Histamine H2 Blockers Research Articles

Analysis of gastrointestinal prophylaxis in patients receiving dual antiplatelet therapy with aspirin and clopidogrel.

Dual antiplatelet therapy (DAPT) has been found to reduce the risk of cardiac death, myocardial infarction, stroke, and stent thrombosis following acute coronary syndrome and percutaneous coronary intervention. However, this therapy has also been shown to increase the risk of gastrointestinal (GI) bleeding as high as 2-fold, especially in patients with multiple risk factors. Proton pump inhibitor (PPI) therapy decreases this risk. The current consensus document on reducing GI risks associated with antiplatelet agents no longer recommends PPI therapy for all patients receiving aspirin (ASA) and clopidogrel. The consensus recommendation reserves PPI therapy for patients receiving DAPT with a history of upper GI bleeding or prespecified risk factors for GI bleeding. To (a) describe the use of GI prophylaxis in patients on DAPT with ASA and clopidogrel and (b) assess the incidence of adverse outcomes that occurred during readmissions within 6 months of the index hospitalization. A retrospective chart review of patients receiving DAPT between February 1, 2011, and October 15, 2011, was performed to assess the appropriateness of GI prophylaxis based on the current consensus document. Therapy was defined as appropriate if an indication for prophylaxis was present and PPI therapy was prescribed, or if no indication was present and no GI prophylaxis was given. Inappropriate prophylaxis was defined as no indication for GI prophylaxis yet therapy received, or prophylaxis indicated but incorrect prophylaxis prescribed. Incorrect prophylaxis included no prophylaxis, histamine H2 blocker therapy, antacid, or combination therapy. During subsequent hospitalizations in the 6-month period following discharge from the index admission, patients were assessed for the development of vascular-, GI-, and PPI-related adverse events. 250 patients receiving DAPT during the study period were evaluated. Gastrointestinal prophylaxis was appropriate in 48% (119/250) of patients. Of the remaining patients, 56.4% (74/131) met guideline criteria for GI prophylaxis but did not receive a PPI at discharge, whereas 43.5% (57/131) of patients received GI prophylaxis when not indicated. Thirty-three adverse events were identified during readmissions, with the most common type being vascular followed by GI and PPI adverse events, respectively. More than half of the patients did not receive GI prophylaxis appropriately. The most common reason for nonadherence to the consensus document was no prophylaxis when indicated. Vascular events could not be directly attributed to PPI use, and GI events occurred despite prophylaxis. Overall, there was a low incidence of adverse events related to the use of PPI therapy.

Differential effects of blockade of ERG channels on gamma oscillations and excitability in rat hippocampal slices

Agents such as sertindole and astemizole affect heart action by inducing long-QT syndrome, suggesting that apart from their neuronal actions through histamine receptors, 5-HT2 serotonin receptors and D2 dopamine receptors they also affect ether-a-go-go channels and particularly ether-a-go-go-related (ERG) potassium (K(+)) channels, comprising the K(v) 11.1, K(v) 11.2 and K(v) 11.3 voltage-gated potassium currents. Changes in ERG K(+) channel expression and activity have been reported and may be linked to schizophrenia [Huffaker, S.J., Chen, J., Nicodemus, K.K., Sambataro, F., Yang, F., Mattay, V., Lipska, B.K., Hyde, T.M., Song, J., Rujescu, D., Giegling, I., Mayilyan, K., Proust, M.J., Soghoyan, A., Caforio, G., Callicott, J.H., Bertolino, A., Meyer-Lindenberg, A., Chang, J., Ji, Y., Egan, M.F., Goldberg, T.E., Kleinman, J.E., Lu, B. & Weinberger DR. (2009). Nat. Med., 15, 509-518; Shepard, P.D., Canavier, C.C. & Levitan, E.S. (2007). Schizophr Bull., 33, 1263-1269]. We have previously shown that histamine H1 blockers augment gamma oscillations (γ) which are thought to be involved in cognition and storage of information. These effects were particularly pronounced for γ induced by acetylcholine. Here we have compared neuronal effects of three agents which interfere with ERG K(+) channels. We found that astemizole and sertindole, but not the K(v) 11 channel blocker E4031, augmented γ induced by acetylcholine in hippocampal slices. Kainate-induced γ were only affected by astemizole. Evoked responses induced by stratum radiatum stimulation in area CA1 revealed that only E4031 augmented stimulus-induced synaptic potentials and neuronal excitability. Our findings suggest that K(v) 11 channels are involved in neuronal excitability without clear effects on γ and that the effect of astemizole is related to actions on H1 receptors.

