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The current positive computed tomography (CT) contrast agents (PCTCAs) including clinical iodides, present high CT density value (CT‐DV). However, they are incapable for the accurate diagnosis of some diseases with high CT‐DV, such as osteosarcoma. Because bones and PCTCAs around osteosarcoma generate similar X‐ray attenuations. Here, an innovative strategy of negative CT contrast agents (NCTCAs) to reduce the CT‐DV of osteosarcoma is proposed, contributing to accurate detection of osteosarcoma. Hollow mesoporous silica nanoparticles, loading ammonia borane molecules and further modified by polyethylene glycol, are synthesized as NCTCAs for the diagnosis of osteosarcoma. The nanocomposites can produce H2 in situ at osteosarcoma areas by responding to the acidic microenvironment of osteosarcoma, resulting in nearly 20 times reduction of CT density in osteosarcoma. This helps form large CT density contrast between bones and osteosarcoma, and successfully achieves accurate diagnosis of osteosarcoma. Meanwhile, The NCTCAs strategy greatly expands the scope of CT application, and provides profound implications for the precise clinical diagnosis, treatment, and prognosis of diseases. A negative computed tomography (CT) contrast agent based on hollow mesoporous silica nanoparticles@ammonia borane@polyethylene glycol nanocomposite can produce H2 in situ at osteosarcoma areas by responding to the acidic microenvironment of osteosarcoma, and prominently reduce the CT density of osteosarcoma, which can form large CT density difference contrast between bones and osteosarcoma, and further realize accurate diagnosis of malignant osteosarcoma.

Background Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. Methods The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. Results Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. Conclusions These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

This article reviews the development of our knowledge of the actions of histamine which have taken place during the course of the 20th century. Histamine has been shown to have a key physiological role in the control of gastric acid secretion and a pathophysiological role in a range of allergic disorders. The synthesis of, and pharmacological studies on, selective agonists and antagonists has established the existence of four types of histamine receptor and histamine receptor antagonists have found very important therapeutic applications. Thus, in the 1940s, H1‐receptor antagonists (‘the antihistamines’) yielded and still provide valuable treatment for allergic conditions such as hay fever and rhinitis. In the late 1970s and 1980s, H2‐receptor antagonists (in the discovery of which the two authors were personally involved) revolutionised the treatment of peptic ulcer and other gastric acid‐related diseases. The H3‐receptor antagonists, although available since 1987, have been slower to find a therapeutic role. However, the discovery of nonimidazole derivatives such as brain‐penetrating H3 antagonists has provided drugs that are in early‐phase clinical trials, possibly for application in obesity, and a variety of central nervous system disorders, such as memory, learning deficits and epilepsy. Finally, the most recently (1999) discovered H4 receptor promises the potential to provide drugs acting on the immunological system with possible applications in asthma and inflammation. British Journal of Pharmacology (2006) 147, S127–S135. doi:10.1038/sj.bjp.0706440

Gastritis, one of the most common clinically diagnosed conditions, is defined as the infiltration of inflammatory cells into the gastric mucosa. Drugs for gastritis include histamine-2 receptor antagonists and proton pump inhibitors (PPIs), which reduce acidity in the stomach, and antacids, which neutralize acid. Esomeprazole is a PPI for gastroesophageal reflux disease and gastric and duodenal ulcers that has been shown to be safe and effective at a 10 mg dose. Dual-release drugs have not yet been approved for the treatment of gastritis domestically or internationally. In this study, a dual delayed-release (DR) esomeprazole (10 mg), was compared to famotidine (20 mg) to determine its effectiveness in the treatment of gastritis. This study was a randomized, open-label, multiple-dose, 2-treatment, 2-period, 2-sequence crossover study with a 7-day washout between periods. In each period, the subjects were administered one dose of esomeprazole (10 mg) or famotidine (20 mg) for 7 days at each period. The 24-hour gastric pH was recorded after single and multiple doses. The percentage of time (duration%) that the pH was maintained above 4 in the 24 hours after 7 days of repeated dosing was evaluated. The mean percentages of time that the gastric pH was above 4 after multiple doses over 7 days of a dual DR esomeprazole (10 mg) and famotidine (20 mg) was 47.31% ± 14.85% and 23.88% ± 10.73%. Multiple doses of a dual DR esomeprazole (10 mg) showed effective gastric acid secretion suppression compared to famotidine with comparable safety and tolerability. These results provide evidence supporting the clinical use of a dual DR esomeprazole (10 mg) to treat gastritis. ClinicalTrials.gov identifier: NCT04967014.

