泰妥拉唑合成新工艺

以2-巯基-5-甲氧基咪唑-〔4,5-b〕吡啶为原料,经缩合、氧化和酸化反应合成泰妥拉唑,总收率为70.3%,目标物结构经MS确证,目标物HPLC纯度为99.8%。改进后的方法简化了操作、降低了成本,适合于工业化生产。     

新型H+/K+-ATP酶抑制剂泰妥拉唑的NMR测定分析

目的：测定泰妥拉唑的分子结构，并对化合物的^H NMR和^13C NMR谱峰信号进行归属分析。方法：采用一维、二维等核磁共振技术研究药物的分子结构。通过一维NOESY和二维远程^1H-^13C COSY技术测定分子中结构单元的连接位置。结果：通过对泰妥拉唑的结构测定，确证了该药物的分子结构。结论：目标化合物的NMR测定分析结果与泰妥拉唑的化学结构式相一致。     

高效液相色谱法测定泰妥拉唑片剂中的有关物质

目的:建立测定泰妥拉唑片中有关物质的高效液相色谱法.方法:采用Diamonsil C18柱(250mm×4.6mm,5μm),以乙腈-磷酸盐缓冲液(30:70)为流动相,检测波长为 306nm,柱温为25℃,流速为1mL·min-1.结果:主药与有关物质达到了较好的分离.测定结果表明3批样品中有关物质含量分别为0.63%,0.71%和0.76%.结论:本方法测定泰妥拉唑片中的有关物质方法简便,结果准确,专属性强.     

测定泰妥拉唑含量的3种方法研究

目的:建立测定泰妥拉唑含量的方法。方法:采用银量法、紫外分光光度法和高效液相色谱法分别对泰妥拉唑进行含量测定。结果:银量法平均回收率为99．9％,RSD为0．13％(n=5),方法精密度为O．09％(n=5); HPLC法在泰妥拉唑浓度为5．020～50．20μg·mL-1的范围内,峰面积与浓度线性关系良好(r=0．999 7),精密度为0．20％(n=6),回收率在99．5％～100．0％;UV法在2．0～12μg·mL-1的范围内线性关系良好(r=0．999 9),精密度为0．81％(n=5),回收率在99．4％～100．3％。结论:3种方法均适用于泰妥拉唑的含量测定,且都有较高的准确度和精密度。银量法结果准确,无需对照品;UV法快速、简便;HPLC法专属性好,可测定主药含量,同时还可进行杂质限度检查。     

潘妥拉唑的临床药理和治疗应用

潘妥拉唑是一种不可逆性的质子泵抑制剂,治疗剂量能有效减少胃酸分泌. 控制性临床实验证明:在短期治疗急性消化性溃疡和反流性食管炎上,潘妥拉唑比雷尼替丁效果好,与奥美拉唑效果相同.潘妥拉唑、奥美拉唑、雷尼替丁使胃溃疡疼痛缓解的时间是相同的,而且潘妥拉唑使十二指肠溃疡疼痛缓解比雷尼替丁更迅速,在溃疡的治愈和疼痛缓解方面,潘妥拉唑比法莫替丁显示出更卓越的效果.潘妥拉唑在缓解烧心和酸反流症状上比雷尼替丁有效,和奥美拉唑效果相似.     

西沙比利、潘妥拉唑联合应用治疗胃食管反流病的临床观察

目的 观察西沙比利联用潘妥拉唑治疗胃食管反流病的临床疗效.方法 将84例胃食管反流病患者随机分为两组,治疗组给予西沙比利联用潘妥拉唑治疗43例,对照组单用潘妥拉唑治疗41例,观察临床症状和内镜下表现.结果 治疗组显效率为93.02%,总有效率为97.67%;对照组显效率为60.98%,总有效率为87.80%,溃疡愈合率分别为88.37%和65.85%.以上两组数据比较差异均有显著性,P＜0.05.结论 西沙比利联合潘妥拉唑对胃食管反流病症状改善迅速,炎症治愈率高,临床疗效优于单用潘妥拉唑,值得临床推广.     