Accumulating Evidence for a Drug–Drug Interaction Between Methotrexate and Proton Pump Inhibitors

A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change based on the accumulating evidence for a possible drug-drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors (PPIs). The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database of spontaneous adverse event reports and the published literature were searched for cases reporting an interaction between methotrexate and PPIs. A search of the AERS database and existing literature found several individual case reports of drug-drug interactions and three additional supportive studies that suggest potential underlying mechanisms for the interaction. There is evidence to suggest that concomitant use of methotrexate (primarily at high doses) with PPIs such as omeprazole, esomeprazole, and pantoprazole may decrease methotrexate clearance, leading to elevated serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In several case reports, no methotrexate toxicity was found when a histamine H2 blocker was substituted for a PPI. Based on the reviewed data, the FDA updated the methotrexate label to include the possible drug-drug interaction between high-dose methotrexate and PPIs. Physicians should be alerted to this potential drug-drug interaction in patients receiving concomitant high-dose methotrexate and PPIs.

Gastric injury caused by low-dose aspirin therapy in consecutive Japanese patients: a prospective study

Low-dose aspirin (<325 mg/day), administered to those with several conditions involving ischemic disorders, can cause upper gastrointestinal (GI) complications. In this prospective study, we aimed to clarify the incidence of aspirin-induced gastric ulcers in consecutive Japanese patients and identify suitable preventive measures. We recruited 125 consecutive adult outpatients who received low-dose aspirin (enteric-coated tablets 100 mg) for >8 weeks. Endoscopy and blood tests were used to evaluate their gastric injury (which was scored using a modified Lanza scale) and anti-Helicobacter pylori antibody titer, respectively. We found that 39.8% of patients received either no upper GI drug or only mucoprotective drugs, 39.8% received medium-dose histamine H2 blockers, and 20.4% received proton-pump inhibitors (PPIs). Anti-H. pylori antibody titers were positive in 43.7% of patients. The incidence of definitive gastric ulcers in this population was 0.97%. Ordered logistic regression analysis revealed that the odds ratio for the increase in the modified Lanza score was 0.20 for medium-dose histamine H2 blockers and 0.09 for PPIs. The incidence of postoperative definitive gastric ulcers in Japanese patients receiving ≤100 mg enteric-coated aspirin was 0.97%. The use of PPIs and histamine H(2) blockers may prevent aspirin-induced gastric injury in such patients.

A Retrospective Analysis of Risk Factors and Therapeutic Outcomes for Clostridium difficile Infection

Purpose To determine the Clostridium difficile infection (CDI) recurrence rate at the Veterans Affairs Medical Center (VAMC) in Fargo, North Dakota, and to determine whether certain variables (eg, type of antibiotic, medication, chronic disease state, CDI symptom control) were predictive of CDI recurrence. Methods Demographic information and laboratory data from 174 adult outpatients and inpatients were collected from electronic medical records between January 1997 and September 2009. In addition, information about the duration of non-CDI antibiotic therapy and the use of proton pump inhibitors, histamine H2 blockers, corticosteroids, and immunosuppressive medications within 60 days of CDI was collected. Information regarding comorbid conditions (eg, cancer, liver or renal disease, diabetes, chronic heart failure) in patients at the time of CDI was also collected. Results Patients below the median age of 69.5 years were more likely to continue to have diarrhea after CDI treatment than patients who were older than the median age (relative risk 1.86; 95% CI, 1.06-3.26). No association was observed between previous non-CDI treatment antibiotic use, other medication use, or comorbid conditions and the recurrence of CDI. Conclusion CDI recurrence rate at VAMC was 14%. No statistically significant association could be made between recurrence of CDI and antibiotic or medication used within 60 days of infection or with chronic disease states at the time of CDI infection. Patients younger than 69.5 years were more likely to continue to have diarrhea after CDI treatment.

