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Effects of pirenzepine on vonoprazan-induced gastric acid inhibition and hypergastrinemia.
Suzuki, T, Higuchi, T, Kagami, T, Uotani, T, Yamade, M, Tani, S, Hamaya, Y, Iwaizumi, M, Osawa, S, Sugimoto, K, et al
European journal of clinical pharmacology. 2021;(7):971-978
Abstract
BACKGROUND Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels. METHODS Eleven healthy volunteers were subjected to 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75 mg alone, vonoprazan 10 mg alone, and vonoprazan 10 mg plus pirenzepine 75 mg administered in a randomized crossover fashion. RESULTS Median pH 4 holding time ratios (range) achieved with pirenzepine 75 mg, vonoprazan 10 mg, and vonoprazan 10 mg plus pirenzepine 75 mg were 6.9% (2.4-32.8%), 88.4% (54.6-100%), and 84.2% (40.3-100%), respectively. Respective serum gastrin levels were 79 (75-210) pg/ml, 310 (110-870) pg/ml, and 170 (140-930) pg/ml. In cases with hypergastrinemia (gastrin ≥ 200 pg/ml) induced by vonoprazan 10 mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370 to 180 pg/ml (P = 0.028). CONCLUSION Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent.
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Impact of Feeding Strategies With Acid Suppression on Esophageal Reflexes in Human Neonates With Gastroesophageal Reflux Disease: A Single-Blinded Randomized Clinical Trial.
Jadcherla, SR, Hasenstab, KA, Gulati, IK, Helmick, R, Ipek, H, Yildiz, V, Wei, L
Clinical and translational gastroenterology. 2020;(11):e00249
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INTRODUCTION Aims were to test hypothesis that esophageal provocation-induced reflexes are superior with acid suppression plus feeding modifications vs acid suppression alone among infants treated for gastroesophageal reflux disease (GERD). METHODS Infants (N = 49, 41.3 ± 2.6 of postmenstrual age) with acid reflux index >3% underwent longitudinal motility testing (weeks 0 and 5) with graded midesophageal provocation to test randomly allocated therapies (4 weeks' proton pump inhibitor [PPI] ± feeding modifications) on sensory-motor aerodigestive reflexes. Feeding modification included restricted fluid volume <140 mL/kg per day, fed over 30 minutes in right lateral position and supine postprandial position. Primary motility outcome was frequency-occurrence of peristaltic reflex. Secondary outcomes included upper esophageal sphincter contractile reflex, lower esophageal sphincter (LES) relaxation reflex, respiratory change, and symptom characteristics. RESULTS Treatment groups did not differ for primary outcome (odds ratio = 0.8, 95% confidence interval 0.4-1.6, P = 0.99) or secondary outcomes (all P > 0.05). For both treatment groups at follow-up, distal esophageal contraction and LES tone decreased, and LES relaxation reflex occurrence is less frequent (all P < 0.05). In a subgroup analysis, comparing infants with PPI washout (N = 40) vs with continued (N = 9) PPI therapy, no differences were noted for aerodigestive reflex response frequency-occurrence (all P > 0.05). DISCUSSION In infants with GERD, feeding modification with acid suppression is not superior to acid suppression alone in modifying aerodigestive reflexes (frequency, sensation, or magnitude). Contiguous areas targeted by GER, i.e., LES and distal esophageal functions, worsened at follow-up for both groups despite PPI therapy. Maturation is likely the key factor for GERD resolution in infants, justifying the use of placebo in clinical trials for objectively determined GERD.
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Effect of the proton-pump Inhibitor pantoprazole on MycoPhenolic ACid exposure in kidney and liver transplant recipienTs (IMPACT study): a randomized trial.
