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.

Rapid Determination of Ranitidine in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry and Its Application to a Clinical Pharmacokinetic Study

A rapid and sensitive assay based on high performance liquid chromatography-tandem mass spectrometry（LC-MS/MS） was developed for the determination of ranitidine（RAN） in human plasma with codeine as internal standard（IS）.After protein precipitation with acetonitrile,the analyte and IS were separated on a Zorbax SB-Aq C18 column（150 mm×4.6 mm i.d.,5 μm） eluted with a mobile phase consisting of methanol/acetonitrile/10 mmol/L ammonium acetate containing 1% formic acid（pH=2.4）（volume ratio 12.5：12.5：75） at a flow rate of 1.0 mL/min.Detection was performed by electrospray ionization in the positive ion mode followed by the multiple reaction monito-ring（MRM） of the transitions of RAN at m/z 315.1→176.3 and of IS at m/z 300.1→165.1.The method was linear over a concentration range of 1―1000 ng/mL（r=0.9991） with a lower limit of quantitation（LLOQ） of 1 ng/mL and a limit of detection（LOD） of 0.3 ng/mL.Accuracy as relative error was from-0.01% to-1.7% and intra-day and inter-day precisions as relative standard deviation were ≤8.9% and ≤5.5%,respectively.The method was successfully applied to a pharmacokinetic study of ranitidine,getting a single oral dose（160 mg） to healthy volunteers.

Effects of ranitidine on contraction and action potentials in normal and potassium depolarized isolated papillary muscles of the guinea pig

The purpose of these experiments was to investigate the possible ionicbases for ranitidine （Ran） in isolated papillary muscles of the guinea pig.Ran,when the concentration was below 300μmol/L,had no influence on contraction ofnormal muscles and only above 0.3 mmol/L,it showed weak negative inotropic ef-fect.The contractile activity elicited by histamine in potassium depolarized mus-cles was depressed by Ran markedly and dose-dependently.The IC50 of Ran was0.273μmol/L.This depressant effect was reversed by an elevation of externalCa2+concentration to 7.7mmol/L.The contraction induced by isoproterenol inpotassium depolarized preparations was not altered by Ran.Ran at theconcentrations of 1,10 and 100μmol/L failed to show influences on fast actionpotentials.However,Ran at 0.5μmol/L time-dependently inhibited slow action po-tentials.It is concluded that the ionic mechanism of Ran might be attributed toantagonized H2 receptor of myocardium which in turn decreases Ca2+ inward cur-rent.

Comparison of intravenous pantoprazole and ranitidine in patients with dyspepsia presented to the emergency department: a randomized, double blind, controlled trial

BACKGROUND:This study aimed to compare pantoprazole,a proton-pomp inhibitors(PPIs),and ranitidine,a H2 receptor antagonists(H2RA),in ceasing dyspeptic symptoms in the emergency department(ED).METHODS:This randomized,double-blinded study compared the effectiveness of 50 mg ranitidine(Ulcuran®)and 40 mg pantoprazole(Pantpas®),given in a 100 m L saline solution by an intravenous rapid infusion within 2–4 minutes in patients with dyspepsia presented to the ED.Pain intensity was measured at baseline,30 and 60 minutes after the drug administration.RESULTS:A total of 72 patients were eligible for the study.Of these patients,2 were excluded from the study because the initial visual analogue scale(VAS)scores were under 20 mm and 4 were excluded from the statistical analysis because of being diagnosed as having other causes of epigastric pain despite being allocated to one of the study groups.Thirty-three patients in the pantoprazole group and 33 patients in the ranitidine group were analyzed ultimately.The mean age of the patients was36.6±15 years,and 26(39.4%)patients were male.Both of the groups reduced pain effectively at 30[27.6±28(18 to 37)vs.28.3±23(20 to 37),respectively]and 60 minutes[39.6±39(26 to 53)vs.42.3±25(33 to 51),respectively].There were 13(39.4%)patients in the pantoprazole group and 8(24.2%)patients in the ranitidine group who required additional drug at the end of the study(P=0.186).CONCLUSION:Intravenous pantoprazole and ranitidine are not superior to each other in ceasing dyspeptic symptoms at 30 and 60 minutes in the ED.

Characterization of N-nitrosodimethylamine formation from the ozonation of ranitidine

N-nitrosodimethylamine（NDMA） is an emerging disinfection by-product which is formed during water disinfection in the presence of amine-based precursors. Ranitidine, as one kind of amine-based pharmaceuticals, has been identified as NDMA precursor with high NDMA molar conversion during chloramination. This study focused on the characterization of NDMA formation during ozonation of ranitidine. Influences of operational variables（ozone dose, pH value） and water matrix on NDMA generation as well as ranitidine degradation were evaluated. The results indicate high reactivity of ranitidine with ozone.Dimethylamine（DMA） and NDMA were generated due to ranitidine oxidation. High pH value caused more NDMA accumulation. NDMA formation was inhibited under acid conditions（pH ≤ 5） mainly due to the protonation of amines. Water matrix such as HCO-3and humic acid impacted NDMA generation due to UOH scavenging. Compared with UOH,ozone molecules dominated the productions of DMA and NDMA. However, UOH was a critical factor in NDMA degradation. Transformation products of ranitidine during ozonation were identified using gas chromatography–mass spectrometry. Among these products, just DMA and N,N-dimethylformamide could contribute to NDMA formation due to the DMA group in the molecular structures. The NDMA formation pathway from ranitidine ozonation was also proposed.