A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade

Histamine has a positive inotropic effect on ventricular myocardium and stimulation of histamine H₂ receptors increases the intracellular cAMP level via Gs protein, as dose stimulation of β-adrenergic receptors, and worsens heart failure. To test whether a histamine H₂ receptor blocker had a beneficial effect in addition to β-adrenergic receptor blockade, we investigated the cardioprotective effect of famotidine, a histamine H₂ receptor blocker, in dogs receiving a β-blocker. We induced heart failure in dogs by rapid ventricular pacing (230 beats/min). Animals received no drugs (control group), famotidine (1 mg/kg daily), carvedilol (0.1 mg/kg daily), or carvedilol plus famotidine. Both cardiac catheterization and echocardiography were performed before and 4 weeks after the initiation of pacing. Immunohistochemical studies showed the appearance of mast cells and histamine in the myocardium after 4 weeks of pacing. In the control group, the left ventricular ejection fraction (LVEF) was decreased after 4 weeks compared with before pacing (71 ± 2 vs. 27 ± 2%, p < 0.05) and mean pulmonary capillary wedge pressure (PCWP) was increased (8 ± 1 vs. 19 ± 3 mmHg). Famotidine ameliorated the decrease of LVEF and increase of PCWP, while the combination of carvedilol plus famotidine further improved both parameters compared with the carvedilol groups. These beneficial effects of famotidine were associated with a decrease of the myocardial cAMP level. Histamine H₂ receptor blockade preserves cardiac systolic function in dogs with pacing-induced heart failure, even in the presence of β-adrenergic receptor blockade. This finding strengthens the rationale for using histamine H₂ blockers in the treatment of heart failure.

Isolated uvular angioedema: Quincke’s disease

A 39-year-old male patient was admitted to the emergency department with the complaints of difficulty swallowing, a sensation of something “stuck” in his throat and a swollen uvula that he had seen in the mirror while brushing his teeth. His complaints had started 1 day before with sore throat as well as difficulty and pain when eating and drinking. He denied any fever, cough or breathing difficulties. His vital signs were stabile with blood pressure 120/70 mmHg, heart rate 86/min, respiration rate 12/min and body temperature 36.6°C. On physical examination, his lung sounds were normal. No lymphadenopathy was noted, but his uvula was erythematous and edematous (Fig. 1). No tonsillar hypertrophy was seen. His laboratory tests showed no significant results; there was no leukocytosis or any alterations in the neutrophil, basophil or eosinophil counts. The postero-anterior chest x-ray was normal. A bedside nasopharyngeal scope revealed a normal epiglottis and vocal cords, with significant uvular edema. He had no medical history of trauma, known food or drug allergy, asthma or frequently repeating infections. The only remarkable point in his medical history was that 1 week before he had been prescribed oral pinaverium bromide 50 mg (Dicetel®) for irritable bowel syndrome. He was treated with intravenous pheniramine hydrogen maleate (Avil®) and dexamethasone (Dekort®) in the emergency department and prescribed oral antihistaminic tablets for the next 48 h. Fig. 1 Oropharyngeal examination of a 39-year-old patient: isolated uvular angioedema (the patient's consent was obtained for the photograph) Isolated uvular angioedema was first defined by Quincke in 1882 [1]. Isolated uvular angioedema, or Quincke's disease, is a relatively rare presentation of angioedema of the upper airway [2]. Several causes of uvular edema have been described, including hereditary angioedema, trauma, inhalation exposure, medication reactions and infectious causes [3, 4]. Isolated uvular angioedema is usually caused by a type I hypersensitivity reaction [2, 3]. This should be differentiated from uvulitis, which is infectious and frequently has concomitant epiglottitis. Direct visualization or a lateral neck plain radiograph should be considered to help rule out epiglottitis [3, 5]. In this situation, the primary strategy should invovle maintaining the airway. In spite of being a rare condition, uvular edema may cause obstructive respiratory distress and require immediate airway care. The general treatment strategies in the emergency department consist of intravenous H1 and H2 histamine blockers, corticosteroids and infrequently epinephrine [2]. Dexamethasone has been considered the medication of choice considering its potent anti-inflammatory properties and long half-life.