Sunderland, A, Russ, G, Sallustio, B, Cervelli, M, Joyce, D, Ooi, E, Jeffrey, G, Boudville, N, Chakera, A, Dogra, G, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(6):1060-1070
Abstract
BACKGROUND Mycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure. METHODS A multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 ('IMPACT' study). RESULTS Of the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20-132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0-65.9) mg*h/L versus pantoprazole: 43.8 (35.6-53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5-49.2) mg*h/L versus pantoprazole: 45.9 (35.5-59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group. CONCLUSIONS The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.
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Beneficial effect of probiotics supplements in reflux esophagitis treated with esomeprazole: A randomized controlled trial.
Sun, QH, Wang, HY, Sun, SD, Zhang, X, Zhang, H
World journal of gastroenterology. 2019;(17):2110-2121
Abstract
BACKGROUND Reflux esophagitis (RE) is a common digestive disorder, and its frequent recurrences cause significant physical pain and are financially burdensome to patients. However, studies on the natural history of treated RE are few. Although proton pump inhibitors (PPIs) as the first-line treatment provide notable symptomatic relief, disordered gut microbiota has been observed among PPI users. Probiotics are commonly administered to patients to regulate the disordered intestinal flora. AIM: To evaluate the therapeutic effects in RE patients treated with a combination of esomeprazole and probiotics [Bacillus subtilis (B. subtilis) and Enterococcus faecium (E. faecium)]. METHODS One hundred and thirty-four RE patients were randomized into two groups of 67 subjects each. The probiotics group was administered with esomeprazole 20 mg b.i.d. and live combined B. subtilis and E. faecium enteric-coated capsules 500 mg t.i.d. for eight weeks; the placebo group was administered with esomeprazole 20 mg b.i.d. and placebo for eight weeks. Subsequently, 12-wk follow-up was carried out on patients who achieved both endoscopic and clinical cure. Endoscopy, reflux diagnostic questionnaire (RDQ), gastrointestinal symptom rating scale (GSRS), and lactulose hydrogen breath test were performed to evaluate the therapeutic effects. A difference of P < 0.05 was considered statistically significant. RESULTS Sixty-six patients in the probiotics group and 64 patients in the placebo group completed the 8-wk treatment. The healing rate and RDQ score had no significant difference between the two groups (P > 0.05). However, the GSRS diarrhea syndrome score was decreased significantly in the probiotics group (P = 0.002), and the small intestinal bacterial overgrowth negative rate in the probiotics group was significantly higher than that in the placebo group (P = 0.002). Of 114 endoscopically and clinically cured patients, 96 completed the follow-up. The log-rank test showed that the time to relapse was shorter in the placebo group than in the probiotics group (P = 0.041). Furthermore, the therapy had a significant influence on relapse time, and the risk of relapse in the probiotics group was lower than that in the placebo group at any time point during the 12-wk follow-up (hazard ratio = 0.52, P = 0.033). CONCLUSION Esomeprazole combined with probiotics (B. subtilis and E. faecium) have a beneficial effect on RE treatment and patient management.
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Efficacy of vonoprazan in prevention of bleeding from endoscopic submucosal dissection-induced gastric ulcers: a prospective randomized phase II study.
Hamada, K, Uedo, N, Tonai, Y, Arao, M, Suzuki, S, Iwatsubo, T, Kato, M, Shichijo, S, Yamasaki, Y, Matsuura, N, et al
Journal of gastroenterology. 2019;(2):122-130
Abstract
BACKGROUND Vonoprazan, potassium-competitive acid blocker, is expected to reduce incidence of delayed bleeding after gastric endoscopic submucosal dissection (ESD); however, preliminary data to design a large-scale comparative study are lacking. This study aimed to assess the efficacy of vonoprazan in preventing delayed bleeding after gastric ESD. METHODS In this single-center randomized phase II trial, a modified screened selection design was used with a threshold non-bleeding rate of 89% and an expected rate of 97%. In this design, Simon's optimal two-stage design was first applied for each parallel group, and efficacy was evaluated in comparison with the threshold rate using binomial testing. Patients were randomly assigned in a 1:1 ratio to receive either vonoprazan 20 mg (VPZ group) or lansoprazole 30 mg (PPI group) for 8 weeks from the day before gastric ESD. The primary endpoint was the incidence of delayed bleeding, defined as endoscopically confirmed bleeding accompanied by hematemesis, melena, or a decrease in hemoglobin of ≥ 2 g/dl. RESULTS Delayed bleeding occurred in three of 69 patients (4.3%, 95% CI 0.9-12.2%, p = 0.047) in the VPZ group, and four of 70 (5.7%, 95% CI 1.6-14.0%, p = 0.104) in the PPI group. As only vonoprazan showed significant reduction in delayed bleeding compared with the threshold rate, it was determined to be efficacious treatment. CONCLUSIONS Vonoprazan efficaciously reduced the delayed bleeding rate in patients with an ESD-induced gastric ulcer. A large-scale, randomized, phase III study is warranted to definitively test the effectiveness of vonoprazan compared with proton pump inhibitors.
