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1.
(Z)-2-(3,4-Dichlorophenyl)-3-(1H-Pyrrol-2-yl)Acrylonitrile Exhibits Selective Antitumor Activity in Breast Cancer Cell Lines via the Aryl Hydrocarbon Receptor Pathway.
Gilbert, J, De Iuliis, GN, Tarleton, M, McCluskey, A, Sakoff, JA
Molecular pharmacology. 2018;(2):168-177
Abstract
We have previously reported the synthesis and breast cancer selectivity of (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (ANI-7) in cancer cell lines. To further evaluate the selectivity of ANI-7, we have expanded upon the initial cell line panel to now include the breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, MDA-MB-231); normal breast cells (MCF-10A); and cell lines derived from colon (HT29), ovarian (A2780), lung (H460), skin (A431), neuronal (BE2C), glial (U87, SJG2), and pancreatic (MIA) cancers. We now show that ANI-7 is up to 263-fold more potent at inhibiting the growth of breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468) than normal breast cells (MCF-10A) or cell lines derived from other tumor types. Measures of growth inhibition, cell cycle analysis, morphologic assessment, Western blotting, receptor binding, gene expression, small interfering RNA technology, reporter activity, and enzyme inhibition assays were exploited to define the mechanism of action of ANI-7. In this work, we report that ANI-7 mediates its effects via the activation of the aryl hydrocarbon receptor (AhR) pathway and the subsequent induction of CYP1-metabolizing mono-oxygenases. The metabolic conversion of ANI-7 induces DNA damage, checkpoint activation, S-phase cell cycle arrest, and cell death in sensitive breast cancer cell lines. Basal expression of AhR, the AhR nuclear translocator, and the CYP1 family members do not predict for sensitivity; however, inherent expression of the phase II-metabolizing enzyme sulfur transferase 1A1 does. For the first time, we identify (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile as a new AhR ligand.
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2.
Vonoprazan, a Novel Potassium-Competitive Acid Blocker, Should Be Used for the Helicobacter pylori Eradication Therapy as First Choice: A Large Sample Study of Vonoprazan in Real World Compared with Our Randomized Control Trial Using Second-Generation Proton Pump Inhibitors for Helicobacter pylori Eradication Therapy.
Ozaki, H, Harada, S, Takeuchi, T, Kawaguchi, S, Takahashi, Y, Kojima, Y, Ota, K, Hongo, Y, Ashida, K, Sakaguchi, M, et al
Digestion. 2018;(3):212-218
Abstract
BACKGROUND/AIMS: Phase III study demonstrated that vonoprazan-based Helicobacter pylori eradication therapy achieved higher eradication rate compared with lansoprazole. However, there is no study that evaluated the efficacy of vonoprazan in a large sample in real world. We investigated the eradication rate and safety of vonoprazan-based eradication therapy compared with our randomized control trial using second-generation proton pump inhibitor (PPIs). METHODS (First study) A total of 147 patients who have H. pylori infection were randomly assigned to receive either, esomeprazole (EPZ) group and rabeprazole (RPZ) group. (Second study) 1,688 patients who have H. pylori infection underwent primary eradication with triple therapy involving vonoprazan. In both studies, triple therapy with amoxicillin, clarithromycin, and PPI or vonoprazan was performed, and eradication effect was assessed by an urea breath test. RESULTS (First study) Eradication rate was 77.5% in the EPZ group and 68.4% in the RPZ group; no significant difference was observed between the 2 groups. (Second study) The successful primary eradication rate was 90.8%. There was no severe adverse effect. CONCLUSIONS The eradication rate of vonoprazan-based triple therapy was remarkably higher compared with second-generation PPIs-based triple therapy in real world. Vonoprazan is very likely to become the first option for future eradication therapy.
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3.
Study of Saroglitazar in Treatment Of Pre-diabetes with Dyslipidemia: STOP-D.
