Objectives To evaluate the efficacy and safety of Ilaprazole in preventing stress ulcer-associated upper gastrointestinal bleeding in critically ill patients. Design A Randomized, Double-Blind, non-inferiority Phase 3 Trial. Setting 70 hospitals across China from July 16, 2021, to April 28, 2022. Patients 441 Patients (mean age 59 years; 150 female) at high risk for stress ulcer bleeding requiring invasive mechanical ventilation were enrolled. Interventions Patients were randomly assigned to receive either Ilaprazole (10 mg once daily, first dose doubled; 220 patients) or esomeprazole (40 mg twice daily; 221 patients). Measurements and main results 441 patients (mean age 59 years; 150 female) were enrolled: 220 received Ilaprazole and 221 received esomeprazole. In FAS set, the primary endpoint occurred in 213 (96.80%) patients in the Ilaprazole and 215 (97.30%) in esomeprazole arms (Absolute Risk Difference: -0.47, 95% CI: -4.02, 3.03, p = 0.772). Secondary outcomes showed comparable incidences of clinically insignificant UGI bleeding, any gastrointestinal bleeding, 28-day mortality, ICU mortality, and pneumonitis. Adverse events were similar between groups, but Ilaprazole had a significantly lower incidence of hepatobiliary disorders (0.9% vs. 5%, p = 0.012). Conclusions Ilaprazole demonstrated non-inferiority to esomeprazole in preventing UGI bleeding in critically ill patients at high risk of stress ulcer.

Background: Previous studies have suggested that proton pump inhibitors could impair the antiplatelet effect of clopidogrel. It is uncertain whether ilaprazole affects the antiplatelet effect of clopidogrel. This study aimed to determine the drug-drug interaction between ilaprazole and clopidogrel. Methods: A randomized crossover trial of 40 healthy subjects was performed. Clopidogrel was administered alone or in combination with ilaprazole for 7 days. The maximal platelet aggregation (MPA) to 5 μmol/L adenosine diphosphate was measured by light transmission aggregometry and the platelet reactivity index (PRI) was determined by vasodilator-stimulated phosphoprotein P2Y 12 assay. High on-treatment platelet reactivity (HOPR) was defined as a MPA of >40%. The inhibition of platelet aggregation (IPA) and PRI in the two phases were compared between two regimens after the last dosing. Results: IPA was comparable between the two regimens at 0, 10 and 24 h ( p > 0.05), but higher at 4 h in the clopidogrel alone regimen compared with that in the combined treatment regimen (75.66 ± 18.44% vs. 70.18 ± 17.67%, p = 0.031). The inhibition of PRI was comparable between the two regimens at 0 and 24 h. There were no significant differences in the area under the time-IPA% curve (AUC) or the incidence of HOPR at all time-points between the two regimens. Conclusion: In healthy subjects, ilaprazole has limited effect on the pharmacodynamics of clopidogrel and it may not be clinically relevant. Clinical Trial Registration : [ www.chictr.org.cn ], identifier [ChiCTR2000031482].

At present, little information on the biopharmaceutical behaviour of proton pump inhibitors (PPIs) describing their absorption and biodistribution in vivo has been reported because the extreme instability of PPIs in the gastrointestinal environment makes it difficult to analyze such behaviour. In this work, a modified rat in situ intestinal perfusion model was employed to investigate absorption in the gastrointestinal tract and subsequent biodistribution of several PPIs (ilaprazole, esomeprazole and rabeprazole), which have different physicochemical properties. Our data indicated that PPIs exhibited significantly enhanced absorption rates in the whole intestine, including the duodenum, jejunum, ileum and colon, corresponding to the increase in the oil-water partition coefficient (LogP). PPIs and corresponding salt types showed no obvious differences in absorption, implying that solubility changes in the PPI have little effect on its absorption in the gastrointestinal tract. Among these PPIs, ilaprazole presented a more stable intestinal absorption behaviour, as well as more distribution and longer residence time in the stomach by HPLC-MS/MS analysis and radioactivity counts after 14C radiolabelling. These results may be useful information for PPI optimization and oral formulation design.