Nab‐Paclitaxel: a bright new SPARC in taxane therapy of cancer

Nab‐Paclitaxel: a bright new SPARC in taxane therapy of cancer

Histamine Upregulates the Expression of Inducible Nitric Oxide Synthase in Human Intimal Smooth Muscle Cells via Histamine H1 Receptor and NF-κB Signaling Pathway

Histamine increases endothelial nitric oxide (NO) production as an endothelium-dependent vasodilator, which acts as a vasoconstrictor in atherosclerotic coronary arteries. To investigate the relation between histamine and NO production in intimal smooth muscle cells (SMCs), we studied the effect of histamine on inducible NO synthase (iNOS) expression in the SMCs. In cultured human intimal SMCs, histamine increased NO production, iNOS expression, and NF-kappaB nuclear translocation, which were inhibited by histamine H1 blocker and NF-kappaB inhibitor. Luciferase assay using -8.3 kb upstream of human iNOS promoter region and electrophoretic mobility shift assay suggested that a NF-kappaB motif located at -3922 to -3914 would be necessary for histamine-inducible promoter activity. In addition, H1 blocker, NF-kappaB inhibitor, and dominant negative IkappaB alpha or IkappaB kinase beta downregulated the histamine-induced iNOS promoter activity. In the human aorta, histamine content was estimated to be 310+/-66 pmol/mg protein in the atherosclerotic intima, while that was to be 43+/-22 pmol/mg protein in the media (P<0.001). Histamine stimulates intimal SMCs to increase iNOS expression via H1 receptors and NF-kappaB signaling pathway. Histamine could be one of NO-regulating factors, by inducing iNOS expression in intimal SMCs, and may be related to atherogenesis.

Histamine H1 Blocker Hydroxyzine Improves Sleep in Patients With Cirrhosis and Minimal Hepatic Encephalopathy: A Randomized Controlled Pilot Trial

Sleep difficulty is common in minimal hepatic encephalopathy (HE) and the mechanisms are not fully elucidated. Dysregulated histamine neurotransmission is associated with an altered circadian rhythmicity that is partially restored following central histamine H1 receptor blockade in cirrhotic animals. We studied the effects of the histamine H1 blocker hydroxyzine in sleep alterations in patients with cirrhosis in a double-blind, randomized controlled fashion. A total of 35 patients (age 56 yr [36-69], Pugh's score 9 [7-12], portosystemic shunt: N = 7) with minimal HE and long-standing sleep difficulties (8 months [4-48]) and free from benzodiazepines were randomized to hydroxyzine 25 mg at bedtime (N = 17) or placebo (N = 18) for a 10-day period. Measurements of sleep behavior using visual analog scale and wrist actigraphy, neuropsychological tests, and protein s100beta serum levels were performed at baseline and at day 10. Subjective improvement in sleep was observed in 40% of hydroxyzine-treated patients but in none receiving placebo (P < 0.04). Objectively, 65% of hydroxyzine-treated patients versus 25% of patients under placebo had a >or=30% increase in sleep efficiency as measured by wrist actigraphy (P < 0.04). Neuropsychological tests (Z scores) and protein s100beta levels remained statistically unchanged in both groups. One patient developed an acute episode of encephalopathy reversible upon cessation of hydroxyzine. In contrast to placebo, hydroxyzine 25 mg at bedtime improved sleep behavior (subjectively and using wrist actigraphy) in patients with cirrhosis and minimal HE. The risk of precipitating overt HE warrants some caution when prescribing this drug.

