Low-dose lansoprazole and clarithromycin plus metronidazole vs. full-dose lansoprazole and clarithromycin plus amoxicillin for eradication of Helicobacter pylori infection

AIM: To compare, in a randomized controlled trial, the efficacy and tolerability of two 1-week triple therapies for Helicobacter pylori eradication. METHODS: One hundred and thirty-four consecutive patients with non-ulcer dyspepsia and H. pylori infection were randomized to receive lansoprazole 30 mg once daily, clarithromycin 250 mg twice daily, and metronidazole 500 mg twice daily (LCM group), or lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1000 mg twice daily (LCA group). H. pylori status was assessed by rapid urease test, histology and 13C-urea breath test before and after therapy. RESULTS: At 3 months, H. pylori eradication (intention- to-treat/per protocol analysis) was 92.4%/93.8% in the LCM group and 83.1%/85.7% in the LCA group (P=N.S.). Side-effects were more frequently reported in the LCA group (37.9%) than in the LCM group (19.7%) (P < 0.05). CONCLUSIONS: In this open, randomized controlled trial, eradication of H. pylori by low-dose lansoprazole and clarithromycin plus metronidazole was higher with significantly less side-effects than by full-dose lansoprazole and clarithromycin plus amoxicillin. This finding may be related to the stronger synergism of clarithromycin plus metronidazole, even at lower doses, than of clarithromycin plus amoxicillin. Considering the lower cost as well, LCM should be preferred to LCA in the eradication of H. pylori.     

Bismuth-based quadruple therapy for Helicobacter pylori - a single triple capsule plus lansoprazole

BACKGROUND: Recently a new 'all in one' single capsule with the three components of bismuth-based triple therapy became available in trials for treating Helicobacter pylori. AIM: To investigate the efficacy and tolerability of this new capsule when combined with lansoprazole. METHODS: A total of 66 consecutive infected patients from a single centre received two single triple capsules four times daily and lansoprazole 30 mg b.d. for 7 days. Each capsule contained 60 mg of bismuth subcitrate, 125 mg of tetracycline and 125 mg of metronidazole. Endoscopy with biopsies for CLO-test, histology and culture from antrum and corpus was performed before and at least 5 weeks after treatment. RESULTS: The per protocol cure rate was 56/64 (88%, 95% CI: 79-95%); by intention-to-treat 56/65 (86%, 95% CI: 78-95%). The per protocol cure rate in metronidazole sensitive strains was 40/43 (93%, 95% CI: 85-100%); in resistant strains 5/9 (56%, 95% CI: 23-88%). There was one drop-out due to adverse events. CONCLUSIONS: It is possible to combine the components of bismuth-based triple therapy into a single capsule. Based on the results it can be assumed that the capsule releases its content in the stomach. When combined with lansoprazole it reaches high cure rates, especially in metronidazole sensitive strains. This new approach simplifies bismuth-based anti-Helicobacter therapy.     

Coadministration of lansoprazole and naproxen does not affect the pharmacokinetic profile of methotrexate in adult patients with rheumatoid arthritis

Drugs prescribed for rheumatoid arthritis are often associated with gastrointestinal toxicity, and proton pump inhibitors may be coadministered for gastroprotection. In this open-label study, the effect of lansoprazole 30 mg qd and naproxen 500 mg bid on the pharmacokinetic profile of methotrexate was investigated. Twenty-seven adult rheumatoid arthritis patients on stable oral methotrexate doses (7.5-15 mg/week) for a minimum of 3 months were enrolled. Methotrexate pharmacokinetics were assessed on days -1 (methotrexate alone) and 7 (methotrexate with lansoprazole and naproxen). Pharmacokinetics of methotrexate and 7-hydroxymethotrexate were not altered by coadministration of methotrexate with lansoprazole and naproxen; point estimates and 90% confidence intervals for the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries. Therefore, coadministration of naproxen and lansoprazole for 7 days does not affect the pharmacokinetic profile of low doses of methotrexate.     

