Vonoprazan vs proton pump inhibitors in treating post-endoscopic submucosal dissection ulcers and preventing bleeding: A meta-analysis of randomized controlled trials and observational studies.

BACKGROUND: Vonoprazan is a potassium-competitive acid blocker (P-CAB) that is frequently used in Japan for Helicobacter pylori (H. pylori) eradication, treatment of gastroesophageal reflux disease, and treatment of post endoscopic submucosal dissection (ESD) complications. We sought to determine if vonoprazan was superior to proton pump inhibitors (PPIs) for treating ESD-induced ulcers (as assessed by ulcer healing and shrinkage ratios) and preventing delayed bleeding over various treatment durations (2, 4, and 8 weeks). METHODS: We collected randomized controlled trials (RCTs) and observational studies that discussed the effectiveness of vonoprazan and PPIs on ESD-induced ulcers and bleeding from PubMed, Cochrane Library, ClinicalTrials.gov, and Google Scholar. Studies were selected according to pre-established eligibility criteria and data were extracted separately by 2 researchers with double-check. We used the Cochrane risk of bias tool to assess RCTs and the Newcastle-Ottawa Quality Assessment Scale to assess observational studies. Meta-analyses, based on the random-effects model, were conducted to compare differences in ulcer shrinkage ratios (%) and odds ratios (ORs) for ulcer healing and delayed bleeding. Publication bias was evaluated using funnel plots and Egger regression test. Heterogeneity was assessed using I statistics. A sensitivity analysis was conducted to check the robustness of results. The evidential quality of the findings was assessed using the GRADE profiler. RESULTS: Thirteen studies were included in this meta-analysis. The OR effect sizes of vonoprazan relative to PPIs for ulcer healing were 1.33 (P = .13) with a 95% CI (0.33-3.21) at 4 weeks and 1.48 (P = .09) with a 95% CI (0.81-5.20) at 8 weeks. The overall effect size for the shrinkage ratio was 12.24% (P = .16) with a 95% CI (-4.96-29.44) at 2 weeks. The effect size of its subgroup of H. pylori-positive patients was 19.51% (P < .001) with a 95% CI (11.91-27.12). The overall OR for the occurrence of delayed bleeding was 0.66 (P = .26) with a 95% CI (0.32-1.35). After excluding combination drug studies, the overall ORs between vonoprazan and PPIs on ulcer healing and delayed bleeding were 1.44 and 0.76, respectively. CONCLUSION: During the first 2 weeks of treatment, vonoprazan was more effective than PPIs for treating H. pylori-positive patients with ESD-induced gastric ulcers.

Development of a stability- indicating HPLC method for simultaneous determination of ten related substances in vonoprazan fumarate drug substance.

Vonoprazan fumarate is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. In the present study, a simple, fast, and economic reversed-phase liquid chromatography (LC) method was developed for the analysis of ten related substances (raw materials, by-products and degradants) in vonoprazan fumarate. The optimized separation was performed on a Phenomenex Kinetex EVO C18 (250mm×4.6mm, 5.0µm) column. The mobile phase consisted of (A) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - methanol - acetonitrile (72:25:3, v/v/v) and (B) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - acetonitrile (30:70, v/v). Detection of the analytes was conducted at 230nm using a UV detector. The stability-indicating ability of this method was demonstrated by carrying out forced degradation studies. Vonoprazan underwent significant degradation when subjected to alkaline and oxidative stress conditions, while the drug proved to be stable to acidic, thermal and photolytic degradation. The degradants did not interfere with the detection of vonoprazan fumarate and its impurities. The performance of this method was validated in accordance to the regulatory guidelines recommended by the International Conference on Harmonisation (ICH) and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The method proposed in this paper could be applied for process development as well as quality assurance of vonoprazan in bulk drug, since no monograph is available in official compendia.

Combination of niacin extended-release and simvastatin results in a less atherogenic lipid profile than atorvastatin monotherapy.