Gastroesophageal Reflux Disease–Associated Esophagitis Induces Endogenous Cytokine Production Leading to Motor Abnormalities

Gastroesophageal reflux disease is a condition frequently associated with esophagitis and motor abnormalities. Recent evidence suggests that proinflammatory cytokines, such as interleukin (IL)-1beta and IL-6, may be implicated because they reduce esophageal muscle contractility, but these results derive from in vitro or animal models of esophagitis. This study used human esophageal cells and tissues to identify the cellular source of cytokines in human esophagitis investigate whether cytokines can be induced by gastric refluxate, and examine whether esophageal tissue- or cell-derived mediators affect muscle contractility. Endoscopic mucosal biopsy specimens were obtained from patients with and without esophagitis, organ-cultured, and undernatants were assessed for cytokine content. The cytokine profile of esophageal epithelial, fibroblast, and muscle cells was analyzed, and esophageal mucosa and cell products were tested in an esophageal circular muscle contraction assay. The mucosa of esophagitis patients produced significantly greater amounts of IL-1beta and IL-6 compared with those of control patients. Cultured esophageal epithelial cells produced IL-6, as did fibroblasts and muscle cells. Epithelial cells exposed to buffered, but not denatured, gastric juice produced IL-6. Undernatants of mucosal biopsy cultures from esophagitis patients reduced esophageal muscle contraction, as did supernatants from esophageal epithelial cell cultures. The human esophagus produces cytokines capable of reducing contractility of esophageal muscle cells. Exposure to gastric juice is sufficient to stimulate esophageal epithelial cells to produce IL-6, a cytokine able to alter esophageal contractility. These results indicate that classic cytokines are important mediators of the motor disturbances associated with human esophageal inflammation.

Noninvasive system for evaluating allergen-induced nasal hypersensitivity in murine allergic rhinitis

Until now there has been no method for physiologically evaluating nasal hypersensitivity in mice. Enhanced pause (Penh) has been used as an indicator that reflects changes in the lower airway. Recently, however, there is disagreement regarding the significance of the Penh system; this is because Penh is not essentially a physiological parameter, and it might not necessarily represent a change in the lower respiratory tract. The purpose of the present study is to investigate whether Penh could be applicable for analyzing nasal hypersensitivity in mice. BALB/c mice were sensitized with ovalbumin (OVA) through a combination of intraperitoneal injection and daily intranasal challenge in an awake condition. Penh was measured at each time point during sensitization, or a serial change in Penh value was followed after the final nasal challenge and the effect of treatment was assessed. Following sensitization and nasal challenge, the Penh value gradually increased and showed a significant difference on day 14. Changes in IgE, eosinophil infiltration into nasal mucosa, and OVA-induced symptoms all strongly correlated with the increase in Penh. On day 19, after OVA nasal provocation, Penh gradually increased and reached maximal values 25 min after the challenge. Pretreatment with dexamethasone or a histamine H1 blocker significantly suppressed this increase in Penh. We confirmed that intranasal OVA challenge did not induce bronchoconstriction by measuring airway resistance and bronchoalveolar lavage fluid, and through histological examination. These results clearly demonstrate that Penh could be a useful noninvasive indicator for studying nasal hypersensitivity.

A therapeutic substitution policy for proton pump inhibitors: Clinical and economic consequences

