Determination of Ten Kinds of Alpha-2 Agonists Residues in Animal Derived Food by UHPLC-Triple Quadrupole/Composite Linear Ion Trap Mass Spectrometry

[Objectives]The paper was to establish an ultra high performance liquid chromatography-quadrupole/linear ion trap complex mass spectrometry for the determination of 10 kinds ofα2-receptor agonists in animal derived food.[Methods]The samples were extracted with sodium carbonate buffer solution and ethyl acetate,and analyzed by mass spectrometry after solid phase extraction and high performance liquid chromatography separation.[Results]Ten kinds ofα2-receptor agonists showed a good linear relationship in the range of 1-100μg/mL,with the average recovery of over 69%and the relative standard deviation less than 8.32%.The detection limit of 10 kinds of α_(2)-receptor agonists was up to 1μg/kg.[Conclusions]The method has good selectivity and strong anti-interference ability,and can meet the requirements of 10 kinds ofα2-receptor agonists residues in animal derived food.

Head-to-head comparison of H_2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: A meta-analysis

AIM: To systematically evaluate the efficacy of H2-receptor antagonists (H2RAs) and proton pump inhibitors in healing erosive esophagitis (EE).METHODS: A meta-analysis was performed. A literature search was conducted in PubMed, Medline, Embase, and Cochrane databases to include randomized controlled head-to-head comparative trials evaluating the efficacy of H2RAs or proton pump inhibitors in healing EE. Relative risk (RR) and 95% confidence interval (CI) were calculated under a random-effects model.RESULTS: RRs of cumulative healing rates for each comparison at 8 wk were: high dose vs standard dose H2RAs,1.17 (95%CI, 1.02-1.33); standard dose proton pump inhibitors vsstandard dose H2RAs, 1.59 (95%CI, 1.44-1.75);standard dose other proton pump inhibitors vs standard dose omeprazole, 1.06 (95%CI, 0.98-1.06). Proton pump inhibitors produced consistently greater healing rates than H2RAs of all doses across all grades of esophagitis, including patients refractory to H2RAs. Healing rates achieved with standard dose omeprazole were similar to those with other proton pump inhibitors in all grades of esophagitis.CONCLUSION: H2RAS are less effective for treating patients with erosive esophagitis, especially in those with severe forms of esophagitis. Standard dose proton pump inhibitors are significantly more effective than H2RAs in healing esophagitis of all grades. Proton pump inhibitors given at the recommended dose are equally effective for healing esophagitis.

Efficacy of the H2-receptor antagonist famotidine on chronic spontaneous urticaria in children

Urticaria is a common pediatric skin disorder. Histamine H1-receptor antagonists are effective in chronic as well as acute urticaria. When H1-anti-histamines are ineffective, add-on use of H2-receptor antagonists is thought to give better symptom relief. However, there are few reports on the therapeutic efficacy in pediatric patients. We retrospectively reviewed the medical records of pediatric patients with chronic spontaneous urticaria (csU) who met the following criteria. They were consulted our outpatient clinic between April 2010 and March 2012;were unsuccessfully treated with H1 antihistamines;and were treated with add-on H2-receptor antagonist (famotidine). In six patients who met the inclusion criteria (mean age 6.1 ± 5.1 years), urticaria activity score was significantly decreased from 4.3 ± 0.8 just before administration of famotidine to 1.3 ± 1.0 on the first outpatient visit within 4 weeks after the first administration of famotidine

EFFECT OF α_1 AND α_2 RECEPTORS IN THE RABBIT THORACIC SPINAL CORD ON ELECTROACUPUNCTURE AT "NEIGUAN" FOR TREATMENT OF ACUTE MYOCARDIAL ISCHEMIA