溃疡病治疗中Ranitidine依赖现象

自1975年Cimetidine在消化性溃疡病治疗中应用以来,H_2受体阴滞剂在溃疡病治疗中占有重要地位,尤其是Ranitidine疗效更高,副作用更小,临床应用更广,但由于夏发率较高.使部分患者长期服用,一旦停药就出现泛酸症状,而胃镜检查未发现溃疡病灶,再服Ranitidine症状即可缓解.本文就这部分患者进行了临床分析,认为这种现象是H_2受体阻滞剂依赖现象,初步探讨了其发生机理和临床意义.

COMPARISON OF RANITIDINE AND PANTOPRAZOLE FOR STRESS ULCER BLEEDING PROPHYLAXIS IN CRITICALLY ILL PATIENTS REQUIRING MECHANICAL VENTILATION

Objective To compare the efficacy of Ranitidine and Pantoprazole for the prevention of haemorrhage from stress ulcer among critical care patients. Methods A total of 121 critically ill patients were included in this retrospective study. The choice of pharmacologic stress ulcer prophylaxis were either Ranitidine or Pantoprazole. The primary outcome was the incidence of stress-related significant upper gastrointestinal bleeding, and the secondary outcome was the incidence of hospital acquired pneumonia (HAP). Results A total of 63 patients were given Ranitidine, and 58 patients were given Pantoprazole for stress ulcer bleeding prophylaxis. Nine patients (7.44%, 9/121) developed clinically-important upper gastrointestinal bleeding, including 5 (7.94%, 5/63) in the Ranitidine group, and 4 (6.90%,4/58) in the Pantoprazole group. The rate of HAP was 3.17% (2/63) in the Ranitidine group, and 15.52% (9/58) in the Pantoprazole group. Conclusion Ranitidine was associated with lower rates of HAP as compared with Pantoprazole, with no statistically significant difference in clinically-important gastrointestinal hemorrhage. Because of limited trial data, future well-designed and powerful randomized, clinical trials are warranted.

Widespread use of gastric acid inhibitors in infants:Are they needed? Are they safe?

Gastroesophageal reflux is a common phenomenon in infants,but the differentiation between gastro-esophageal reflux and gastroesophageal reflux disease can be difficult.Symptoms are non-specific and there is increasing evidence that the majority of symptoms may not be acid-related.Despite this,gastric acid inhibitors such as proton pump inhibitors are widely and increasingly used,often without objective evidence or investigations to guide treatment.Several studies have shown that these medications are ineffective at treating symptoms associated with reflux in the absence of endoscopically proven oesophagitis.With a lack of evidence for efficacy,attention is now being turned to the potential risks of gastric acid suppression.Previously assumed safety of these medications is being challenged with evidence of potential side effects including GI and respiratory infections,bacterial overgrowth,adverse bone health,food allergy and drug interactions.

Protective effect of Luffa acutangula extracts on gastric ulceration in NIDDM rats:Role of gastric mucosal glycoproteins and antioxidants

Objective:To study the comparative gastroprotective effect of Luffa acutangula methanolic extract(LAM) and aqueous extract(LAW) on typeⅡdiabetes rats.Methods:Streptozotocin(65 mg/kg,Lp.) along with nicotinamide(120 mg/kg,Lp.) was used to induce non insulin dependent diabetes mellitus(NIDDM) in rats.A daily oral dose of aspirin(200 mg/kg,Lp.) was administered for initial seven days to induce gastric ulcerations in the diabetic rats.LAM and LAW were administered orally in the doses of 100,200 and 400 mg/kg once daily for 21 days.Clibenclamide and ranitidine were used as standards for comparing the antidiabetic and antiulcer effect respectively.Results:LAM significantly(P【0.01) increased mucosal glycoprotein and antioxidant enzyme level in gastric mucosa of diabetic rats than LAW(P 【0.05).LAM was efficient in reversing the delayed healing of gastric ulcer in diabetic rats close to the normal level.LAM exhibited better ulcer healing effect than glibenclamide and LAW,because of its both antihyperglycemic and mucosal defensive actions.Conclusions:Thus,LAM is proved to be a better alternative for treating gastric ulcers co-occurring with diabetes.

美国FDA下令立即撤回所有雷尼替丁产品

美国食品药品监督管理局(FDA)于2020年4月1日下令要求所有生产商立即从美国市场撤回所有雷尼替丁(ranitidine,商品名Zantac)产品,包括处方药和非处方药,原因是有调查发现雷尼替丁药品中含有致癌物N-亚硝基二甲胺(N-Nitrosodimethylamine,NDMA),而且当储藏温度高于室温时某些雷尼替丁药品中NDMA的含量会随着时间持续增加。

Capability of cation exchange technology to remove proven N-nitrosodimethylamine precursors

N-nitrosodimethylamine（NDMA） precursors consist of a positively charged dimethylamine group and a non-polar moiety, which inspired us to develop a targeted cation exchange technology to remove NDMA precursors. In this study, we tested the removal of two representative NDMA precursors, dimethylamine（DMA） and ranitidine（RNTD）, by strong acidic cation exchange resin. The results showed that pH greatly affected the exchange efficiency, with high removal（DMA 〉 78% and RNTD 〉 94%） observed at pH 〈 pk_a-1 when the molar ratio of exchange capacity to precursor was 4. The exchange order was obtained as follows： Ca^（2＋）〉 Mg^（2＋）〉 RNTD~＋〉 K~＋〉 DMA~＋〉 NH_4~＋〉 Na~＋. The partition coefficient of DMA~＋to Na~＋was 1.41 ± 0.26, while that of RNTD~＋to Na~＋was 12.1 ± 1.9. The pseudo second-order equation fitted the cation exchange kinetics well. Bivalent inorganic cations such as Ca^（2＋）were found to have a notable effect on NA precursor removal in softening column test. Besides DMA and RNTD, cation exchange process also worked well for removing other 7 model NDMA precursors. Overall, NDMA precursor removal can be an added benefit of making use of cation exchange water softening processes.