泰妥拉唑的合成

2,3-二氨基-6-甲氧基吡啶和乙氧基荒酸钾经闭环得到5-甲氧基-1H-咪唑并[4，5-自]吡啶-2-硫醇，再与2-氯甲基-3,5-二甲基-4-甲氧基吡啶缩合后氧化得到抗溃疡药泰妥拉唑，总收率48％。     

新型质子泵抑制剂的研究进展

质子泵抑制剂是目前最有效的胃酸分泌抑制剂和抗溃疡药物,在治疗胃渍疡、十二指肠溃疡和反流性食管炎等疾病方面发挥着重要作用。新型质子泵抑制剂的不断涌现为相关疾病治疗带来了新的希望。本文综述近年来出现的几种新型质子泵抑制剂如泰妥拉唑、莱米诺拉唑和盐酸瑞伐拉赞的作用机制及其独特优点,为临床应用提供参考。     

潘妥拉唑联合克拉霉素根除幽门螺杆菌的疗效观察

目的评价潘妥拉唑联合克拉霉素根除幽门螺杆菌(Hp)的疗效。方法将2007—2009年住院治疗的160例消化性溃疡患者随机分入治疗组与对照组,每组80例。治疗组给予潘妥拉唑联合克拉霉素治疗;对照组给予奥美拉唑治疗。每组疗程均为1周。结果治疗组与对照组临床治疗总有效率分别为90.0%及87.5%,差异无统计学意义;治疗组与对照组Hp根除率分别为88.8%及28.8%,治疗组明显优于对照组,二者比较有统计学意义(P<0.01);组内比较胃溃疡及十二指肠溃疡患者Hp根除率无统计学意义。结论潘妥拉唑联合克拉霉素治疗消化性溃疡Hp根除率高,效果优于单用奥美拉唑治疗。     

潘妥拉唑钠注射液治疗消化性溃疡合并上消化道出血的疗效观察

潘妥拉唑钠属于质子泵抑制剂,其抑制作用是不可逆的,属于强效的抑制胃酸分泌药物。当前,临床上质子泵抑制剂类药物应用较多,而潘妥拉唑用于治疗消化道疾病的疗效确切,对于消化性溃疡合并上消化道出血的治疗也较为有效。本次研究探讨了潘妥拉唑钠注射液治疗消化性溃疡合并上消化道出血的治疗效果,并分析了潘妥拉唑的药理作用机制,旨在提升消化性溃疡合并上消化道出血的治疗效果。     

Characterization of the inhibitory activity of tenatoprazole on the gastric H+,K+ -ATPase in vitro and in vivo

Tenatoprazole is a prodrug of the proton pump inhibitor (PPI) class, which is converted to the active sulfenamide or sulfenic acid by acid in the secretory canaliculus of the stimulated parietal cell of the stomach. This active species binds to luminally accessible cysteines of the gastric H+,K+ -ATPase resulting in disulfide formation and acid secretion inhibition. Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg(-1) of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg(-1) of the enzyme at 2 h after IV administration. The binding sites of tenatoprazole were in the TM5/6 region at Cys813 and Cys822 as shown by tryptic and thermolysin digestion of the ATPase labeled by tenatoprazole. Decay of tenatoprazole binding on the gastric H+,K+ -ATPase consisted of two components. One was relatively fast, with a half-life 3.9 h due to reversal of binding at cysteine 813, and the other was a plateau phase corresponding to ATPase turnover reflecting binding at cysteine 822 that also results in sustained inhibition in the presence of reducing agents in vitro. The stability of inhibition and the long plasma half-life of tenatoprazole should result in prolonged inhibition of acid secretion as compared to omeprazole. Further, the bioavailability of tenatoprazole was two-fold greater in the (S)-tenatoprazole sodium salt hydrate form as compared to the free form in dogs which is due to differences in the crystal structure and hydrophobic nature of the two forms.     

The pharmacodynamics and pharmacokinetics of S‐tenatoprazole‐Na 30 mg, 60 mg and 90 mg vs. esomeprazole 40 mg in healthy male subjects

Aliment Pharmacol Ther 31 , 648–657

Summary

Background Racemic tenatoprazole 40 mg/day provides more prolonged acid suppression than esomeprazole 40 mg/day. Aim To compare pharmacodynamic and pharmacokinetic profiles of tenatoprazole and esomeprazole. Methods A single‐centre, double‐blind, double‐dummy, randomized, 4‐way, cross‐over study was conducted in 32 healthy male subjects. S‐tenatoprazole‐Na 30, 60 or 90 mg, or esomeprazole 40 mg was administered once daily for 5 days with 10‐day washout intervals. The 24‐h intragastric pH was recorded at baseline and on day 5 of each period. Results On day 5, median pH (5.34 ± 0.45 and 5.19 ± 0.52 vs. 4.76 ± 0.82, respectively, P < 0.002) and percentage time with pH > 4 (80 ± 11 and 77 ± 12, vs. 63 ± 11 respectively, P < 0.0001) for 24‐h were higher with S‐tenatoprazole‐Na 90 mg and 60 mg than esomeprazole. In nocturnal periods, S‐tenatoprazole‐Na 90 mg, 60 mg and 30 mg were superior to esomeprazole with regard to median pH (5.14 ± 0.64, 4.94 ± 0.65, 4.65 ± 0.86 and 3.69 ± 1.18 respectively, P < 0.0001) and percentage time with pH > 4 (77 ± 12, 73 ± 17, 64 ± 17 and 46 ± 17 respectively, P < 0.0001). Proportion of subjects with nocturnal acid breakthrough with S‐tenatoprazole‐Na 90 mg, 60 mg and 30 mg was significantly less than with esomeprazole (54.8, 43.3, 56.7 and 90.3 respectively, P < 0.04). The proportion of subjects with >16 hrs with pH >4 was significantly higher with S‐tenatoprazole‐Na 90 mg and 60 mg than with esomeprazole (87.1%, 83.3% and 41.9% respectively, P < 0.02). Conclusions S‐tenatoprazole‐Na produced significantly greater and more prolonged dose‐dependent 24‐h and nocturnal acid suppression than esomeprazole. S‐tenatoprazole‐Na may provide greater clinical efficacy compared with current PPIs for patients with ineffective once‐daily therapy.     