Bhosle, D, Bhosle, V, Bobde, J, Bhagat, A, Shaikh, H, Kadam, R
The Journal of the Association of Physicians of India. 2018;(3):14-7
Abstract
OBJECTIVES Patients with prediabetes are not only at increased risk of progression to type 2 diabetes, but they are also at high risk of developing cardiovascular risk compared to normoglycemic people. Further, prediabetes is also often associated with abnormal lipid levels (dyslipidemia). We therefore aimed to evaluate the effect of Saroglitazar in patients with prediabetes and dyslipidemia. METHODS This was a prospective, single centre, single arm study involving patients with pre-diabetes and dyslipidemia. Subjects with baseline HbA1c 5.7-6.4% and dyslipidemia (Total cholesterol > 200mg/dl, LDL-C > 130 mg/dl, triglycerides > 150 mg/dl and HDL< 40 mg/dl) were enrolled in this study. Subjects with on-going medications affecting blood glucose or lipids were excluded from the study. Saroglitazar 4mg once daily was administered for a period of 24 weeks. The primary outcome was change in serum triglycerides and secondary outcome parameters included changes in other lipid parameters and HbA1c levels at 24 weeks follow-up. RESULTS Forty patients with prediabetes and dyslipidemia were enrolled in the study. At 24 weeks follow-up, serum triglycerides was significantly reduced from 348 ± 86.98 mg/dl to 216.4 ± 72.34 mg/dl (P <0.0001). HbA1c was significantly reduced from 6.3 ± 0.16 % to 5.5 ± 0.30 % after 24 weeks of Saroglitazar therapy (P<0.0001). There were significant improvements observed in other lipid parameters at 24 weeks follow-up period. Saroglitazar was found to be safe and well tolerated, no serious adverse event reported during entire study period. CONCLUSION Saroglitazar is safe and effective in prediabetes with dyslipidemia by exerting its dual lipid lowering and glycemic actions.
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4.
Comparison of the Effects of Vonoprazan and Lansoprazole for Treating Endoscopic Submucosal Dissection-Induced Artificial Ulcers.
Hirai, A, Takeuchi, T, Takahashi, Y, Kawaguchi, S, Ota, K, Harada, S, Kojima, Y, Tominaga, K, Tokioka, S, Higuchi, K
Digestive diseases and sciences. 2018;(4):974-981
Abstract
BACKGROUND Vonoprazan exhibits a more potent, rapid, and longer-lasting inhibitory effect on gastric acid secretion than proton pump inhibitors; however, whether it is more effective than PPI for treating endoscopic submucosal dissection (ESD)-induced artificial ulcers remains controversial. AIM: This study aimed to assess and compare the effects of vonoprazan and lansoprazole for treating ESD-induced artificial ulcers. METHODS This prospective, randomized controlled trial enrolled 149 patients who underwent ESD for the treatment of early gastric neoplasms from April 2015 to May 2017. They were randomly treated with either 20 mg/day vonoprazan (V group) or 30 mg/day lansoprazole (L group) orally. The primary end points were the area and shrinkage ratio of the ulcers at 4 and 8 weeks post-ESD. RESULTS Data from 127 patients were analyzed, which showed that the 4- and 8-week healing ratios were not significantly different between the V and L groups (4 weeks, 16.3 vs. 25.8%; 8 weeks, 86.9 vs. 90.9%, respectively). Similarly, the shrinkage ratio, categorized as less than 90%, 90% or more but less than 100%, or 100% at 4 weeks and as less than 100% or 100% at 8 weeks were not statistically different between the V and L groups (4 weeks: 12, 41, 8 vs. 13, 41, 12, p = 0.7246; 8 weeks: 9, 52 vs. 9, 57, p = 0.8568). Delayed bleeding was also not significantly different between both the groups (5.4 vs. 5.3%; p = 0.9844). CONCLUSIONS Vonoprazan is as effective as lansoprazole in treating ESD-induced ulcers.
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5.
