Efficacy and safety of vonoprazan in the treatment of gastroesophageal reflux disease：a meta-analysis / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of vonoprazan in the treatment of gastroesophageal reflux disease， and to provide evidence-based reference for clinical drug use. METHODS Randomized controlled trials （RCTs） about vonoprazan （trial group） versus placebo or proton pump inhibitor （control group） were searched in PubMed， the Cochrane Library， Web of Science， CNKI， Wanfang， VIP and CBM databases from the inception to June， 2022. After literature screening and data extraction， the qualities of included literature were evaluated with bias assessment tool recommended by Cochrane system evaluator manual 5.1.0. Meta-analysis， sensitivity analysis and publication bias analysis were conducted by using RevMan 5.4 software. RESULTS A total of 9 RCTs were included， involving 1 882 patients. The results of meta-analysis showed that： total response rate [OR＝1.94，95%CI（1.45，2.58），P＜0.000 01]， cure rate [OR＝2.27，95%CI（1.33，3.86），P＝0.003] and remission rate [OR＝1.81，95%CI（1.28， 2.55）， P＝0.000 7] of trial group were significantly higher than control group； there was no significant difference in the incidence of adverse drug events， diarrhea， nasopharyngitis， upper respiratory tract infection and alkaline phosphatase elevation between two groups （P＞0.05）. The results of subgroup analysis showed that cure rate of trial group was significantly higher than control group at 2 weeks of treatment （P＜0.05）； at 4 and 8 weeks of treatment， there was no significant difference in the cure rate between two groups （P＞0.05）. There was no statistically significant difference in the cure rate between two groups at 2， 4 and 8 weeks of treatment among the patients with Los Angeles grade A/B （P＞0.05）； among the patients with Los Angeles grade C/D， the cure rate of patients in the trial group was significantly higher than control group at 2， 4 and 8 weeks of treatment （P＜0.05）. The results of sensitivity analysis and publication bias analysis showed that the results of this study were robust and the possibility of publication bias was small. CONCLUSIONS Vonoprazan has a considerable effectiveness and safety in the treatment of gastroesophageal reflux disease.

Systematic review of vonoprazan as Helicobacter pylori eradication therapy / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of vonoprazan （VPZ） for Helicobacter pylori （Hp） eradication therapy. METHODS Retrieved from The Cochrane Library， Embase， PubMed， CNKI， VIP and Wanfang database， randomized controlled trials about VPZ for Hp eradication therapy （trial group） versus proton pump inhibitor （PPI） （control group） were collected during the inception to July 2022. After data extraction and quality evaluation with bias risk assessment tool recommended by Cochrane System Evaluation Manual 5.1.0， meta-analysis was performed by using RevMan5.3 software. RESULTS Nine studies with 2 134 patients were included. Compared with control group， the overall Hp eradication rate of trial group increased significantly in either the ITT analysis or PP analysis， being 87.5% vs. 76.2% [RR＝1.14， 95%CI （1.06，1.21）， P＜0.001] and 92.4% vs. 80.5% [RR＝1.11， 95%CI （1.03，1.21）， P＜0.01]， respectively. According to ITT and PP analysis of primary treatment subgroup， compared with control group， the overall Hp eradication rate of trial group increased significantly， being 88.4% vs. 76.5% [RR＝1.15， 95%CI （1.09，1.22）， P＜0.000 01] and 92.8% vs. 80.9% [RR＝1.12， 95%CI（1.03，1.23）， P＜ 0.05]； according to ITT and PP analysis of rescue therapy subgroup， there was no significant difference in the overall Hp eradication rate between control group and trial group （P＞0.05）. According to ITT and PP analysis of triple therapy subgroup， compared with control group， overall Hp eradication rate of trial group increased significantly， being 88.3% vs. 75.6% [RR＝1.16， 95%CI （1.08， 1.25）， P＜0.000 1] and 92.6% vs. 77.6% [RR=1.15， 95%CI （1.04， 1.28）， P＜0.01]； according to ITT and PP analysis of quadruple therapy subgroup， there was no significant difference in the overall Hp eradication rate between control group and trial group （P＞0.05）. Compared with control group， the incidence of adverse events in trial group decreased significantly， being 34.2% vs. 40.9% [RR＝0.84， 95%CI（0.70，0.99）， P＜ 0.05]. There was no statistical significance in the incidence of serious adverse events between 2 groups （P＞0.05）. CONCLUSIONS Compared with PPI therapy， the efficacy of VPZ-based triple therapy is better， particularly in primary treatment patients. However， VPZ has no significant advantage in rescue treatment and bismuth-containing quadruple regimen. And the safety and tolerance of VPZ for Hp eradication therapy are well， even better than PPI.