In the present paper, the effect of α1 and α2 subtypes of the thoracic spinal cord on electroacupuncture (EA)-induced improvement of ischemic cardiac electrical and mechanical activities was observed in 80 anesthetized rabbits by using ECG-ST, MBP, LVP and dp/dt max as indexes. Results showed that:1) EA at "Neiguan" could significantly improve the electrical and mechanical activities of the ischemic heart; 2) the effect of EA could be enhanced to a certain degree when α1 receptors of the thoracic spinal cord were activated by subarachnoid microinjection of phenylephrine, while it was weakened when α1 receptors were inhibited by microinjection of parison; and 3) activation or inhibition of α2 receptors of the thoracic spinal cord by microinjection of clonidine and yohimbine had no marked influence on the effect of EA in improving electrical activity of the ischemic heart, but when activated,they could weaken the effect of EA in raising MBP; while suppressed, they had no any striking influence on the effect of EA in raising MBP. It suggests that among α-receptors, predominantly α1-receptors participate in the process of EA-induced improvement of performance of ischemic heart.

Human ciliary muscle cell responses to kinins:Activation of ERK1/2 and pro-matrix metalloproteinases secretion

AIM To study activation of extracellular signal-regulated kinase-1/2(ERK1/2) and pro-matrix metalloproteinases(pro-MMPs) secretion from isolated primary human ciliary muscle(h-CM) cells in response to bradykinin(BK) and other agonists. METHODS Serum-starved h-CM cells were challenged with vehicle, BK agonists or antagonists. Cell lysates were evaluated for phosphorylated ERK1/2 using homogeneous timeresolved fluorescence technology based on a sandwich immunoassay. Rabbit polyclonal anti-pro-MMP antibodies were used to measure pro-MMPs using immunoblot analysis.RESULTS A 10 min incubation time using 5 × 104 h-CM cells/well was optimum condition for studying stimulation of ERK1/2 phosphorylation. BK(100 nmol/L) caused a 1.86 ± 0.26 fold(n = 3) increase in ERK1/2 phosphorylation above baseline. BK analogs, Met-Lys-BK and RMP-7(100 nmol/L), also stimulated ERK1/2 phosphorylation by 1.57 ± 0.04 and 1.55 ± 0.09 fold, respectively. However, DesArg9-Bradykinin, a B1 receptor-selective agonist(0.1-1 μmol/L), was essentially inactive. HOE-140 or WIN-64338(B2-antagonists) appreciably blocked phosphorylation of ERK1/2 induced by various BK agonists. Pre-treatmentof cells with a prostaglandin(PG) synthase inhibitor(bromfenac; 1 μmol/L) failed to alter kinin-induced ERK1/2 activation. BK and a non-peptide BK agonist(FR-190997)(10 nmol/L-1 μmol/L) also enhanced pro-MMPs secretion(pro-MMP-1 > pro-MMP-3 > pro-MMP-2; 1.45-1.75-fold over baseline) from h-CM cells. CONCLUSION These collective data suggest that B2 kinin receptors initiate signaling in h-CM cells by a relatively rapid mechanism(within minutes) involving ERK1/2 activation which in turn regulates MMPs production(within hours). The latter process does not involve PGs.

A Prospective, Multicentric, Post Marketing Surveillance to Evaluate Efficacy & Safety of Ranitidine HCl (150 & 300 mg IR/CR) in Indian Patients with Gastroesophageal Reflux Disease (PROGRADE)