兰索拉唑及其片剂的稳定性研究

目的 考察兰索拉唑原料及片剂的稳定性。方法 兰索拉唑原料及片剂在光照、高热条件下露置,包装条件下在湿热、室温、阴凉处、冷处贮存,定时取样,兰索拉唑的含量及降解产物,同时测定片剂的溶出度。结果 兰索拉唑光照、高热下均不稳定,在温热条件下放置3个月均产生降解产物,同时含量下降近10％;原料在室温、凉暗处贮存24个月不稳定,在冷处贮存24个月基本稳定;片剂在室温下24个月不稳定,在凉暗处稳定。结论 兰索拉唑对光、热、湿均敏感,应避光,原料最好冷处贮存,片剂应置于阴凉处,有效期约为两年。     

Helicobacter pylori eradication using one-week low-dose lansoprazole plus amoxycillin and either clarithromycin or azithromycin

Aim : To evaluate and compare two 1-week low-dose triple therapies based on lansoprazole, amoxycillin and a macrolide in eradicating Helicobacter pylori .
Methods : Seventy consecutive patients, suffering from dyspeptic symptoms with H. pylori infection, were randomly allocated to one of two treatment groups: (A) (LAC; n =35) lansoprazole 30 mg once daily, amoxycillin 1000 mg b.d., clarithromycin 250 mg b.d., all for 7 days; and (B) (LAA; n =35) lansoprazole 30 mg once daily and amoxycillin 1000 mg b.d., both for 7 days, plus azithromycin 500 mg once daily for only 3 days. The H. pylori status was evaluated by means of histology and rapid urease test at entry and 8 weeks after treatment.
Results : Three patients did not complete the treatment: one in the LAC group was withdrawn owing to severe side-effects; two patients in the LAA group stopped the treatment prematurely. H. pylori eradication was obtained in 28 of 34 (82%; 95% CI=66–93%) patients in the LAC group and in 20 of 33 (61%; 95% CI=42–77%) patients in the LAA group. The difference is significant ( P <0.029). On intention-to-treat analysis, the rates of eradication were (28 of 35 patients, 80% in the LAC group and 20 of 35 patients, 57% in the LAA group. Side-effects occurred in nine (26%) and six (18%) patients in the LAC and LAA groups, respectively.
Conclusions : Low-dose lansoprazole plus amoxycillin and clarithromycin is more effective than low-dose lansoprazole plus amoxycillin and azithromycin, but it gave a greater incidence of side-effects.     

Eradication rates of clarithromycin-resistant Helicobacter pylori using either rabeprazole or lansoprazole plus amoxicillin and clarithromycin

BACKGROUND: The resistance of Helicobacter pylori to clarithromycin has become one of the primary reasons for eradication failure. AIM: To compare the eradication rates of triple therapy using amoxicillin (A), clarithromycin (C) and rabeprazole (R) or lansoprazole (L) against clarithromycin-sensitive and clarithromycin-resistant strains. METHODS: Two hundred and ninety-five patients were randomly divided into four groups and treated for 1 week: 147 cases were treated with RAC, i.e. 49 cases with R20C400 (10 mg R + 750 mg A + 200 mg C, twice daily), 48 cases with R40C400 (20 mg R + 750 mg A + 200 mg C, twice daily) and 50 cases with R40C800 (20 mg R + 750 mg A + 400 mg C, twice daily); 148 cases with treated with LAC (30 mg L + 750 mg A + 200 mg C, twice daily). RESULTS: According to intention-to-treat and per protocol analyses, the eradication rates were 88% and 91% with RAC and 78% and 81% with LAC; the eradication rates with R20C400, R40C400 and R40C800 were 94%, 81% and 86%, respectively, in the intention-to-treat analysis. In addition, the eradication rates for clarithromycin-sensitive strains with RAC and LAC were 98% and 89%, respectively, and for clarithromycin-resistant strains with RAC and LAC were 8.1% and 0%, respectively. CONCLUSIONS: The eradication rate was significantly higher with RAC than LAC. The eradication rate for clarithromycin-resistant strains was low in both groups, and an improved eradication rate could not be achieved by changing the dose of clarithromycin or proton pump inhibitor.     

舒肝解郁胶囊联合兰索拉唑及莫沙必利治疗胃食管反流的临床疗效

目的探讨舒肝解郁胶囊联合兰索拉唑及莫沙必利治疗胃食管反流的临床疗效。方法将2013年11月—2015年10月共92例胃食管反流患者分为对照组(仅使用兰索拉唑和莫沙必利治疗)和舒肝解郁胶囊联合兰索拉唑和莫沙必利治疗组,8周后对两组患者临床疗效进行比较。结果治疗组总有效率(89.4%)明显高于对照组总有效率(64.4%)(P<0.05);治疗组症状消失率(74.5%)明显高于对照组症状消失率(46.7%)(P<0.05);而治疗组患者复发率(12.8%)明显低于对照组患者(35.6%)(P<0.05)。结论舒肝解郁胶囊联合兰索拉唑和莫沙必利临床疗效优于对照组,且复发率低、临床症状消失快,可为治疗胃食管反流的安全有效的方法。     