Investigation of Factors Affecting the Success Rate of Third-Line Therapy against Helicobacter pylori Infection / 医薬品情報学

Objective: The success rate of third-line treatment for Helicobacter pylori (H. pylori) infection has been reported to depend on the use of antibacterial agents, potassium-competitive acid blockers, and proton pump inhibitors. However, there is insufficient information on the success rate of H. pylori treatment due to the differences in the clinically used drugs. Here, the factors influencing the success rate of third-line treatment for H. pylori infection was investigated.Methods: Patients aged 20 years or older, who had received third-line treatment for H. pylori infection from January 2013 to December 2021 at the Kameda Medical Center were included. The exclusion criteria were as follows: patients with unknown treatment results and discontinuation of treatment. The primary endpoint was treatment success rate, based on the differences in the treatment regimen and drug choice, which was retroactively investigated from medical records. Confounding factors were adjusted by multivariate logistic regression analysis.Results: Treatment regimens containing sitafloxacin resulted in higher treatment success rates (p<0.05). Multivariate logistic regression analysis showed that the administration of sitafloxacin was the only statistically significant factor influencing treatment success. However, vonoprazan also tended to influence treatment success.Conclusion: Treatment with sitafloxacin and vonoprazan increases the success rate of third-line treatment against H. pylori infection.

Success rate of helicobacter pylori eradication using vonoprazan-based triple therapy as first-line treatment at a tertiary hospital in Baguio City

Background@#Helicobacter pylori is acknowledged to cause chronic gastritis and peptic ulcer disease and is also implicated in gastric carcinoma and B cell mucosa-associated lymphoid tissue (MALT) lymphoma development. It has infected at least half of the world’s population. Proton Pump Inhibitors (PPIs) have been the conventional antacid of choice for H. pylori eradication triple therapy, while vonoprazan is a novel drug of its class that was recently studied but is limited to an oral form which makes it less feasible in cases of acute gastrointestinal bleeding. According to several systematic reviews and meta-analyses, the vonoprazan-based triple therapy regimen for H. pylori eradication is a non-inferior treatment to traditional PPI-based treatment when given in 1 week for patients having no active gastrointestinal bleeding. Likewise, a safety profile has been established with its use, offering an alternative treatment option.@*Objectives@#The research aims to identify the H. pylori eradication rate among H. pylori-positive patients who received a vonoprazan-based triple therapy regimen as outpatients, describe their clinicodemographic profile, and identify potential side effects associated with the treatment.@*Methods@#This study utilized a cross-sectional study design in a single tertiary institution from January 2018 to December 2020. Descriptive and inferential statistics were used in data analysis. Frequency and percentage were utilized to determine the success and failure rates of H. pylori eradication, describe the clinicodemographic profile of patients who underwent vonoprazan-based triple therapy, and the potential side effects with treatment. The chi-square test of independence was applied to assess the significant difference in the successful and failed eradication rates across the clinicodemographic profile. A P-value of <0.05 was considered statistically significant, and statistical analyses were conducted using SPSS version 20.0.@*Results@#32 (91%) had successful H. pylori eradication, with the majority of them determined by a negative 13C-UBT result (62.8%) and the rest with a negative H. pylori stool antigen test (28.6%). The majority of patients undergoing H. pylori eradication using a vonoprazan-based regimen with documented successful eradication belonged to the 19 to 39 years old group (50%), clerical support workers (40.63%), with a chief complaint of abdominal pain (46.88%), with no known co- morbid illness (75%), and with endoscopic finding limited to antral gastritis alone (46.88%). This study described only two documented side effects of treatment: diarrhea and abdominal pain (2.9%).@*Conclusion@#Vonoprazan-based triple therapy, given at 20 mg twice daily for 7 days, has shown a high H. pylori eradication rate among hemodynamically stable patients, without active bleeding, and treated on an outpatient basis. There was a significant difference in eradication success and failure across co-morbidities, with a higher success rate in those without co-morbid illness. A high success rate was also seen in patients <40 years of age, with a single chief complaint, and with antral gastritis as the sole endoscopic finding.

Real-world research of vonoprazan and amoxicillin dual therapy for Helicobacter pylori eradication / 中国药房