Purpose: Ranitidine hydrochloride (HCl) remains an important medication for treating acid-peptic ailments such as Gastroesophageal reflux disease (GERD). The main objective of this Post Marketing Surveillance (PMS) clinical study was to test the efficacy and safety of Ranitidine HCl in Indian patients suffering from GERD. Patients and Methods: Data of 2446 patients (1307 males;1121 females) from 21 centers across India were analyzed. Patients received either of the three treatments: Ranitidine HCl 150 mg twice a day (BID) (ARM-A), Ranitidine HCl 300 mg once daily (OD) or BID (ARM-B), and Ranitidine HCl 300 mg OD (ARM-C). Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS) score and Heartburn Severity score were used to assess the drug’s efficacy. The adverse events reported by patients or investigators were analyzed to assess the safety profile of Ranitidine. Results: Of the 2446 subjects screened, 2428 were enrolled. There was a significant reduction in GSAS scores from baseline to the end of the study visit in all three ARMs. The GSAS scores reduced from 2.02 to 0.23 in ARM-A, 2.01 to 0.24 in ARM-B, and 2.07 to 0.26 in ARM-C patients. In ARM A, 72.82% had 24 hours heartburn-free days, and 66.89% had 7 consecutive heartburn-free days, which was more significant than the other two ARMs. 128 (5.27%) patients reported ADRs due to Ranitidine HCl at different doses. The most frequently reported ADR was constipation (17.18%), followed by oliguria (14.06%), cold (13.28%), and dysuria (12.5%). Of 128 ADRs, 113 (88.28%) were mild, and only 11 (8.59%) ADRs were related to the study drug. No severe ADRs were reported during the study. Conclusion: Ranitidine HCl 150/300 mg tablet was found to be an effective and safe H2-receptor antagonist for treating GERD in Indian Patients.

盐酸马布特罗的合成

目的研究β2-受体兴奋剂盐酸马布特罗的合成工艺。方法以3-氯-4-氨基-5-三氟甲基苯乙酮为起始原料,经溴代、胺解、还原和成盐反应制得盐酸马布特罗。结果与结论目标化合物的结构经红外光谱1、H-NMR1、3C-NMR和质谱确证,总收率为8.5%。该合成工艺操作简便,适合工业化生产。

Acid suppressive drugs and gastric cancer: A meta-analysis of observational studies

AIM: To evaluate the association between acid suppressive drug use and the development of gastric cancer. METHODS: A systematic search of relevant studies that were published through June 2012 was conducted using the MEDLINE (PubMed), EMBASE, and Cochrane Library databases. The search included observational studies on the use of histamine 2-receptor antagonists (H 2 RAs) or proton pump inhibitors and the associated risk of gastric cancer, which was measured using the adjusted odds ratio (OR) or the relative risk and 95%CI. An independent extraction was performed by two of the authors, and a consensus was reached. RESULTS: Of 4595 screened articles, 11 observational studies (n = 94558) with 5980 gastric cancer patients were included in the final analyses. When all the studies were pooled, acid suppressive drug use was associated with an increased risk of gastric cancer risk (adjusted OR = 1.42; 95%CI: 1.29-1.56, I2 = 48.9%, P = 0.034). The overall risk of gastric cancer increased among H 2 RA users (adjusted OR = 1.40; 95%CI: 1.24-1.59, I2 = 59.5%, P = 0.008) and PPI users (adjusted OR = 1.39; 95%CI: 1.19-1.64, I2 = 0.0%, P = 0.377). CONCLUSION: Acid suppressive drugs are associated with an increased risk of gastric cancer. Further studies are needed to test the effect of acid suppressive drugs on gastric cancer.

Gastro-protective action of lafutidine mediated by capsaicin-sensitive afferent neurons without interaction with TRPV1 and involvement of endogenous prostaglandins