Delayed-release tablets using hydroxyethylcellulose as a gel-forming matrix

Delayed-release tablets containing diltiazem hydrochloride (DIL) were prepared by using CM-type hydroxyethylcellulose (HEC) of three viscosity grades. The tablets consisted of a core containing 30 mg of DIL and an outer shell formed by compressing HEC. DIL in the core was rapidly released from the tablets after a lag time of several hours in all cases. The lag time to the start of release of DIL was more prolonged with an increase in viscosity of CM-type HEC. The rate of water-uptake was greater in the CM-L4 type HEC tablet of a low viscosity grade (14 cps) than those in CM-L3 and CM-L2 type HEC (27 and 95 cps, respectively) tablets. There was little difference in lag time to the start of release of DIL from CM-type HEC tablets between JP XII 1st (pH 1.2) and 2nd (pH 6.8) fluids. A human volunteer study was performed using the delayed-release tablets prepared with CM-type HEC of two or three viscosity grades. The t_maxand MRT values of CM-type HEC tablets were significantly increased with an increase in viscosity of HEC and showed only small variations between subjects, respectively. On the other hand, although the AUC values were almost the same, the C_max values decreased with prolongation of lag time. The lag time in vivo for appearance of DIL in the blood corresponded well to the lag time in vitro for drug release, but tended to be shortened as compared with the lag time in vitro. These results indicate that the lag time can be optionally controlled by selecting HEC with a proper viscosity and/or by changing the amount of HEC forming the outer shell. This delayed-release tablet using HEC will be useful for control of time-related symptoms which need time-controlled or site-specific delivery in the gastrointestinal tract.     

Effects of lansoprazole plus amoxycillin on the cure of Helicobacter pylori infection in Japanese peptic ulcer patients

Aim : The effect of lansoprazole plus amoxycillin on curing Helicobacter pylori infection and peptic ulcer recurrence was evaluated.
Method : The study group was composed of 68 patients with gastric ulcers and 51 with duodenal ulcers, all were H. pylori -positive. The participants were assigned at random to the lansoprazole alone group (lansoprazole 30 mg o.m. for 6 or 8 weeks) or the lansoprazole plus amoxycillin group (lansoprazole alone regimen plus amoxycillin at 500 mg q.d.s. concomitantly for the first 2 weeks). Healed patients were not given maintenance treatment with acid secretion inhibitors. The cure rate for H. pylori infection and the ulcer recurrence rate after 1 year were investigated.
Result : The cure rate for H. pylori infection was 4.2% in patients receiving lansoprazole alone and 38.5% in patients receiving lansoprazole plus amoxycillin ( P < 0.01) for gastric ulcers, and 0% in patients receiving lansoprazole alone and 61.9% in patients receiving lansoprazole plus amoxycillin ( P <0.001) for duodenal ulcers. The recurrence rate was 42.3% in patients receiving lansoprazole alone and 28.6% in patients receiving lansoprazole plus amoxycillin for gastric ulcers, and 66.7% for patients receiving lansoprazole alone and 11.1% for patients receiving lansoprazole plus amoxycillin ( P <0.001) for duodenal ulcers. None of the patients with gastric or duodenal ulcers cured of H. pylori infection had a recurrence.
Conclusion : Concomitant use of lansoprazole and amoxycillin increased the curative effects on H. pylori infection. However, the cure rates with this regimen remained inadequate.     

美沙拉嗪肠溶缓释片的制备与体外释放度考察

目的 制备美沙拉嗪肠溶缓释片,考察其体外释放.方法 以体外释放相似因子(f2)为主要评价指标,通过单因素处方筛选和正交试验设计得到最优处方,重现3批,比较自制美沙拉嗪肠溶缓释片与参比制剂的体外释放行为.结果 片芯中羧甲基纤维素钠(CMC 7HXF PH)用量为45 mg,羧甲淀粉钠(CMSNa)用量为35 mg;肠溶包...     