Maintenance for healed erosive esophagitis: Phase III comparison of vonoprazan with lansoprazole.
Ashida, K, Iwakiri, K, Hiramatsu, N, Sakurai, Y, Hori, T, Kudou, K, Nishimura, A, Umegaki, E
World journal of gastroenterology. 2018;(14):1550-1561
Abstract
AIM: To compare vonoprazan 10 and 20 mg vs lansoprazole 15 mg as maintenance therapy in healed erosive esophagitis (EE). METHODS A total of 607 patients aged ≥ 20 years, with endoscopically-confirmed healed EE following 8 wk of treatment with vonoprazan 20 mg once daily, were randomized 1:1:1 to receive lansoprazole 15 mg (n = 201), vonoprazan 10 mg (n = 202), or vonoprazan 20 mg (n = 204), once daily. The primary endpoint of the study was the rate of endoscopically-confirmed EE recurrence during a 24-wk maintenance period. The secondary endpoint was the EE recurrence rate at Week 12 during maintenance treatment. Additional efficacy endpoints included the incidence of heartburn and acid reflux, and the EE healing rate 4 wk after the initiation of maintenance treatment. Safety endpoints comprised adverse events (AEs), vital signs, electrocardiogram findings, clinical laboratory results, serum gastrin and pepsinogen I/II levels, and gastric mucosa histopathology results. RESULTS Rates of EE recurrence during the 24-wk maintenance period were 16.8%, 5.1%, and 2.0% with lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg, respectively. Vonoprazan was shown to be non-inferior to lansoprazole 15 mg (P < 0.0001 for both doses). In a post-hoc analysis, EE recurrence at Week 24 was significantly reduced with vonoprazan at both the 10 mg and the 20 mg dose vs lansoprazole 15 mg (5.1% vs 16.8%, P = 0.0002, and 2.0% vs 16.8%, P < 0.0001, respectively); by contrast, the EE recurrence rate did not differ significantly between the two doses of vonoprazan (P = 0.1090). The safety profiles of vonoprazan 10 and 20 mg were similar to that of lansoprazole 15 mg in patients with healed EE. Treatment-related AEs were reported in 11.4%, 10.4%, and 10.3% of patients in the lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg arms, respectively. CONCLUSION Our findings confirm the non-inferiority of vonoprazan 10 and 20 mg to lansoprazole 15 mg as maintenance therapy for patients with healed EE.
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6.
Vonoprazan: A Novel and Potent Alternative in the Treatment of Acid-Related Diseases.
Yang, X, Li, Y, Sun, Y, Zhang, M, Guo, C, Mirza, IA, Li, YQ
Digestive diseases and sciences. 2018;(2):302-311
Abstract
Although proton pump inhibitors (PPIs) have been used widely, acid-related diseases are still associated with a huge burden on the health care system. Recently, the efficacy and safety of a new acid suppressant named vonoprazan in the treatment of acid-related diseases have been evaluated by a series of studies. As a novel potassium-competitive acid blocker, vonoprazan may provide reversible acid suppression by preventing K+ from binding to gastric H+/K+-ATPase. It has been clinically used for the short-term treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease and Helicobacter pylori (H. pylori) infection in Japan. The healing rate of GERD and gastric ulcers by vonoprazan is more than 95 and 90%, respectively; also, it is effective in curing PPI-resistant GERD. It increases H. pylori eradication rate to more than 88% as part of both first-line and second-line therapy. It is also effective in the eradication of clarithromycin-resistant H. pylori strains. All of these short-term studies show vonoprazan is safe and well-tolerated. As a safe and effective acid inhibitor, vonoprazan might be a novel alternative in the treatment of acid-related diseases.
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7.
Efficacy of On-Demand Therapy Using 20-mg Vonoprazan for Mild Reflux Esophagitis.