OBJECTIVE To explore the efficacy， safety and economics of a dual therapy consisting of conventional dose of vonoprazan combined with conventional dose of amoxicillin in patients with primary treatment of Helicobacter pylori （HP） infection. METHODS Using a prospective cohort study， the patients diagnosed with HP infection and receiving initial treatment in Chengdu Xinhua Hospital from July 2021 to July 2022 were collected according to inclusion and exclusion criteria. The patients were given vonoprazan/amoxicillin dual therapy （i.e. VA group， Vonoprazan fumarate tablets 20 mg， once a day+Amoxicillin capsules 1.0 g， twice a day， 14 days） and bismuth-containing quadruple therapy （i.e. LJAF group， Rabeprazole sodium enteric- coated tablets 20 mg， twice a day+Colloidal bismuth pectin capsules 200 mg， twice a day+Amoxicillin capsules 1.0 g， twice a day+ Furazolidone tablets 100 mg， twice a day， for 14 days） according to the patient’s medication willingness. Four weeks after the end of the treatment， HP eradication rates of the two groups were compared by using intention-to-treat （ITT）， modified intention-to- treat （MITT） and per-protocol （PP） analysis. The occurrence of adverse drug reactions （ADR） was recorded， and an economic evaluation was performed for them. RESULTS Among the 58 patients in VA group， 55 completed the trial， 2 were lost to follow- up and one withdrew due to rash； among the 62 patients in LJAF group， 57 completed the trial， 3 were lost to follow-up and 2 withdrew due to rash. Results of ITT， MITT and PP analysis showed that HP eradication rates of VA group were 86.2%， 89.3% and 90.9%， and those of LJAF group were 87.1%，91.5% and 94.7%， respectively； there was no statistical significance among different groups （P＞0.05）. The incidences of ADR in VA group and LJAF group were 6.9% and 14.5%，which were not significantly different （P＞0.05）. The result of cost minimization analysis showed that the treatment cost of VA group was 340.9 yuan， which was lower than 373.5 yuan of LJAF group. CONCLUSIONS In patients with primary treatment of HP infection， the efficacy and safety of dual therapy of conventional dose of vonoprazan combined with conventional dose of amoxicillin is equivalent to the bismuth-containing quadruplex therapy with low cost.

Clinical Effect of Shugan Hewei Prescription Combined with Vonoprazan on Refractory Gastroesophageal Reflux Disease Due to Qi Depression and Phlegm Obstruction / 中国实验方剂学杂志

ObjectiveTo evaluate the clinical efficacy and adverse effects of Shugan Hewei prescription combined with vonoprazan in the treatment of refractory gastroesophageal reflux disease （RGERD） due to qi depression and phlegm obstruction. MethodEighty RGERD patients who met the inclusion criteria underwent 24-hour pH impedance and high-resolution esophageal manometry and electronic gastroscopy. The 80 patients were randomly assigned to an observation group （Shugan Hewei prescription， one bag each time， twice a day + vonoprazan， 20 mg each time， once a day） and a control group （vonoprazan， 20 mg each time， once a day） by the random number table method. The treatment in both groups lasted for 4 weeks. The clinical efficacy was examined. The scores of TCM symptoms （pharyngeal discomforts such as phlegm obstruction， retrosternal discomfort， and belching）， somatic symptoms， quality of life， and improvement of esophageal mucosa under gastroscopy were observed in both groups before treatment and after treatment for 2 and 4 weeks. ResultSeventy-five patients completed the trial were included in this study， including 38 patients in the observation group and 37 patients in the control group. The total response rate in the observation group was 89.47%（34/38）， which was higher than that （62.16%，23/37） in the control group （χ2=13.014， P<0.01）. After treatment， the scores of esophageal mucous membrane， reflux disease symptoms， TCM symptoms， gastroesophageal reflux disease health-related quality of life scale （GERD-HRQL）， and somatic self-rating scale （SSS） decreased in both groups（P<0.05）. Moreover， the observation group outperformed the control group in alleviating heartburn， acid reflux， throat discomforts， midnight coughing， nausea and dry vomiting， mucousy mouth， and insomnia in the patients with GERD （P<0.05，P<0.01）. However， the two groups showed no statistically significant differences in the improvement of esophageal mucosa after treatment. ConclusionThe combination of Shugan Hewei prescription with vonoprazan was superior to vonoprazan alone in treating RGERD regarding clinical symptoms， physical signs， quality of life， and somatic symptoms， without causing obvious adverse effects.

Research Progress on Dual Therapy in Primary Treatment of Helicobacter pylori Infection / 胃肠病学

At present, the global prevalence of Helicobacter pylori (Hp) infection is still high. Although bismuth-containing quadruple regimens are recommended by international consensus and guidelines as a first-line treatment for Hp infection, the compliance is decreasing due to more drugs needed and higher adverse events. In recent years, many studies on eradication regimen containing high-dose proton pump inhibitor (PPI) and amoxicillin, a low-resistance and acid-labile antibiotic, demonstrated that the dual therapy could achieve high eradication rate equivalent to the mainstream fist-line therapies and had the advantages of less adverse events, simpler drug composition and higher compliance. However, there are discrepancies in dosage and frequencies of drugs in dual therapies, and cannot reach a unified regimen. This article reviewed all kinds of the dual therapy regimens, which might be helpful for determining the optimal dosage, frequencies, and treatment course, so as to standardize the dual therapy.