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Intraluminal therapy for Helicobacter pylori infection.
Liou, TC, Liao, PH, Lin, YC, Chu, CH, Shih, SC
Journal of gastroenterology and hepatology. 2019;(8):1337-1343
Abstract
BACKGROUND AND AIM Several strategies have been proposed to increase the eradication rate of Helicobacter pylori. However, the widespread increasing resistance rates to current multiple-dose oral antibiotic therapies call for alternative therapeutic approaches. We aim to develop a novel intraluminal therapy for H. pylori infection (ILTHPI). METHODS From April 2017 to December 2017, 100 H. pylori-infected treatment-naïve patients with upper abdominal pain or discomfort underwent endoscopic examinations and concomitant ILTHPI, which comprised the control of intragastric pH, the irrigation of gastric mucosal surface with a mucolytic agent, and the application of single-dose medicaments containing antibiotic powders. The safety profiles while conducting ILTHPI and adverse events after ILTHPI were evaluated. The success of eradication was assessed based on the result of the 13 C-urea breath test 6 weeks after ILTHPI. In addition, a patient with successful ILTHPI was reconfirmed by a negative H. pylori stool antigen test four to 6 months after ILTHPI to exclude short-term recurrence. RESULTS All the 100 enrolled patients completed the ILTHPI with good safety profiles and mild adverse events (6%). Five patients dropped out, and 51 of 95 patients (53.7%) achieved successful eradication immediately after endoscopic examinations. All 51 patients revealed negative stool H. pylori antigen tests four to 6 months after successful ILTHPI. No short-term recurrence was observed. CONCLUSIONS We have developed a novel therapeutic approach. With the ILTHPI, H. pylori can be eradicated immediately by administrating a single-dose regimen while conducting an endoscopic examination. CLINICAL TRIALS NUMBER NCT03124420.
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Effect of Gastric Acid Suppressants on Response to a Physical Activity Intervention and Major Mobility Disability in Older Adults: Results from the Lifestyle Interventions for Elders (LIFE) Study.