Umezawa, M, Kawami, N, Hoshino, S, Hoshikawa, Y, Koizumi, E, Takenouchi, N, Hanada, Y, Kaise, M, Iwakiri, K
Digestion. 2018;(4):309-315
Abstract
BACKGROUND The study aimed to evaluate the efficacy of on-demand therapy using 20-mg vonoprazan for mild reflux esophagitis (RE). METHODS On-demand therapy by taking one 20-mg tablet of vonoprazan only when reflux symptoms occurred was performed for 24 weeks using 30 patients with mild RE who were receiving maintenance therapy with proton pomp inhibitors (PPIs). The presence or absence of RE, degree of overall satisfaction with the treatment, score of symptoms, and fasting gastrin level before breakfast were examined before and after on-demand therapy. The number of tablets taken during the 24-week period was also noted. RESULTS One of the 30 patients dropped out of on-demand therapy 1 week after its initiation. Remission was maintained in 25 (86.2%) of the 29 patients (all 10 [100%] Los Angeles classification grade A patients and 15 (78.9%) of the 19 grade B patients). However, 4 grade B patients exhibited grade B relapse. There were no differences in the degree of overall satisfaction, score of symptoms or the gastrin level between PPI and on-demand therapies. The number of vonoprazan tablets taken during the observation period was 33 tablets (median)/24 weeks. CONCLUSION On-demand therapy using 20-mg vonoprazan tablets is an effective alternative maintenance therapy for mild RE.
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8.
Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial.
Nagel, M, Schulz, J, Maderer, A, Goepfert, K, Gehrke, N, Thomaidis, T, Thuss-Patience, PC, Al-Batran, SE, Hegewisch-Becker, S, Grimminger, P, et al
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2018;(3):1010428318764007
Abstract
BACKGROUND Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required. This study explored the cytokeratin-18 fragment M30 and full-length cytokeratin-18 M65 in predicting treatment response and survival in a randomized, placebo-controlled trial of advanced gastric cancer. METHODS Patients enrolled in the SUN-CASE study received sunitinib or placebo as an adjunct to standard therapy with leucovorin (Ca-folinate), 5-fluorouracil, and irinotecan in second or third line. Treatment response rates, progression-free survival and overall survival were assessed during a follow-up period of 12 months. Cytokeratin-18 fragments were analyzed in 52 patients at baseline and day 14 of therapy. RESULTS Levels of M30 correlated with the presence of metastasis and lymph node involvement and decreased significantly during chemotherapy. Importantly, baseline levels of M30 were significantly higher in patients who failed therapy. In addition, patients who did not respond to treatment were also identifiable at day 14 based on elevated M30 levels. By stepwise regression analysis, M30 at day 14 was identified as independent predictor of treatment response. Likewise, serum levels of full-length cytokeratin-18 M65 at baseline also correlated with treatment failure and progression-free survival. The addition of sunitinib did not exert any effects on serum levels of M30 or M65. CONCLUSION The cytokeratin-18 fragment M30 at day 14 identifies patients that fail to second- or third-line therapy for advanced gastric cancer. Validation of this non-invasive biomarker in gastric cancer is warranted.
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9.
Effect of Food on the Pharmacokinetics of Saroglitazar Magnesium, a Novel Dual PPARαγ Agonist, in Healthy Adult Subjects.
