastomys (controls) and from animals treated with loxtidine for 8 wk (hyperplasia). Tumor ECL cells were obtained by hand-dissection of gastric ECL cell nodules from animals treated with loxtidine for >16 wk and from a spontaneously developed ECL cell tumor. RNA was isolated, examined on rat U34A GeneChips, and comparison analysis was performed to identify altered gene expression. Alterations in gene expressions were examined further by immunohistochemistry, quantitative RT-PCR (Q-RT-PCR), sequencing and Western blot. GeneSpring analysis demonstrated alterations in few genes (<20) in hyperplastic and tumor mucosa. The histamine H1 receptor was consistently increased in proliferating mucosa. This gene change was confirmed by Q-RT-PCR. Other genes showing alterations included neural-(chromogranin A and somatostatin), cell-cycle-, and AP-1-associated genes. Immunostaining confirmed alterations in neural markers. Cluster analysis of ECL cell-enriched samples demonstrated that c-fos and junD were differently regulated. Q-RT-PCR and Western blot in prospectively collected gastric mucosal samples confirmed the differential expression of Fos and Jun. The negative regulators of AP-1, JunD, and Menin were decreased in tumor mucosa. A missense of unknown function was noted in the menin gene. Hypergastrinemia in an animal model of gastric carcinoids differentially altered the histamine type 1 receptor and gene expression and protein composition of AP-1. These results suggest that expression of this receptor and an altered composition of AP-1 with a loss of inhibition play a role in ECL cell transformation.

Counselling in multiple endocrine neoplasia syndromes: from individual experience to general guidelines

Counselling of patients and closely related family members has to take a central place in management of hereditary diseases, like multiple endocrine neoplasia (MEN) syndromes including von Hippel-Lindau (VHL) disease. In the strategy of health care, preventive medicine such as periodic clinical examination of families at-risk needs a high priority, because in general it is assumed that continuity in attendance is cost-effective. Counselling has to be based on individual medical experience of the doctor, adjusted to common guidelines and the findings in the family. Information leaflets, appropriate outpatient departments and an extensive network of specialists will facilitate continuity in care. Flow diagrams involving practical guidelines for diagnosis, treatment and follow up need to be applicable and after adjustment, should be accepted generally. Specially trained paramedics for counselling are required as a network that will guarantee periodic clinical examination and secure optimal prevention. Such paramedics will coordinate nationwide multidisciplinary guidance, and organize preventive and emergency cure for these patients. They will be supervised by expert clinicians in the field, and collaborate with specialists for social and psychological issues, patient organizations and clinical genetic centres. All of these professionals are responsible together for providing patients with up to date clinical information (via newsletters, Internet, etc.). Recently, in the Netherlands, a project was initiated to guarantee continuity in care and study the delivery of care. In order to realize this plan, funding has to be provided in the current research programme. In a future system support has to be obtained on a continuous base, preferably by the government and health care insurers and supervised by the national institute for health care.

Atazanavir for the Treatment of Human Immunodeficiency Virus Infection

Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross-resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment-naive patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment-experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate-glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22-47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor-containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. John's wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once-daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.

The Effect of H2Antagonists on Proliferation and Apoptosis in Human Colorectal Cancer Cell Lines

Cimetidine is known to enhance the survival of gastro-intestinal cancer patients, though the mechanisms involved are incompletely understood. Postulated modes of action include blocking the proliferative effect of tumors and inhibiting T suppressor cell activity, both of which are thought to be mediated by histamine type 2 receptors. Apoptotic cell death may offer an alternative explanation for reduced cell growth. We aimed to examine the effects of histamine, cimetidine, and ranitidine on in vitro proliferation and apoptosis in two human colorectal cancer cell lines, Caco-2 and LoVo. A cell proliferation assay was used as an index of cell growth. Histamine receptor status was determined by quantifying cyclic adenosine monophosphate and apoptosis via DNA fragmentation. Results show that histamine (10(-5) to 10(-9) M) had no effect on the growth of either cell line. The proliferation of Caco-2 was inhibited by ranitidine (10(-7) M) alone and in combination with histamine. Cimetidine (10(-5) M) only suppressed the growth of Caco-2 in the presence of histamine. The H2 antagonists had no effect on LoVo irrespective of histamine. There was no accumulation of cyclic adenosine monophosphate in Caco-2 cells in response to histamine at a similar concentration. Apoptosis was induced in Caco-2 by both antisecretory drugs, and only ranitidine caused apoptotic cell death in LoVo cells. We conclude that cimetidine and ranitidine inhibit Caco-2 cancer cells in vitro, independently of the H2 receptor. In addition, both drugs induce apoptosis in the same cell line. Growth inhibition and apoptosis are likely to contribute to the tumor regressive properties of cimetidine and ranitidine in vivo.

Effects of cimetidine, a histamine type 2 receptor antagonist, on microcirculatory disturbance of the stomach induced by full-thickness burn injuries as a model for surgical stress in rats

BackgroundWe have reported the preventive effect of cimetidine, a histamine type 2 receptor antagonist, on decreased gastric mucosal blood flow induced by burn injury, a model of surgical stress. ObjectiveThe present study was performed to assess the effects of cimetidine on gastric microcirculatory disturbance induced by surgical stress. MethodsTwelve male Wistar rats were anesthetized and a 30% full-thickness dorsal scald burn was inflicted. The total lengths of gastric erosions were measured using stereoscopic microscopy. Microvascular images in the basal region of the gastric mucosa were observed using an intravital microscope, and the diameters of venules and collecting venules were measured. Rolling leukocytes inside and along the venules, an indication of endothelial damage to the microcirculation, were observed. The rats were assigned to the cimetidine group or the control group (both, n = 6). Cimetidine 100 mg/kg was administered 30 minutes before and 2.5 hours after infliction of the burn injury. Animals in the control group were given only isotonic saline. Values are expressed as mean (SD). ResultsContraction of venules was easily observed in all rats in the control group. However, venular contraction was rarely observed in the cimetidine group. The total length of gastric erosions was significantly decreased in the cimetidine group compared with the control group (0.93 [0.58] μm vs 5.98 [5.18] μm, respectively; P ≤ 0.05). The percentages of rolling leukocytes that passed the confluence of a prevenule and a venule were also significantly decreased in the cimetidine group compared with the control group (4.7% [7.3%] vs 22.6% [5.7%]; P ≤ 0.01). The diameters of the venules and collecting venules were significantly larger in the cimetidine group (57.3 [6.8] μm and 75.9 [3.6] μm, respectively) than in the control group (30.9 [9.2] μm and 46.8 [8.0] μm, respectively) (both, P ≤ 0.01). ConclusionsThe present study suggests that cimetidine may have a protective effect against gastric microcirculatory disturbances induced by burn injury, a model of surgical stress.