Urine Excretion of Vonoprazan Pyroglutamate in SD Rats / 中国药学杂志

OBJECTIVE: To develop an LC-MS/MS method for the determination of vonoprazan pyroglutamate and vonoprazan fumarate in rat urine to determince the urine excretion of the two drugs in SD rats. METHODS: The detection was performed on an API 4000 tandem mass spectrometer equipped with an electrospray ionization (ESI) source. Multiple reaction monitoring (MRM) was selected with the transitions of m/z 346.2 to 315.2 for TAK-438 P and m/z 237.2 to 194 for IS, respectively. Separation of the analytes was achieved by a Shimadzu liquid chromatography system with an Agelient C18 analytical column (4.6 mm×150 mm, 3.5 μm). Isocratic elution was adopted with mobile phase A (10 mmol•L-1 ammonium acetate and 0.1% formic acid) and mobile phase B (methanol) at the ratio of 40:60, at a flow rate of 0.6 mL•min-1. The total run time was 6 min and the injected sample volume was 5 μL. All the features of the developed method suggested it met the criteria for bioanalytical METHODS recommended by regulatory authorities. The accumulative urine excretion rates of TAK-438 F and TAK-438 P were determined after oral administration of TAK-438 P and equimolar TAK-438 F in SD rats. RESULTS: The accumulative urine excretion rates of the prototype drugs were 2.11% and 2.03%, respectively. The low excretion rates indicated that metabolism might be the major clearance mechanism of TAK-438 P and TAK-438 F. CONCLUSION: This was the first time to establish and validate a simple, rapid and sensitive LC-MS/MS method for the quantification of TAK-438 P. There is no significant difference of the accumulative urine excretion rate between TAK-438 P and TAK-438 F in SD rats, which provides the basis for the druggability of TAK-438 P.

Determination of Vonoprazan Pyroglutamate and Vonoprazan Fumarate by HPLC / 中国药师

Objective:To develop an HPLC method for the determination of vonoprazan pyroglutamate and vonoprazan fumarate. Methods:The column of Intertsil ODS-3 (150 mm×4.6 mm,5 μm) was used. The mobile phase was composed of methanol and a mixture of 0.15% phosphoric acid(ajust pH of 3 with 0.15% triethylamine solution). Gradient elution was adopted and the flow rate was set at 1.0 ml·min-1. The detection wavelength was 230 nm and the column temperature was 30℃. The sample size was 10 μl. Results: The standard curve of vonoprazan pyroglutamate showed a good linearity over the range of 2.060-131.800 μg·ml-1with a correlation coefficient of 0.999 7. The average spiked recovery of vonoprazan pyroglutamate was 99.40% (RSD=0.63%, n=9). The content of three batches of TAK-438 P was 98.7%,99.0% and 98.4%(n=3),respectively. The standard curve of vonoprazan fumarate showed a good linearity over the range of 1.844-118.000 μg·ml-1with a correlation coefficient of 0.999 9. The average spiked recovery of TAK-438 F was 100.67%(RSD =0.52%, n =9). The content of three batches of vonoprazan fumarate was 98.5%,98.2% and 98.9%(n=3),respectively. Conclusion:A reliable and sensitive HPLC method for the quantification of vono-prazan pyroglutamate is established and validated,which provides the basis for the content determination.

Comparative pharmacokinetic study of vonoprazan in acute hepatic injury rats and normal rats / 药学学报

Hepatic disease is one of the high-prevalence diseases in China, of which gastrointestinal bleeding is a common complication treated by proton pump inhibitors. Vonoprazan is a novel proton pump inhibitor which acts better than lansoprazole in pharmacokinetics and pharmacodynamics. In this study, the pharmacokinetics of vonoprazan was compared between acute hepatic injury and normal condition in rats. Results showed that the exposure (AUC) of vonoprazan was significantly higher in rats with acute hepatic injury than in normal rats, and the metabolites formation rates of vonoprazan also slowed down, which might be due to the change of activity of enzymes and transporters. This find may provide a theoretical basis for the dose regulation of vonoprazan in patients with hepatic injury.

Synthetic study of vonoprazan fumarate / 国际药学研究杂志

Objective To develop a practical synthetic process of vonoprazan fumarate with high-yield and lower impurities to meet the quality requirements. Methods By using 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde as the starting material,the qualified vonoprazan fumarate was synthesized via the following steps:①N-sulfonylation and the chloride impurity was removed by recrystalli-zation from MeOH;②the aldehyde was converted to amine by reductive amination,followed by forming the vonoprazan chloride to re-move the dimethylamino impurity;③vonoprazan free base was obtained by neutralization and then converted to fumarate at room tem-perature and finally recrystallized from MeOH/H2O(1:1). Results An impurity controllable synthetic process was developed with a 4％total yield improving. The final product was confirmed by ESI-MS and 1H NMR. Conclusion The synthetic process with single im-purity less than 0.1％and purity above 99.5％was obtained and suitable for scale production of vonoprazan fumarate.