With the growing need to provide prescription drug benefits to older patients and to contain costs, it will be necessary to direct that coverage so as to make expenditures as efficient as possible. We evaluated the clinical and economic consequences of coverage restriction for 3 leading proton pump inhibitors (PPIs) in a large-scale natural experiment. The study design was a time-trend analysis in the setting of a provincial drug benefits program in British Columbia, Canada. We studied all British Columbia residents aged 66 or older (N = 501,104) using linked data on all prescription drug dispensings, physician services, and hospitalizations between January 2002 and June 2004. The new policy restricted coverage to rabeprazole and required treatment failure with a histamine H2 blocker. More widely used PPIs (omeprazole, pantoprazole, and lansoprazole) had to be paid for out of pocket, unless the physician requested an exemption. The main outcome measures were utilization of PPIs, drug discontinuation rates, gastrointestinal hemorrhage rates, and drug expenditures. Utilization of the restricted PPIs declined sharply after the policy change (-14,850 daily doses per month per 10,000 residents, P < .0001), whereas use of the covered PPI increased sharply (+19,300, P < .0001), with 45% of all PPI users switching to the covered agent within 6 months. We found no increased use of H2 blockers or stopping of gastroprotective drugs. There was no increase in the monthly rate of hospitalization for gastrointestinal hemorrhage after the PPI restriction (P = .35) even though the study had the power to detect increases of 24 events per 10,000 residents with 95% confidence. There was a slight increase in physician visits 3 months after the policy change (P = .01) for a 2-month period when 9% of new rabeprazole users were switched back to a restricted PPI. In the first 6 months of the policy change, the provincial health plan saved at least 2.9 million Canadian dollars as a result of the policy change. Coverage restriction of 3 leading PPIs led to substantial utilization changes and savings, without increased noncompliance or clinical complication.

Chronopharmacology and controlled drug release

Circadian rhythms in the body are well established and are an important factor to consider when administering drugs. Many diseases display symptoms and onset characteristics that are not randomly distributed within 24 h (e.g., coronary infarction, angina pectoris, asthmatic attacks and peptic ulcer perforations); therefore, it is not surprising that the effects and/or pharmacokinetics of drugs can display significant daily variations. Recent data, primarily concerned with the chronopharmacokinetics of antiasthmatics, histamine H2-blockers and cardiovascular active drugs (e.g., propanolol, organic nitrate and nifedipine) are described as representative examples in this review. The data demonstrate that biological rhythms should have been taken into account when evaluating drug delivery systems, galenic formulations and pharmacokinetics as a basis for drug treatment.

Risk factors for the development of pneumonia in acute psychotropic drugs poisoning

Pneumonia is the most frequent complication in acute psychotropic drugs poisoning, which results in substantial morbidity and mortality, but which also increases the costs of treatment. Risk factors for pneumonia are numerous: age, sex, place of the appearance of pneumonia, severity of underlying disease, airway instrumentation (intubation, reintubation, etc). The incidence of pneumonia varies in poisoning caused by the various groups of drugs. The aim of this study was to determine the incidence and risk factors for pneumonia in the patients with acute psychotropic drugs poisoning. A group of 782 patients, out of which 614 (78.5%) with psychotropic and 168 (21.5%) nonpsychotropic drug poisoning were analyzed prospectively during a two-year period. The diagnosis of pneumonia was made according to: clinical presentation, new and persistent pulmonary infiltrates on chest radiography, positive nonspecific parameters of inflammation, and the microbiological confirmation of causative microorganisms. To analyze predisposing risk factors for pneumonia, the following variables were recorded: sex, age, underlying diseases, endotracheal intubation, coma, severity of poisoning with different drugs, histamine H2 blockers, corticosteroids, mechanical ventilation, central venous catheter. The univariate analysis for pneumonia risk factors in all patients, and for each group separately was done. The multivariate analysis was performed using the logistic regression technique. Pneumonia was found in 94 (12.02%) of the patients, 86 of which (91.5%) in psychotropic and 8 (8.5%) in nonpsychotropic drug poisoning. In the psychotropic drug group, pneumonia was the most frequent in antidepressant (47%), and the rarest in benzodiazepine poisoning (3.8%). A statistically significant incidence of pneumonia was found in the patients with acute antidpressant poisoning (p < 0.001). Univariate analysis showed statistical significance for the following parameters: sex (p < 0.05), chronic alcohol intake (p < 0.05), underlying diseases (p < 0.01), central venous catheter (p < 0.05) vasopressors (p < 0.05), coma (p < 0.001), H2 blockers (p < 0.001) and corticosteroids (p < 0.001). The multivariate analysis retained endotracheal intubation and antidepressant drug poisoning as an independent risk factor for pneumonia. Using univariate and multivariate analysis, risk factors for developing pneumonia were disclosed. Some of these factors may be modified by simple medical procedures, thus the incidence and mortality rate of pneumonia in drug poisoning might be substantially reduced.