盐酸左氧氟沙星缓释滴眼液的毒性及刺激性反应

目的:进行盐酸左氧氟沙星缓释滴眼液的安全性评价。方法:采用琼脂扩散法,以褪色指数和溶解指数为指标得到的细胞反应级数评价该滴眼液的体外细胞毒性;20只小鼠一次性静脉注射盐酸左氧氟沙星缓释滴眼液(15mg·kg-1)进行急性毒性实验,观察14d内小鼠死亡数和体质量变化;12只兔敷贴滴眼液(1.5mg·d-1,连续用药7d)进行皮肤刺激性实验,观察末次用药24h后1、24、48、72h的红斑和水肿评分。结果:盐酸左氧氟沙星缓释滴眼液体外细胞毒性反应为1级;14d内小鼠无死亡且体质量变化没有明显差异;兔皮肤红斑和水肿评分均小于0.05,评价均为无刺激性。结论:盐酸左氧氟沙星缓释滴眼液具有良好的生物安全性。     

混合水分散体肠溶迟释薄膜性能研究

目的 采用肠溶型水分散体Eudragit?L30D-55和控释型水分散体Kollicoat?SR30D混合制备一种全新的对周围环境pH值具有响应的,同时具有迟释性能的聚合物薄膜。方法 采用铸膜法制备L30D-55∶SR30D混合水分散体游离膜,采用差示扫描量热法(DSC)测定薄膜玻璃化转变温度(glass transition temperature,Tg),万能材料试验机测试薄膜拉伸性能,杯法考察薄膜透湿性能。考察聚合物比例、附加剂种类和用量对薄膜性能的影响,并以制备泮托拉唑钠(PAZ-Na)肠溶迟释微丸考察包衣膜特性。结果 随着SR30D的增加,薄膜的Tg逐渐降低,强度和刚性变弱,韧性变强,透湿性能先不变后增加。随着增塑剂增加,薄膜刚性减弱,渗透性能增强。不溶性成分的加入可不同程度降低薄膜的渗透性。制备的肠溶迟释微丸在0.1 mol·L^-1盐酸中2 h药物损失量<5%,在pH 6.8缓冲液中可延迟10~20 min开始释放,并至90 min释放完全。结论 L30D-55∶SR30D混合水分散体制备的游离膜和包衣膜具有良好的理化性能,可用于肠溶调释制剂的研究和开发。     

兰索拉唑的合成工艺改进

目的 改进兰索拉唑的合成工艺。 方法 以2,3-二甲基吡啶为起始原料,经4步反应合成目标化合物。结果与结论 目标化合物的总收率由文献的12.7% 提高到21.2%,其结构经熔点、质谱和¹H-NMR谱测试确证。改进后的合成方法较原工艺路线缩短,易于工业化生产。     

Crystal forms of naproxen

The objective of this work was to investigate the existence of polymorphs and pseudopolymorphs of naproxen and the transformation of crystal forms. Four crystal forms of naproxen have been isolated by recrystallization and characterized by differential scanning calorimetry, powder X-ray diffractometry and thermogravimetric analysis. The differential scanning calorimetry and powder X-ray diffractometry patterns of the four crystal forms were different respectively. In the dissolution studies in pH 6.8 ± 0.05 buffer equilibrated at 37 ± 0.5°C, the solubility of four crystal forms was similar (within the error range). After storage of 1 month at 0% RH (silica gel, 20°C), 52% RH (saturated solution of Na₂Cr₂O_7.2H₂O/20°C) and 95% RH (saturated solution of Na₂HPO₄/20°C), Form 2 and Form 4 were transformed to Form 1, but Form 3 and Form 1 were not transformed and they were shown to have a good physical stability at room temperature for 1 month.     

Hypoprothrombinemia in naproxen overdose

Transient prolongation of the prothrombin time was observed in the setting of a 10-g overdose of naproxen. The patient reported was previously healthy, without chronic liver disease, bleeding disorders, or malnutrition. The most likely mechanism for this effect is direct inhibition of the synthesis of vitamin-K-dependent clotting factors, possibly via production of "abnormal" prothrombin.     

Clinical trial: the incidence of NSAID‐associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric‐coated naproxen alone

Aliment Pharmacol Ther 2010; 32: 401–413

Summary

Background Gastroprotective co‐therapy may reduce the risk of nonsteroidal anti‐inflammatory drug (NSAID)‐associated gastric ulcers, but adherence is suboptimal. Aim To compare the incidence of gastric ulcers with PN 400 [enteric‐coated (EC) naproxen 500 mg and immediate‐release esomeprazole 20 mg], or EC naproxen. Methods Two randomized, double‐blind, multicentre studies (PN400‐301, PN400‐302). Patients [stratified by low‐dose aspirin (≤325 mg) use] aged ≥50 years or 18–49 years with a history of ulcer, received PN 400 BID (301, n = 218; 302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210) for 6 months. The primary endpoint was the cumulative incidence of endoscopic gastric ulcers. Results The cumulative incidence of gastric ulcers was significantly lower with PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs. 24.3%, P < 0.001). PN 400 was associated with a lower combined incidence of gastric ulcers vs. EC naproxen in low‐dose aspirin users (n = 201) (3.0% vs. 28.4%, P < 0.001) and non‐users (n = 653) (6.4% vs. 22.2%, P < 0.001). The incidence of, and discontinuations due to, upper gastrointestinal (UGI) AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01, both studies). Conclusions PN 400 significantly reduces the incidence of gastric ulcers, regardless of low‐dose aspirin use, in at‐risk patients, and is associated with improved UGI tolerability relative to EC naproxen (ClinicalTrials.gov, NCT00527782).     