The major therapeutic strategy for acid-related gastrointestinal diseases in clinic is to reduce the excretion of gastric acid by oral administration of proton-pump inhibitors (PPIs). However, it is quite a challenge to study the oral absorption behaviors of PPIs considering their extreme instability under gastrointestinal environment. As a result, little information has been reported on PPI oral absorption so far, hindering the further development of PPI-contained oral preparations. Here, we first investigated the degradation rate of three representative PPIs, including ilaprazole, ilaprazole sodium and rabeprazole sodium. Then a modified in situ intestine absorption method in rat was established: through the temperature control by the heat exchangers, the perfusate was kept at physiological temperature only when passing through the intestine while it was maintained at 4 °C outside the intestine. Therefore PPIs could maintained sufficiently high stability under proper temperature control. Our data demonstrated that both ilaprazole and ilaprazole sodium exhibited significantly higher absorption efficiency than rabeprazole sodium did through the comparison of their apparent permeability coefficients and steady-state plasma concentrations after perfusion in the duodenum, jejunum, ileum and colon, mainly attributing to their more suitable oil-water partition coefficient. The duodenum could be the best site for the oral absorption of PPIs. Ilaprazole outperformed its sodium salt form with its stable absorption behavior in tested four intestinal segments. Furthermore, after intravenous or oral administration, ilaprazole exhibited a longer residence time and a higher accumulation in the stomach than in most of other tissues/organs. However, it was also found that the accumulation was heterogeneous and mainly located in mucosa cells of the stomach. Our further study indicated that there was no significant difference on the oral absorption efficiency of ilaprazole between female and male rats but ilaprazole underwent a faster metabolism in male rats after oral absorption. Our study provided a valuable guidance for the design of oral formulation and the optimization of PPI-contained formulations.

目的 评价性别对艾普拉唑的药代动力学和药效学的影响.方法 整合不同剂量注射用艾普拉唑在男性和女性受试者中的药代动力学和药效学数据,用剂量归一化、体重校正、方差分析等处理方法分析性别的潜在影响.结果 在药代动力学方面,给药不同剂量(5,10和20 mg)艾普拉唑钠男女受试者的内在清除率分别为(3627.06±986.01),(3305.23±947.62),(3532.19±840.13)mL· h-1和(2636.25±739.45),(2739.25±910.40),(2590.67±584.09)mL·h-1,差异均有统计学意义(均P＜0.05),但AUC和Cmax差异均无统计学意义(均P＞0.05).在药效学方面,5,10和20 mg剂量组女性受试者胃pH值-时间曲线下面积(AUEC0-24h)分别为(137.17±25.43),(142.74±19.11),(156.98±22.4),虽然高于男性的(102.61±37.4),(127.58±27.22),(145.32±25.51),差异均无统计学意义(均P＞0.05).结论 性别对艾普拉唑的药代动力学有一定影响,但是对药效学没有显著影响.

Aims The objectives were to investigate the pharmacokinetics, pharmacodynamics and safety of ilaprazole infusion in healthy subjects and patients with esomeprazole as positive control, and then recommend the dosage regimen for Phase 2b/3 studies. Methods Three clinical studies were performed. First, 16 healthy subjects received infusion of ilaprazole 30 mg or esomeprazole 80 mg. Second, 12 healthy subjects received ilaprazole 20 mg followed by 10 mg once daily for 2 days. Finally, 20 patients with duodenal ulcers received ilaprazole 20 mg followed by 10 mg for 2 days or esomeprazole 40 mg twice daily for 3 days. Serial blood samples were collected and intragastric pH was recorded. Results The mean percentages time of intragastric pH >6 was 63.6 and 51.7% for healthy subjects after receiving ilaprazole 30 mg and esomeprazole 80 mg. Linear pharmacokinetics was observed when the dose was increased to 30 mg but the effect was saturated. Ilaprazole 20 mg followed by 10 mg for 2 days provided higher plasma exposure in healthy subjects than patients, but the effect was comparable. After multiple administrations, ilaprazole provided similar effect to esomeprazole. Ilaprazole infusion was safe and well tolerated without serious adverse events. Conclusions Ilaprazole provided comparable effect of pH control to esomeprazole, with lower dose and fewer times of administration. There was no significant difference of ilaprazole between healthy subjects and patients regarding intragastric acid inhibition. A loading dose of ilaprazole 20 mg followed by 10 mg once daily for 2 days was recommended for Phase 2b/3 studies.

T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to ilaprazole. Results of an in vivo study demonstrated that gavage of ilaprazole in HCT116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after ilaprazole treatment. Our results suggested that ilaprazole inhibited the cancer growth by targeting TOPK both in vitro and in vivo.