A comparative study of the early effects of tenatoprazole 40 mg and esomeprazole 40 mg on intragastric pH in healthy volunteers

BACKGROUND: Tenatoprazole is a novel proton pump inhibitor with a seven-hour plasma half-life. AIM: To compare the effects of tenatoprazole 40 mg and esomeprazole 40 mg on intragastric acidity during the first 48 h in healthy volunteers. METHODS: This randomized two-period crossover study included 24 Helicobacter Pylori-negative subjects; tenatoprazole 40 mg or esomeprazole 40 mg daily were given before breakfast for two consecutive days, with a 2-week wash-out between the administration periods. Intragastric pH was monitored for 48 h. RESULTS: Over 48 h, tenatoprazole 40 mg exerted a more potent acid inhibition than esomeprazole 40 mg (median pH: 4.3 vs. 3.9, P < 0.08; per cent of time above pH 4: 57% vs. 49%, P < 0.03; proportion of subjects with at least half of the time above pH 4: 71% vs. 46%). These differences resulted from better night-time acid control with tenatoprazole 40 mg than esomeprazole 40 mg (first night median pH: 4.2 vs. 2.9, P < 0.0001; second night: 4.5 vs. 3.2, P < 0.0001). The duration of nocturnal acid breakthroughs was significantly reduced during both nights. In contrast, no significant difference was detected during the daytime periods between both regimens. CONCLUSION: Over the first 48 h, tenatoprazole 40 mg achieves a better overall and night-time control of gastric pH than esomeprazole 40 mg. The translation of better early control of acidity into clinical benefits deserves further studies.     

Comparison of the effects of fasting morning, fasting evening and fed bedtime administration of tenatoprazole on intragastric pH in healthy volunteers: a randomized three-way crossover study

BACKGROUND: The effectiveness of proton pump inhibitors is influenced by meals and administration time. AIM: To compare the effects on intragastric acidity of times of dosing of tenatoprazole, a novel imidazopyridine-based proton pump inhibitor with a prolonged plasma half-life. METHODS: This randomized three-period crossover study included 12 Helicobacter pylori-negative healthy subjects, who received tenatoprazole 40 mg either fasting at 7.00 AM, fasting at 7.00 PM or fed at 9.30 PM for 7 days, with a 2-week washout between periods. Twenty-four hour intragastric pH was monitored on day 7 of each period. RESULTS: On day 7, median 24-h pH was 4.7, 5.1 and 4.7 after breakfast, dinner and bedtime dosing, respectively (P = 0.11), whereas night-time pH was 4.2, 5.0 and 4.4 (P = 0.13). The mean 24-h percentage of time over pH 4 was 62, 72 and 64 after breakfast, dinner and bedtime dosing, respectively (N.S.), and 54, 68 and 56 during night-time (P = 0.06). Nocturnal acid breakthrough incidence decreased from 100% at baseline to 83%, 55% and 75% after 7.00 AM, 7.00 PM and 9.30 PM dosing, respectively (P = 0.18), and its mean duration dropped from 6.2 to 2.8, 1.0 and 2.2 h, respectively (P < 0.05). CONCLUSION: Seven-day administration of tenatoprazole provides a prolonged duration of acid suppression, especially during the night-time, with little effect of food or time of dosing.     

Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in healthy volunteers

BACKGROUND: Proton pump inhibitors control gastric acidity better during the day than at night, when nocturnal acid breakthrough can occur. Tenatoprazole is a novel proton pump inhibitor with a seven-fold longer plasma half-life. Aim : To compare the effects of tenatoprazole 20 mg (T20), tenatoprazole 40 mg (T40) and esomeprazole 40 mg (E40) on intragastric acidity in healthy volunteers. METHODS: This randomized, three-period, cross-over study enrolled 18 Helicobacter pylori-negative volunteers, who received E40, T20 and T40 once daily for 7 days with a 14-day washout between periods. Twenty-four-hour gastric pH monitoring was performed on day 7. Serum gastrin was assessed on day 8. RESULTS: T40 induced a more potent acid inhibition than T20 (24-h median pH: 4.6 vs. 4.0, P < 0.01; daytime: 4.5 vs. 3.9, P < 0.01; night-time: 4.7 vs. 4.1, P < 0.05). T40 was more potent than E40 (24-h median pH: 4.6 vs. 4.2, P < 0.05; night-time: 4.7 vs. 3.6, P < 0.01); the pH > 4 holding time was higher during the night for T40 than for E40: 64.3% vs. 46.8%, P < 0.01; the nocturnal acid breakthrough duration was significantly shorter for T40 than for E40. No significant gastrin increase was observed and all drugs were well tolerated. CONCLUSION: T40 is significantly more potent than T20 and E40 during the night. The therapeutic relevance of this pharmacological advantage deserves further study.     

Pharmacokinetics of tenatoprazole, a newly synthesized proton pump inhibitor, in healthy male Caucasian volunteers

The pharmacokinetics of tenatoprazole (CAS 113712-98-4), a newly synthesized proton pump inhibitor, and its metabolites TU-501 (sulfide form) and TU-502 (sulfone form) were investigated in an ascending-dose parallel-group study at the dose levels of 10, 20, 40, 80 and 120 mg. A total of 30 healthy Caucasian male volunteers (6 in each dose group) received a single dose at Day 1 (fasted state) and repeated doses from Day 14 to Day 20. CYP2C19 genotype status was determined in all subjects. Concentrations of tenatoprazole, TU-501 and TU-502 in plasma and urine were measured by a validated HPLC/MS/MS method. The single and multiple-dose study provided reliable tolerance. After the single administrations, plasma concentrations reached a maximum between 2.5 and 4.3 h post dose, and thereafter decreased according to a terminal half live (T1/2) ranging from 4.8 to 7.7 h. Similar T1/2 were obtained on first and the last administration, and the steady state was reached after 5 days. Cmax and AUC increased linearly between 10 to 80 mg. However, with the 120 mg dose, the observed Cmax was higher than expected, especially at steady state. For TU-501 and TU-502 metabolites, Cmax and AUC increased linearly after repeated administration between 40 and 120 mg.     

Gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is increasingly common worldwide; symptoms differ between individuals and endoscopically visible injury is present in only about 50% of cases. Although GERD is a disorder of gastrointestinal motility and structure, the most effective therapy is based on the use of acid antisecretory drugs. Proton pump inhibitors (PPIs), the most effective class of acid suppression agents to date, have revolutionised the management of GERD. However, PPIs do have some shortcomings and recent developments include documentation of increased healing rates with more prolonged acid suppression, more prolonged acid suppression with a new PPI (tenatoprazole) and more rapid onset of acid suppression with a new class of drugs, the reversible, potassium-competitive acid blockers. Studies with motility agents, such as the 5-HT(4) partial agonist tegaserod and the GABA(B) agonist baclofen, indicate that motility is important in the pathogenesis of GERD but, for several reasons, it will be a challenge to develop new classes of drug that outperform current PPIs with respect to efficacy, broad applicability and safety.     

LC–UV and LC–MS evaluation of stress degradation behaviour of tenatoprazole

In the present study, comprehensive stress testing of tenatoprazole was carried out according to ICH guideline Q1A (R2). Tenatoprazole was subjected to stress conditions of hydrolysis, oxidation, photolysis and neutral decomposition. Additionally, the solid drug was subjected to 50 °C for 60 days in dry-bath, and to the combined effect of temperature and humidity at 40 °C/75% RH. Extensive degradation was found to occur in acidic, neutral and oxidative conditions. Mild degradation was observed in basic conditions. The drug is relatively stable in the solid-state. The products formed under different stress conditions were investigated by LC and LC–MS. Successful separation of drug from degradation products formed under stress conditions was achieved on a Chemito ODS-3 column [C₁₈ (5 μm, 250 mm × 4.6 mm, i.d.)] using methanol: 0.01 M acetate buffer pH 4.5 adjusted with glacial acetic acid (55:45) as the mobile phase at flow rate of 1 mL/min and the peak was detected using a UV detector set at 306 nm. The LC–MS m/z values and fragmentation patterns of degradation products formed under different stress conditions were studied and characterized through LC–MS fragmentation. Based on the results, degradation pathway for drug has been proposed.