Night-time gastro-oesophageal reflux disease

Patients who complain of symptoms of gastro-oesophageal reflux disease (GORD) that occur at night require special attention. Night-time GORD can profoundly impair quality of life by causing pain, disturbing sleep, and interfering with next-day mental and physical functioning. Sleep impairs oesophageal acid clearance resulting in a prolongation of acid mucosal contact, and nocturnal reflux portends a greater risk of erosive oesophagitis and other significant complications of gastro-oesophageal reflux. Lifestyle changes such as elevating the head of the bed and adjusting the sleeping position can relieve night-time heartburn, and instituting some dietary changes along with occasional use of histamine H2 blockers can also be helpful. Relief of night-time reflux and its attendant symptoms usually requires a medication with acid-suppressing properties that extend into the sleeping interval. In most instances, more powerful acid suppression in the form of proton-pump inhibitors will be required. Clinical studies have shown that 40 mg esomeprazole provides better control of night-time GORD symptoms than 20 mg omeprazole or 30 mg lansoprazole. Furthermore, 40 mg pantoprazole offers even faster relief than 40 mg esomeprazole for night-time GORD symptoms. Of the several proton-pump inhibitors available on the market, esomeprazole and pantoprazole appear to have some advantages, which have been documented in recent studies. Esomeprazole has been shown to be more effective than lansoprazole in relieving GORD symptoms, and esomeprazole and pantoprazole appear to be equally effective in resolving GORD symptoms in a comparative study. Pantoprazole has pharmacokinetic properties that document a longer half-life compared with the other proton-pump inhibitors, and pantoprazole has the slowest inhibition recovery rate. These properties lend credence to pantoprazole as an effective treatment for associated symptoms of night-time reflux.

Treatment of gastric hemorrhage by pulverized omeprazole and antacid – concomitant administration via a nasogastric tube

Gastroesophageal reflux (GER) is a common episode in pediatric patients with severe motor and intellectual disabilities (SMID) and occasionally leads to a severe clinical state accompanied with nausea, hematemesis, melena, wheezing, pneumonia, anemia and/or failure to thrive. We report here a case of a 14-year-old male with Lennox syndrome who had been treated with a histamine H2 blocker intravenously or via a nasogastric tube for repeated gastric hemorrhage due to severe GER. Since his gastric hemorrhage became resistant to the H2 blocker, we decided to replace it with a proton pump inhibitor (PPI). Although lansoprazole can be decapsulated for administration via a nasogastric tube, it tends to block fine tubes. The acid-sensitive drug omeprazole, another oral PPI, is commercially available as enteric-coated tablets. Therefore, we pulverized the tablets and administered omeprazole, mixed with a small amount of antacid, via a nasogastric tube. The patient's gastric hemorrhage was dramatically improved. Thus, administration of pulverized omeprazole concomitantly with antacid via a fine nasogastric tube may provide a novel approach for the treatment of chronic GER in pediatric patients with SMID.

Acute inflammatory reactions caused by histamine via monocytes/macrophages chronically participate in the initiation and progression of atherosclerosis.