消化性溃疡是一种常见的多发性疾病，病程长、易反复，是消化道肿瘤发病的重要诱因。临床治疗药物以抑制胃酸分泌的质子泵抑制剂（PPIs）为主，市场占有率94%。全球仅有5个同类药物上市，均由国际制药巨头研发并垄断，且临床上存在抑酸时间短、个体差异大、药物相互作用多等缺陷。丽珠集团在11个项目支持下，历时14年研发出中国消化领域1.1类新药艾普拉唑。它具有抑酸活性强、起效快；作用时间长，半衰期3.5小时，比其它平均1.5小时都长。通过体内、体外试验证明，艾普拉唑用药剂量小，5毫克艾普拉唑的效果等同于20毫克的奥美拉唑，不良反应少；艾普拉唑是目前不经CYP2C19酶代谢的PPI，药物相互作用小，联合用药更安全。

Ilaprazole is a novel proton pump inhibitor that has been marketed as an oral therapy for acid-related diseases in China and Korea. This study aimed to compare the gastroprotective effects of intravenous and enteral ilaprazole in rat models.

目的建立了人血浆中丁咯地尔含量的高效液相色谱法,考察了国产与进口盐酸丁咯地尔片的人体药动学,并进行了生物等效性评价。方法 20名健康志愿者随机交叉单剂量口服两种片剂各300mg,采用反相HPLC测定血药浓度。结果国产和进口盐酸丁咯地尔片的体内药动学过程均符合线性二房室模型,Tmax分别为(1.55±0.67)h、(1.83±0.82)h,Cmax分别为(2.84±0.58)g/mL、(2.65±0.70)g/mL,t1/2λz分别为(4.60±0.73)h、(5.52±1.94)h,AUC0-24分别为(16.65±4.98)g h/mL、(17.49±7.28)g h/mL,国产盐酸丁咯地尔片的相对生物利用度为(102.10±25.60)%。结论两种制剂具有生物等效性。

Objective To investigate the efficacy and safety of weitong granules in treatment of functional dyspepsia. Methods The randomized controlled-multicenter and open clinical trails was conducted in 448 patients with functional dyspepsia. Group weitong granules and muxin shunqi Pills,group weitong granules and domperidone were using completely randomized, double-blind double-dummy controlled method (293 patients),open control group was using before and after of their own control method (155 patients).The treatment groups were administrated by double-blind double-dummy controlled numbers,and open group was administrated the on marked number of granules. The above groups were administrated one package one time with warm water,three times a day.Duration of treatment was seven days. Results The treatment group,control group and open group were similar of main symptoms of total effective rate.Markedly effective rate of treatment group,open group were better than control group(P<0.01).The functional gastric emptying of total effective rate and markedly effective rate were no significant difference(P>0.05). The traditional chinese medicine (TCM) syndrome of total effective rate and markedly effective rate, the treatment group and open group were better than control group(P<0.05,P<0.01). Conclusion The weitong granules for functional dyspepsia treatment is safe and good clinical efficacy.

Objective To evaluate four new drugs-buflonedil hydrochlorede injection developed by Livzon on chronic lower limb arterial occlusion disease clinical curative effect and safety.Methods Using a multicenter, randomized, single blind parallel controlled study, appli- cation of buflomedil hydrochloride injection and control drug fonzylane injection was performed in 121 cases of bioequivalence test.Results Buflomedil hydrochloride injection in treatment of chronic arterial occlusive disease of lower extremity, the intermittent claudication, pain, cold, numb and ulcer-like symptoms were significantly improved, laboratory index showed no peripheral blood platelet count, prothrombin time changed.Conclusion Buflomedil hydrochloride injection in treatment of chronic ischemia of lower extremity is a safe and effective drug.

胃通颗粒由乌药、槟榔等药组成,具理气消胀、和胃清热的功效,主治功能性消化不良,是即将批准的三类中药新药.其中,槟榔中所合成分槟榔碱,具有兴奋胆碱受体的作用,使消化液分泌旺盛,增加食欲,是槟榔中的特征性及主要活性成分.文献报道槟榔药材中槟榔碱的含量测定,方法主要有水蒸气蒸馏后酸碱滴定法、非水滴定法、电位滴定法、极谱法、酸性离子比色法、薄层扫描法,液相色谱法主要为离子交换色谱法[1].