Structure and hydration properties of hydroxypropyl methylcellulose matrices containing naproxen and naproxen sodium

The present study was conducted to obtain a deeper insight into the mechanism of drug release from HPMC matrices. The microstructure, mobility, internal pH and the state of water within the gel layer of hydrated HPMC matrices (having different molecular weights) containing naproxen sodium (NS) and naproxen (N) were studied using Electron Paramagnetic Resonance (EPR), Nuclear Magnetic Resonance (NMR) and Differential Scanning Calorimetry (DSC) techniques. The study show that matrices composed of various viscosity grades of HPMC are characterized by similar microviscosity values in spite of the difference in their molecular weight. The NMR and DSC results led to the conclusion that higher molecular weights of HPMC are characterized by higher water absorption capacity and higher swelling. Analysis of non-freezable water in HPMC(K4M)–NS system revealed that addition of NS to solution increased the fraction of water bound to K4M+NS compared with the equivalent solutions without NS. The results suggest that the drug is participating in the crystallization of water and leads to the formation of a three dimensional network structure that decreases the freedom of water in K4M+NS samples. Calculation of the number of hydration shells showed that up to 2.2 layers are involved in HPMC-NS hydration compared to 1.5 layers for HPMC gel without NS. This was explained based on the different water ordering in the gel induced by NS as results of its absorption to polymer surface. Microviscosity values measured by EPR for K4M/N and K4M/NS hydrated matrices were found to be higher for K4M/N matrices, especially at initial stage of hydration. Mobile compartment calculations showed lower values for K4M/N compared with K4M/NS matrices. pH measurements by EPR revealed that incorporation of N to HPMC matrix led to lower internal pH value inside the hydrated tablet compared with NS. This behavior led to lower solubility of N which dictates its surface erosion mechanism, compared with NS matrix that was characterized by higher internal pH value and higher drug solubility. These properties of HPMC/NS increased chain hydration and stability, and led to drug release by the diffusion mechanism.     

反相高效液相色谱法测定兰索拉唑及其代谢产物5''-羟基兰索拉唑和兰索拉唑砜的血药浓度

目的 :建立测定兰索拉唑及其代谢产物 5’ 羟基兰索拉唑和兰索拉唑砜的血药浓度的方法 ,用于测定其血药浓度并进行临床药代动力学研究。方法 :采用高效液相 二极管阵列色谱法测定兰索拉唑及其代谢产物 5’ 羟基兰索拉唑和兰索拉唑砜的血药浓度。结果 :兰索拉唑的校正标准曲线为Y =0 .0 135 8+0 .0 0 12 2 7X (r =0 .9994 ) ,其 2 5 ,2 0 0 ,2 0 0 0μg·L-1三浓度的血样回收率分别为 87.99% ,94 .38% ,77.2 1% ;精密度分别 7.79% ,1.2 1% ,5 .4 9% ;5’ 羟基兰索拉唑的校正标准曲线分别为Y=0 .0 0 2 5 36+0 .0 0 0 912 6X (r=0 .9990 ) ,其 2 0 ,10 0 ,5 0 0 μg·L-1三浓度的血样回收率分别为 85 .85 % ,87.64% ,10 7.70 % ;精密度分别为 10 .73% ,6.98% ,5 .62 % ;兰索拉唑砜的校正标准曲线分别为Y =0 .0 1486+0 .0 0 1462X (r =0 .9995 ) ,其 2 0 ,10 0 ,10 0 0μg·L-1三浓度的血样回收率分别为 79.84 % ,85 .18% ,10 0 .68% ;精密度分别为 9.2 2 % ,2 .36% ,4 .81%。志愿受试者禁食口服 30mg兰索拉唑胶囊后 ,兰索拉唑及其代谢产物 5’ 羟基兰索拉唑和兰索拉唑砜的Cmax 分别为 113.2 1,15 61.5 4 ,131.14μg·L-1。结论 :此方法可满足测定要求 ,可用于兰索拉唑的药代动力学研究。