Patel, MR, Kansagra, KA, Parikh, DP, Parmar, DV, Patel, HB, Soni, MM, Patil, US, Patel, HV, Patel, JA, Gujarathi, SS, et al
Clinical drug investigation. 2018;(1):57-65
Abstract
BACKGROUND AND OBJECTIVE Peroxisome proliferator-activated receptors (PPARs) have recently become a focus of interest for their important roles in glucose and lipid metabolism. In humans, PPARα activation causes a decrease in plasma triglyceride (TG) levels, enhancement of high-density lipoprotein cholesterol (HDL-C) and simultaneous enhancement of very-low-density lipoprotein (VLDL) lipolysis, whereas PPARγ agonists act as insulin sensitizers and improve insulin resistance, which is very useful in patients with type 2 diabetes mellitus (T2DM). Saroglitazar magnesium is a dual PPAR agonist with potent predominant PPARα and moderate PPARγ activity and the first glitazar to be granted marketing authorization in India. This study was conducted to evaluate the oral bioavailability and safety and tolerability of a Lipaglyn™ (saroglitazar magnesium) 4-mg tablet in healthy, adult human subjects under fed relative to fasting conditions. METHODS This was a single-dose, open-label, randomized, single-treatment, two-period, two-conditions (fed vs. fasting), two-sequence, crossover study planned in 54 healthy subjects. Food effect (high-calorie and high-fat breakfast) was examined by comparing pharmacokinetic data of saroglitazar and its metabolite saroglitazar sulfoxide in plasma samples collected pre-dose and serially up to 72 h post-dose. Pharmacokinetic data were analyzed using the standard non-compartmental approach. RESULTS A total of 54 subjects were enrolled in the study, out of them 50 subjects had completed the study and were analyzed. The presence of food had a minor impact on the disposition of saroglitazar. While food reduced C max (maximum concentration) of saroglitazar by 30%, the extent of absorption as measured by AUC∞ (area under the concentration time curve from time zero to infinity) was not influenced. This was further supported by the bioequivalence data between fasted and fed conditions for saroglitazar, where 90% CIs (confidence intervals) of the adjusted geometric mean of the fed relative to the fasted condition ranged from 101.37% to 108.07% for AUC∞ and from 63.45% to 74.68% for C max. Other parameters such as T max (time of maximum concentration) and T 1/2 (elimination half-life) were not influenced by the food intake. Saroglitazar was well tolerated in the study, and the reported adverse events were mild in nature. CONCLUSION For the single-dose study, the absorption rate is affected by food as the 90% CI of C max is outside 80.00-125.00%. However, there is no impact of food on the extent of absorption of saroglitazar. The observed lower C max of saroglitazar with food has no clinical relevance since the therapeutic efficacy of saroglitazar was achieved after multiple-dose administration, suggesting the importance of total exposure.
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10.
Effect of vonoprazan on the treatment of artificial gastric ulcers after endoscopic submucosal dissection: Prospective randomized controlled trial.
Tsuchiya, I, Kato, Y, Tanida, E, Masui, Y, Kato, S, Nakajima, A, Izumi, M
Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society. 2017;(5):576-583
Abstract
BACKGROUND AND AIM Proton pump inhibitors are effective for the treatment of gastric ulcers after endoscopic submucosal dissection (ESD). However, the most excellent therapy is controversial. Vonoprazan, an active potassium-competitive acid blocker, has a strong gastric acid secretion inhibitory effect, but its efficacy for the treatment of post-ESD gastric ulcers is unclear. Herein, we aimed to determine the healing effect of vonoprazan on post-ESD gastric ulcers. METHODS We carried out a prospective randomized controlled trial examining 92 patients who had undergone ESD for the treatment of gastric neoplasms between April 2015 and June 2016 at Machida Municipal Hospital. Patients were treated with 20 mg/day vonoprazan (V group) or 20 mg/day esomeprazole (E group) for 8 weeks. We evaluated the 8-week cure rate for artificial ulcers and any complications after ESD. RESULTS A total of 80 patients (median age, 73.5 years; 71.3% male) were analyzed. Cure rate for the V group was significantly higher than that for the E group (94.9% [37/39] vs 78.0% [32/41], respectively; P = 0.049). In a multivariate analysis, only vonoprazan was correlated with ulcer healing (odds ratio = 6.33; 95% CI = 1.21-33.20; P = 0.029). Delayed bleeding was experienced only in the E group (7.3% [3/41]), but no significant difference compared with the V group was observed (P = 0.241). CONCLUSION Vonoprazan was significantly superior to esomeprazole for the healing of post-ESD gastric ulcers and should be considered as a treatment of first choice.