Previously we demonstrated that histidine decarboxylase (HDC), which produces histamine from l-histidine, was detected in monocytes/macrophages located in human atherosclerotic lesions. As monocytic migration is a key event of atherogenesis, we investigated whether histamine induces monocytic expression of monocyte chemoattractant protein (MCP)-1 and its receptors CCR2-A and -B, and also endothelial expression of ICAM-1 and VCAM-1. Furthermore, we studied the effect of interleukin (IL)-4, which inhibits the HDC expression, on the expression of MCP-1 and CCR2. Histamine stimulated monocytes, but not macrophages, to express MCP-1 and CCR2-A and -B. The expression of MCP-1 was inhibited by histamine H2 blocker. In contrast, IL-4 enhanced CCR2 expression but not MCP-1. Histamine stimulated endothelial cells to express ICAM-1 and VCAM-1. These results indicate that histamine and IL-4, which are both synthesized in the arterial intima, chronically participates in the pathogenesis of atherosclerosis via the enhanced expression of monocytic MCP-1, CCR2 and endothelial adhesion molecules.

The antiallergic drug oxatomide promotes human eosinophil apoptosis and suppresses IL-5-induced eosinophil survival

Background: Eosinophils accumulated in sites of allergic inflammation are thought to play a crucial role in the pathogenesis of allergic disorders including asthma, allergic rhinitis, and atopic dermatitis, and tissue eosinophilia is attributable to increased eosinophil survival or decreased eosinophil apoptosis. Objective: Effects of the antiallergic, histamine H1 blocker oxatomide on viability and apoptosis of eosinophils isolated from the peripheral blood of atopic subjects were studied. Methods: Eosinophil viability and apoptosis were evaluated by using a colorimetric assay and annexin V-labeling, caspase-3 activity, and DNA fragmentation assay. Results: The viability of eosinophils increased in the presence of IL-5 (10 ng/mL), confirming that IL-5 prolongs eosinophil survival in vitro. Application of oxatomide at concentrations over 20 μmol/L for 24 hours decreased the IL-5-induced enhancement of eosinophil viability. Double staining of the cells with annexin V and propidium iodide showed that deprivation of IL-5 promoted spontaneous eosinophil apoptosis and that oxatomide facilitated apoptosis and suppressed the prolongation of eosinophil survival stimulated by IL-5. In the absence of IL-5, approximately 71% and 96% of eosinophils after 24 and 48 hours, respectively, underwent spontaneous apoptosis. IL-5 decreased the rate of eosinophil apoptosis to 38% and 52% after 24 and 48 hours, respectively. Oxatomide increased eosinophil apoptosis in a concentration-dependent manner in the presence of IL-5. Furthermore, oxatomide increased caspase-3 activity and DNA fragmentation. Conclusion: We demonstrated that oxatomide possesses a novel therapeutic effect of apoptosis promotion on eosinophils and prevents the antiapoptotic effects of IL-5, suggesting that oxatomide may contribute to resolution of tissue eosinophilia in allergic inflammation. (J Allergy Clin Immunol 2003;111:567-72.)

Neurochemical regulation of cough response to capsaicin in guinea‐pigs

1. Although monumental efforts have been made to define the action sites of cough, the importance of neurotransmitter systems in the cough reflex has received limited attention. We studied the roles for four major neurotransmitters [acetylcholine, histamine, serotonin (5-hydroxytryptamine, 5-HT) and dopamine] in the modulation of the cough reflex. 2. Atropine (muscarinic cholinergic blocking agent), pyrilamine maleate (PM, histamine H1 blocker), cimetidine (histamine H2 blocker), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, specific 5-HT1A receptor agonist) and SCH-23390 (selective dopamine D1 receptor antagonist) were examined on the cough response to inhaled capsaicin in conscious guinea-pigs. 3. All the drugs significantly decreased the number of capsaicin-induced coughs in a dose-dependent manner. To compare the sensitivity of these drugs on cough response, we calculated the effective doses for 50% inhibition of cough (ED50) when the animals were exposed to 3 x 10-4 m capsaicin. The ED50 values were 0.03 microm kg-1 for atropine, 0.2 microm kg-1 for 8-OH-DPAT, 6.2 microm kg-1 for SCH-23390, 8.5 microm kg-1 for PM and 13.9 microm kg-1 for cimetidine. 4. These findings indicated that all these four neurotransmitters may be involved in the regulation of the cough reflex. Multiple changes of these neurotransmitters in disorders of the central nervous system might synergically affect the cough reflex.