OBJECTIVE: To compare the effects of combination niacin extended-release + simvastatin (NER/S) versus atorvastatin alone on apolipoproteins and lipid fractions in a post hoc analysis from SUPREME, a study which compared the lipid effects of niacin extended-release + simvastatin and atorvastatin in patients with hyperlipidemia or mixed dyslipidemia. PATIENTS AND METHODS: Patients (n = 137) with dyslipidemia (not previously receiving statin therapy or having discontinued any lipid-altering treatment 4-5 weeks prior to the study) received NER/S (1000/40 mg/day for four weeks, then 2000/40 mg/day for eight weeks) or atorvastatin 40 mg/day for 12 weeks. Median percent changes in apolipoprotein (apo) A-1, apo B, and the apo B:A-I ratio, and nuclear magnetic resonance lipoprotein subclasses from baseline to week 12 were compared using the Wilcoxon rank-sum test and Fisher's exact test. RESULTS: NER/S treatment produced significantly greater percent changes in apo A-I and apo B:A-I, and, at the final visit, apo B < 80 mg/dL was attained by 59% versus 33% of patients, compared with atorvastatin treatment (P = 0.003). NER/S treatment resulted in greater percent reductions in calculated particle numbers for low-density lipoprotein (LDL, 52% versus 43%; P = 0.022), small LDL (55% versus 45%; P = 0.011), very low-density lipoprotein (VLDL) and total chylomicrons (63% versus 39%; P < 0.001), and greater increases in particle size for LDL (2.7% versus 1.0%; P = 0.007) and VLDL (9.3% versus 0.1%; P < 0.001), compared with atorvastatin. CONCLUSION: NER/S treatment significantly improved apo A-I levels and the apo B:A-I ratio, significantly lowered the number of atherogenic LDL particles and VLDL and chylomicron particles, and increased the mean size of LDL and VLDL particles, compared with atorvastatin.

Rosuvastatin is cost-effective compared with atorvastatin in reaching cholesterol goals.

BACKGROUND: Lowering low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of coronary heart disease. The introduction of a highly efficacious new statin, rosuvastatin, may enable more patients to be treated to LDL-C goal within a fixed budget. OBJECTIVES: To compare the cost-effectiveness of rosuvastatin 10 mg and atorvastatin 10 mg in lowering LDL-C and achieving guideline goals after 12 weeks of treatment. The LDL-C goals were those recommended by the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III and the Third Joint European Task Force. METHODS: The analysis was performed on pooled data from three clinical trials. Efficacy was measured as the percent reduction in LDL-C and the proportion of patients who reached guideline LDL-C goals following the first 12 weeks of treatment, prior to dose titration. Costs comprised drug acquisition costs only. The cost-effectiveness measures were cost per 1% reduction in LDL-C and cost per patient treated to their LDL-C goal. RESULTS: Treatment with rosuvastatin 10 mg costs 1.85 per 1% reduction in LDL-C, compared with 2.37 per 1% reduction with atorvastatin 10 mg. The average costs per patient treated to the European LDL-C goals were 130.18 for rosuvastatin 10 mg and 242.44 for atorvastatin 10 mg. Treating to NCEP ATP III goals costs 115 per patient treated with rosuvastatin 10 mg vs. 163 per patient treated with atorvastatin 10 mg. CONCLUSIONS: Rosuvastatin has the same acquisition costs as and is more efficacious than atorvastatin in lowering LDL-C and treating patients to target LDL-C levels.

Simultaneous determination of Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone (SU5416) and its interconvertible geometric isomer (SU5886) in rat plasma by LC/MS/MS.

Z-3-[(2,4-Dimethylpyrrol-5-yl)methylidenyl]-2-indolinone (SU5416) is a cytostatic substance in development as an anti-angiogenic agent. SU5416 exists as the thermodynamically stable cis or Z-isomer as a solid. Studies have shown that in light exposed solutions of SU5416, the unstable trans or E-isomer, namely SU5886, is formed. The E-isomer converts back to the Z-isomer when protected from light. The E-isomer is unstable for synthesis and isolation; therefore, the analytical standard of the E-isomer is not available. In this study, a simple, fast and reliable LC/MS/MS method has been developed to determinate both isomers simultaneously in rat plasma samples to support the study of disposition kinetics of SU5416. This method is sensitive (limit of quantitation (LOQ=0.5 ng/mL)), reproducible and has a wide linear range (0.5-2500 ng/mL). There was no conversion between E- and Z-isomer during sample preparation procedure and sample determination with LC/MS/MS. Experimental results proved that SU5416 and SU5886 have identical detection response. Therefore, SU5416 (Z-isomer) was used successfully as analytical standard for SU5886 (E-isomer). This method has been applied to rat plasma samples obtained from a pharmacokinetic study. This study underscores the use of LC/MS/MS technique for bioanalytical methods where analytical standards are not available and analytes are interconvertible.

Evaluation of biocompatibility of polypyrrole in vitro and in vivo.