The role of histamine as a newly recognized sympathetic neurotransmitter has been presented previously, and its postsynaptic effects greatly depended on the activities of sympathetic nerves. Cardiac sympathetic nerves become overactivated under acute myocardial ischemic conditions and release neurotransmitters in large amounts, inducing ventricular arrhythmia. Therefore, it is proposed that cardiac sympathetic histamine, in addition to norepinephrine, may have a significant arrhythmogenic effect. To test this hypothesis, we observed the release of cardiac sympathetic histamine and associated ventricular arrhythmogenesis that was induced by acute ischemia in isolated mouse hearts. Mast cell-deficient mice (MCDM) and histidine decarboxylase knockout ( HDC −/− ) mice were used to exclude the potential involvement of mast cells. Electrical field stimulation and acute ischemia-reperfusion evoked chemical sympathectomy-sensitive histamine release from the hearts of both MCDM and wild-type (WT) mice but not from HDC −/− mice. The release of histamine from the hearts of MCDM and WT mice was associated with the development of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. The incidence and duration of induced ventricular arrhythmias were found to decrease in the presence of the selective histamine H 2 receptor antagonist famotidine. Additionally, the released histamine facilitated the arrhythmogenic effect of simultaneously released norepinephrine. We conclude that, under acute ischemic conditions, cardiac sympathetic histamine released by overactive sympathetic nerve terminals plays a certain arrhythmogenic role via H 2 receptors. These findings provided novel insight into the pathophysiological roles of sympathetic histamine, which may be a new therapeutic target for acute ischemia-induced arrhythmias.

The World Health Organization (WHO) has reported that globally 235 million people suffer from chronic and other inflammatory diseases. The short half-lives of nonsteroidal anti-inflammatory drugs (NSAIDs) and their notoriety in causing gastrointestinal discomforts, warrants these drugs to be released in a controlled and sustained manner. Although polymeric particles have been widely used for drug delivery, there are few reports that showcase their ability in encapsulating and sustaining the release of NSAIDs. In this paper, polymeric nanoencapsulating microcapsules loaded with NSAIDs were fabricated using solid/water/oil/water emulsion solvent evaporation method. Two NSAIDs, ibuprofen and naproxen, were first pre-loaded into nanoparticles and then encapsulated into a larger hollow microcapsule that contained the third NSAID, celecoxib. A high encapsulation efficiency (%) of these NSAIDs was achieved and a sustained release (up to 30 days) of these drugs in phosphate-buffered saline was observed. Then, a gastrointestinal drug - cimetidine (CIM) - was co-loaded with the NSAIDs. This floating delivery system exhibited excellent buoyancy (~88% up to 24 h) in simulated gastric fluid. It also allowed a sequential release of the drugs, whereby an immediate release of CIM followed by NSAIDs was observed. Drug release of the NSAIDs observed Fickian diffusion mechanism, whereas CIM observed non-Fickian diffusion. Therefore, this delivery system is a promising platform to control the delivery of NSAIDs to combat inflammatory diseases, thereby protecting against possible gastrointestinal side effects that may arise from the overuse of NSAIDs.

In order to demonstrate that high dilutions of histamine are able to inhibit basophil activation in a reproducible fashion, several techniques were used in different research laboratories. The aim of the study was to investigate the action of histamine dilutions on basophil activation. Basophil activation was assessed by alcian blue staining, measurement of histamine release and CD63 expression. Study 1 used a blinded multi-centre approach in 4 centres. Study 2, related to the confirmation of the multi-centre study by flow cytometry, was performed independently in 3 laboratories. Study 3 examined the histamine release (one laboratory) and the activity of H(2) receptor antagonists and structural analogues (two laboratories). High dilutions of histamine (10(-30)-10(-38) M) influence the activation of human basophils measured by alcian blue staining. The degree of inhibition depends on the initial level of anti-IgE induced stimulation, with the greatest inhibitory effects seen at lower levels of stimulation. This multicentre study was confirmed in the three laboratories by using flow cytometry and in one laboratory by histamine release. Inhibition of CD63 expression by histamine high dilutions was reversed by cimetidine (effect observed in two laboratories) and not by ranitidine (one laboratory). Histidine tested in parallel with histamine showed no activity on this model. In 3 different types of experiment, it has been shown that high dilutions of histamine may indeed exert an effect on basophil activity. This activity observed by staining basophils with alcian blue was confirmed by flow cytometry. Inhibition by histamine was reversed by anti-H2 and was not observed with histidine these results being in favour of the specificity of this effect We are however unable to explain our findings and are reporting them to encourage others to investigate this phenomenon.