AIM： Lafutidine, a histamine H2 receptor antagonist, exhibits gastro-protective action mediated by capsaicinsensitive afferent neurons （CSN）. We compared the effect between lafutidine and capsaicin, with respect to the interaction with endogenous prostaglandins （PG）, nitric oxide （NO） and the afferent neurons, including transient receptor potential vanilloid subtype 1 （TRPV1）. METHODS： Male SD rats and C57BL/6 mice, both wildtype and prostacyclin IP receptor knockout animals, were used after 18 h of fasting. Gastric lesions were induced by the po administration of HCl/ethanol （60% in 150 mmol/L HCl） in a volume of 1 mL for rats or 0.3 mL for mice. RESULTS： Both lafutidine and capsaicin （1-10 mg/kg, po） afforded dose-dependent protection against HCI/ ethanol in rats and mice. The effects were attenuated by both the ablation of CSN and pretreatment with NG-nitro- L-arginine methyl ester, yet only the effect of capsaicin was mitigated by prior administration of capsazepine, the TRPV1 antagonist, as well as indomethacin. Lafutidine protected the stomach against HCl/ethanol in IP receptor knockout mice, similar to wild-type animals, while capsaicin failed to afford protection in the animals lacking IP receptors. Neither of these agents affected the mucosal PGE2 or 6-keto PGF1α contents in rat stomachs. Capsaicin evoked an increase in [Ca^2＋]i in rat TRPV1-transfected HEK293 cells while lafutidine did not. CONCLUSION： These results suggest that although both lafutidine and capsaicin exhibit gastro-protective action mediated by CSN, the mode of their effects differs regarding the dependency on endogenous PGs/IP receptors and TRPV1. It is assumed that lafutidine interacts with CSN at yet unidentified sites other than TRPV1.

Poor awareness of preventing aspirin-induced gastrointestinal injury with combined protective medications

AIM:To investigate prescribing pattern in low-dose aspirin users and physician awareness of preventing aspirin-induced gastrointestinal(GI) injury with combined protective medications.METHODS:A retrospective drug utilization study was conducted in the 2nd Affiliated Hospital,School of Medicine,Zhejiang University.The hospital has 2300 beds and 2.5 million outpatient visits annually.Data mining was performed on all aspirin prescriptions for outpatients and emergency patients admitted in 2011.Concomitant use of proton-pump inhibitors(PPIs),histamine 2-receptor antagonists(H2RA) and mucoprotective drugs(MPs) were analyzed.A defined daily dose(DDD) methodology was applied to each MP.A further investigation was performed in aspirin users on combination use of GI injurious medicines [non-steoid anti-inflammatory drugs(NSAIDs),corticosteroids and clopidogrel and warfarin] or intestinal protective drugs(misoprostol,rebamipide,teprenone and gefarnate).Data of major bleeding episodes were derived from medical records and adverse drug reaction monitoring records.The annual incidence of major GI bleeding due to low-dose aspirin was estimated for outpatients.RESULTS:Prescriptions for aspirin users receiving PPIs,H2RA and MPs(n = 1039) accounted for only 3.46% of total aspirin prescriptions(n = 30 015).The ratios of coadministration of aspirin/PPI,aspirin/H2RA,aspirin/MP and aspirin/PPI/MP to the total aspirin prescriptions were 2.82%,0.12%,0.40% and 0.12%,respectively.No statistically significant difference was observed in age between patients not receiving any GI protective medications and patients receiving PPIs,H2RA or MPs.The combined medication of aspirin and PPI was used more frequently than that of aspirin and MPs(2.82% vs 0.40%,P < 0.05) and aspirin/H2RA(2.82% vs 0.12%,P < 0.05).The values of DDDs of MPs in descending order were as follows:gefarnate,hydrotalcite > teprenone > sucralfate oral suspension > L-glutamine and sodium gualenate granules > rebamipide > sucralfate chewable tablets.The ratio of MP plus aspirin prescriptions to the total MP prescriptions was as follows:rebamipide(0.47%),teprenone(0.91%),L-glutamine and sodium gualenate granules(0.92%),gefarnate(0.31%),hydrotalcite(1.00%) and sucralfate oral suspension(0.13%).Percentages of prescriptions containing aspirin and intestinal protective drugs among the total aspirin prescriptions were:rebamipide(0.010%),PPI/rebamipide(0.027%),teprenone(0.11%),PPI/teprenone(0.037%),gefarnate(0.017%),and PPI/gefarnate(0.013%).No prescriptions were found containing coadministration of aspirin and other NSAIDs.Among the 3196 prescriptions containing aspirin/clopidogrel,3088(96.6%) prescriptions did not contain any GI protective medicines.Of the 389 prescriptions containing aspirin/corticosteroids,236(60.7%) contained no GI protective medicines.None of the prescriptions using aspirin/warfarin(n = 22) contained GI protective medicines.Thirty-five patients were admitted to this hospital in 2011 because of acute hemorrhage of upper digestive tract induced by low-dose aspirin.The annual incidence rates of major GI bleeding were estimated at 0.25% for outpatients taking aspirin and 0.5% for outpatients taking aspirin/warfarin,respectively.CONCLUSION:The prescribing pattern of low-dose aspirin revealed a poor awareness of preventing GI injury with combined protective medications.Actions should be taken to address this issue.