In this study, the biocompatibility of the electrically conductive polymer polypyrrole (PPy) with nerve tissue was evaluated in vitro and in vivo. The extraction solution of PPy powder, which was synthesized chemically, was tested for acute toxicity, subacute toxicity, pyretogen, quantitative measure of cell viability, hemolysis, allergen, and micronuclei. The PPy membrane was synthesized electrochemically on the indium tin oxide conductive borosilicate glass. The dorsal root ganglia from 1-3-day-old Sprague-Dawley rats were cultured above PPy membrane and observed by light or scanning electron microscopy. The PPy-silicone tube (PPy membrane on the inner surface of the silicone tube) also synthesized electrochemically was used to bridge across 10-mm sciatic nerve gap in rats. Twenty-four weeks after the operation to rats, the regenerated tissues were observed by electrophysiological and histological techniques. PPy extraction solution showed no evidence of acute and subacute toxicity, pyretogen, hemolysis, allergen, and mutagenesis, and the Schwann cells from the PPy extraction solution group showed better survival rate and proliferation rate as compared with the saline solution control group. The migration of the Schwann cells and the neurite extension from dorsal root ganglia on the surface of PPy membrane-coated glass was better than those of bare glass. There was only lightly inflammation during 6 months of the postoperation, when the PPy-silicone tube bridged across the gap of the transected sciatic nerve. The regeneration of nerve tissue in the PPy-silicone tube was slightly better than that in the plain silicone tube by means of electrophysiological and histological examination. The results of this study indicate that PPy has a good biocompatibility with rat peripheral nerve tissue and that PPy might be a candidate material for bridging the peripheral nerve gap.

More Western hypercholesterolemic patients achieve Japan Atherosclerosis Society LDL-C goals with rosuvastatin therapy than with atorvastatin, pravastatin, or simvastatin therapy.

BACKGROUND: Data from Western comparative trials suggest that rosuvastatin is more effective than atorvastatin, simvastatin, and pravastatin in helping hypercholesterolemic patients achieve US and European lipid-lowering guidelines. The purpose of this analysis was to assess the comparative efficacy of rosuvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to levels recommended by the Japan Atherosclerosis Society (JAS). METHODS AND RESULTS: A post hoc analysis of data from 6 randomized, double-blind, active-controlled trials was conducted to evaluate the relative efficacy of rosuvastatin and comparator statins in helping patients achieve the LDL-C goals established by the JAS. The first 5 trials, prospectively designed for pooling, were originally conducted to compare the effects of rosuvastatin with either atorvastatin, simvastatin, or pravastatin in reducing lipid levels and helping patients achieve the LDL-C goals established by the National Cholesterol Education Program. The 6th trial was conducted with similar objectives, but in patients with heterozygous familial hypercholesterolemia (HeFH). Data from 2,139 hypercholesterolemic patients in the first 5 trials were pooled for analysis: rosuvastatin 5 mg (n=390) or 10 mg (n=389) vs atorvastatin 10 mg (n=393); rosuvastatin 5 mg (n=240) or 10 mg (n=226) vs simvastatin 20 mg (n=249) or pravastatin 20 mg (n=252). In the studies with atorvastatin as the comparator, JAS-defined LDL-C goals were reached by 67.2% of the rosuvastatin 5-mg group, 82.3% of the rosuvastatin 10-mg group, and 58.0% of the atorvastatin 10-mg group (p<0.001 for both rosuvastatin groups vs atorvastatin) at 12 weeks. Similarly, in the trials with pravastatin and simvastatin as comparators, the JAS LDL-C goals were reached by 77.5% of the rosuvastatin 5-mg group, 86.7% of the rosuvastatin 10-mg group, 45.2% of the pravastatin 20-mg group and 65.5% of the simvastatin 20-mg group (p<0.001 for both rosuvastatin groups vs pravastatin and simvastatin). In the trial of HeFH patients (n=433 for rosuvastatin, n=187 for atorvastatin), 31.9% of patients treated with rosuvastatin 20 mg achieved JAS LDL-C goals, compared with 17.6% of patients treated with atorvastatin 20 mg (p<0.001). CONCLUSIONS: Rosuvastatin has demonstrated clinical superiority over atorvastatin, pravastatin, and simvastatin in reducing LDL-C levels and in enabling patients to reach goals established by the JAS.

An HPLC method for the determination of atorvastatin and its impurities in bulk drug and tablets.

A simple high-performance liquid chromatographic (HPLC) method was developed for the analysis of atorvastatin (AT) and its impurities in bulk drug and tablets. This method has shown good resolution for AT, desfluoro-atorvastatin (DFAT), diastereomer-atorvastatin (DSAT), unknown impurities and formulation excipients of tablets. A gradient reverse-phase HPLC assay was used with UV detection. Some solvent systems prepared using methanol or acetonitrile and water or buffer systems with different pH values were tested. Capacity factors of related substances were calculated at all tested systems. Best resolution has been determined using a Luna C18 column with acetonitrile-ammonium acetate buffer pH 4-tetrahydrofuran (THF) as mobile phase. Samples were eluted gradiently with the mobile phase at flowrate 1.0 ml min(-1) and detected at 248 nm. The proposed method was applied to the determination of impurities and were found to contain 0.057-0.081, 0.072-0.097, 0.608-0.664% of the DFAT, DSAT and total impurity, respectively.