Background. The pathogenic mechanisms involved in Helicobacter pylori-induced duodenal mucosal injury are incompletely understood. In the present study, we sought to investigate the effect of H. pylori vacuolating cytotoxin (VacA) on duodenal mucosal bicarbonate (HCO−3) secretion. Methods. Concentrated bacterial culture supernatants from an H. pylori wild-type strain producing VacA with s1/m1 genotypes (P12) and from an isogenic mutant lacking VacA (P12ΔvacA) were used. HCO−3 secretion by murine duodenal mucosa was examined in vitro in Ussing chambers. Duodenal mucosal histamine release was measured using enzyme-linked immunosorbent assay. The expression of histamine H2 receptor was examined by immunohistochemical analysis. Results. In a dose-dependent manner, the VacA-positive supernatant P12 reduced prostaglandin E2 (PGE2)- stimulated duodenal mucosal HCO−3 secretion to a maximum of 49% (P < .0001), whereas P12ΔvacA did not result in significant inhibition (P > .05). Purified VacA had a similar effect. Histamine H2 receptor antagonists attenuated the effect of P12 on PGE2-induced HCO−3 secretion. P12 stimulated duodenal histamine release in a dose-dependent manner, and exogenous histamine inhibited PGE2-stimulated duodenal HCO−3 secretion. H2 receptor expression was found in duodenal epithelial cells, the enteric nerve plexus, and lymphocytes in Peyer's patch. Conclusion. H. pylori VacA inhibits PGE2-stimulated duodenal epithelial HCO−3 secretion by a histaminedependent mechanism. This effect likely contributes to the damaging effect of H. pylori in the duodenal mucosa.

Mesenteric traction syndrome is described as sudden tachycardia, hypotension and flush. Among other etiological factors eventeration or mesenteric traction of the small intestine may cause histamine release from mesenteric mast cells. We hypothesized that mesenteric traction syndrome may be positively influenced by prophylactic antihistamine administration. Male patients (n = 17, ASA groups III-IV, 48-78 years old) were investigated in a randomised double blind study during elective abdominal aortic aneurysm (AAA) repair. Eight patients had pre-anaesthetic prophylaxis with dimetindene (H1-receptor antagonist) plus cimetidine (H2-receptor antagonist), 9 patients received placebo. Anaesthesia and invasive haemodynamic monitoring were standardised in all patients. Haemodynamic parameters, plasma histamine concentrations and clinical symptoms were determined 1 min after skin incision, as well as 5 and 20 min after mesenteric traction. Statistical analyses were performed using the Student's t-test, Chi2-test for incidences and Mann-Whitney-U-test for continuous data. The incidence of histamine release was 55.5% (5/9) in the placebo group vs. 37.5% (3/8) in the antihistamine group (p > 0.05, Chi2-test). Plasma histamine levels (mean +/- SD) were higher in the placebo group than in the antihistamine group at 5 and 20 min after mesenteric traction but the difference did not reach statistical significance. Arrhythmias were significantly more frequent in the placebo group (6 times) than in the antihistamine group (none) (p = 0.005 Chi2-test). Systolic blood pressure was not statistically different between groups (e.g. 5 min after mesenteric traction, mean +/- SD; placebo 111 +/- 20 mm Hg vs. antihistamines 119 +/- 35 mm Hg). However, in the placebo group the haemodynamics only stabilised 5 min after mesenteric traction when anaesthetic gas concentration was repeatedly reduced and vasopressor/volume administration was increased (placebo-group = 20 times/antihistamine-group = 8 times, p = 0.001, t-test). Prophylactic administration of antihistamines reduced the incidence of histamine release as well as the incidence of arrhythmias and the amount of stabilising measures during mesenteric traction. Prophylaxis with H1 and H2 antihistamines may be of perioperative benefit and should therefore be considered in AAA-surgery.

The prophylactic effects of H1- and H2-receptor antagonist against histamine release and clinical symptoms (e.g. skin reactions, hemodynamic changes) were examined in 80 allergic patients after the administration of midazolam-ketamine. We examined 80 allergic patients undergoing oral surgery. A prospective randomized controlled study was performed in four groups of 20 patients who received either hydroxyzine (H1-receptor antagonist), chlorpheniramine (H1-receptor antagonist), a combination of chlorpheniramine and famotidine (H1- and H2-receptor antagonist) or a placebo (control) as premedications. Venous blood samples were obtained before introduction as a control and 0.5, 1, 3, 5 min after the administration of midazolam-ketamine in order to measure the plasma histamine level. In addition, any observed hemodynamic changes were simultaneously recorded. The plasma histamine level was measured using the HPLC (high performance liquid chromatography) post-label system. The patients who were treated with both chlorpheniramine and famotidine demonstrated a high level of basal plasma histamine compared to the patients who were treated by hydroxyzine alone (p < 0.05), and they also showed less histamine release and anaphylactoid reactions during midazolam-ketamine anesthesia. Allergic patients demonstrated a high percentage of eosinophils, with an average of 4.79 +/- 3.78%. The administration of midazolam-ketamine in allergic patients demonstrated no significant problems. The combined premedication with chlorpheniramine and famotidine was thus found to have the most prophylactic effect against histamine release after the administration of midazolam-ketamine in allergic patients in spite of a high level of basal plasma histamine.