A randomized open-label trial of on-demand rabeprazole vs ranitidine for patients with non-erosive reflux disease

AIM： To compare the efficacy of the proton-pump inhibitor, rabeprazole, with that of the H2-receptor antagonist, ranitidine, as on-demand therapy for relieving symptoms associated with non-erosive reflux disease （NEED）.METHODS： This is a single center, prospective, randomized, open-label trial of on-demand therapy with rabeprazole （group A） vs ranitidine （group B） for 4 wk. Eighty-three patients who presented to the American University of Beirut Medical Center with persistent gas- troesophageal reflux disease （GERD） symptoms and a normal upper gastrointestinal endoscopy were eligible for the study. Patients in group A （n = 44） were al-lowed a maximum rabeprazole dose of 20 mg twice daily, while those in group B （n = 39） were allowed a maximum ranitidine dose of 300 mg twice daily. Ef- ficacy was assessed by patient evaluation of global symptom relief, scores of the SF-36 quality of life （QoL） questionnaires, total number of pills used, and number of medication-free days.RESULTS： Among the 83 patients who were enrolled in the study, 76 patients （40 in the rabeprazole group and 36 in the ranitidine group） completed the 4-wk trial. Baseline characteristics were comparable between both groups. After 4 wk, there was no significant difference in the subjective global symptom relief between the rabeprazole and the ranitidine groups （71.4% vs 65.4%, respectively; P = 0.9）. There were no statistically significant differences between mean cumulative scores of the SF-36 QoL questionnaire for the two study groups （rabeprazole 22.40±27.53 vs ranitidine 17.28 ± 37.06; P = 0.582）. There was no significant difference in the mean number of pills used （rabeprazole 35.70±29.75 vs ranitidine 32.86±26.98; P = 0.66）. There was also no statistically significant difference in the mean number of medication-free days between both groups.CONCLUSION： Rabeprazole has a comparable efficacy compared to ranitidine when given on-demand for the treatment of NERD. Both medications were associated with improved quality of life.

Early effects of oral administration of omeprazole and roxatidine on intragastric pH

Objective： The ideal medication for the treatment of acid-related diseases, e.g., peptic ulcers, stress- related gastric bleeding, functional dyspepsia, and gastroesophageal reflux disease, should have a rapid onset of action to promote hemostasis and relieve the symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of a proton pump inhibitor, omeprazole 20 mg, and an H2-receptor antagonist, roxatidine 75 mg. Methods： Ten Heficobacterpylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 h after single oral admini- stration of omeprazole 20 mg and roxatidine 75 mg. Each administration was separated by a 7-d washout period. Results： During the 6-h study period, the average pH after administration of roxatidine was higher than that after administration of omeprazole （median： 4.45 vs. 2.65; P=0.0367）. Also during the 6-h study period, a longer duration of maintenance at pH above 2, 5, and 6 was observed after administration of roxatidine 75 mg than after administration of omeprazole 20 mg （median： 90.6% vs. 55.2%, P=-0.0284; 43.7% vs. 10.6%, P=0.0125; 40.3% vs. 3.3%, P=0.0125; respectively）. Conclusions： In Helicobacter pylori-negative healthy male subjects, oral administration of roxatidine 75 mg increased the intragastric pH more rapidly than that of omeprazole 20 mg.