Squires, PJ, Pahor, M, Manini, TM, Brown, JD
Pharmacotherapy. 2019;(8):816-826
Abstract
OBJECTIVES Proton pump inhibitors (PPIs) and histamine2 receptor antagonists (H2 RAs) are associated with pharmacologic effects that may be detrimental to mobility and response to physical activity. Mobility disability and injurious fall outcomes in PPI and H2 RA users were compared with nonusers in this secondary analysis of data from the Lifestyle Interventions for Elders (LIFE) study. METHODS Participants ages 70-89 years were randomized to a physical activity (PA) or successful aging intervention and evaluated by medication use. Confounders included baseline demographic characteristics, physical function, cognitive function, sleep quality, and acid reflux symptoms that were adjusted via propensity score weighting. Outcomes were incident and persistent major mobility disability (MMD and pMMD) and injurious falls. Weighted proportional hazard models evaluated independent and interaction effects of PPIs and H2 RAs. RESULTS No interaction was found between PPIs and H2 RAs and the PA intervention. Drug use associations were significant for H2 RAs (hazard ratio [HR] 1.74 [95% confidence interval [CI] 1.12-2.68]) and PPIs (HR 1.32 [95% CI 1.02-1.70]) compared with nonusers for pMMD. PPIs were associated with increased injurious falls compared with nonusers (HR 1.44 [95% CI 1.06-1.96]). Pooling of data from the H2 RA and PPI exposure groups showed a 26% increase in MMD (HR 1.26 [95% CI 1.07-1.48]), a 44% increase in pMMD (HR 1.44 [95% CI 1.16-1.77]), and a 48% increase in injurious falls (HR 1.48 [95% CI 1.15-1.91]) compared with nonusers. All direct comparisons between PPIs and H2 RAs were nonsignificant. CONCLUSIONS Compared with nonusers, participants using either PPIs or H2 RAs had an increased risk of MMD, pMMD, and injurious falls. It is not known if these effects are related to the individual pharmacology of each medication, reduced acid secretion, or the underlying disease state. Further study is required to determine causality.
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High Effective of 14-Day High-Dose PPI- Bismuth-Containing Quadruple Therapy with Probiotics Supplement for Helicobacter Pylori Eradication: A Double Blinded-Randomized Placebo-Controlled Study.
Poonyam, P, Chotivitayatarakorn, P, Vilaichone, RK
Asian Pacific journal of cancer prevention : APJCP. 2019;(9):2859-2864
Abstract
Background: Helicobacter pylori (H. pylori) infection is important risk factors for chronic gastritis, peptic ulcer and gastric cancer. Bismuth-containing quadruple therapy has recently been the first-line regimen recommended in many European countries but has limited efficacy in ASEAN especially Thailand. This study was aim to evaluate efficacy of high dose PPI Bismuth-containing quadruple therapy with probiotics supplement for H. pylori eradication. Methods: In this double-blind randomized placebo-controlled study, H. pylori infected patients were randomized to receive 7-or 14-day high dose PPI- bismuth-containing quadruple therapy with or without probiotics supplement. Probiotic was 37.5 mg Lactobacillus reuteri (Biogaia®) in tablet twice daily. CYP2C19 genotyping and antibiotic susceptibility tests were also done. H. pylori eradication was defined as a negative 13C-urea breath test at least 4 weeks after treatment. Results: 100 subjects were enrolled (72 females, 28 males, mean age=54 years). Antibiotic resistance was 15.6% for clarithromycin, 34.1% for metronidazole. CYP2C19 genotyping was performed in both group and revealed 13%, 50% and 37% for poor, intermediate and rapid metabolizers, respectively. Overall eradication rates of 7-day and 14-day regimens with probiotic were 68% and 96%; P value=0.027. The eradication rate for all patients with poor and rapid metabolizers were 100% with 14-day regimen. 14-day regimen with probiotics can provide 100% eradication with clarithromycin resistance, metronidazole resistance or dual clarithromycin and metronidazole resistance group. Furthermore, the incidence of nausea and vomiting, abdominal discomfort, and bitter taste were significantly lower in patients with probiotics group compared with placebo (6%vs.26%, P=0.002,OR=0.126,95% CI=0.03-0.53; 4%vs.18.0%, P=0.017, OR= 0.155,95% CI=0.03-0.81 and 4%vs.26%, P= 0.001,OR= 0.08, 95%CI= 0.016-0.41, respectively). Conclusions: The 14-day high dose PPI- bismuth-containing quadruple therapy with probiotic can provide an excellent cure rate for H. pylori infection as first line treatment irrespective of CYP2C19 and antibiotic resistance pattern. Adding probiotic also significantly reduced treatment-related adverse events and improve the patients’ compliance.
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A prospective randomized trial of a potassium competitive acid blocker vs proton pump inhibitors on the effect of ulcer healing after endoscopic submucosal dissection of gastric neoplasia.
Komori, H, Ueyama, H, Nagahara, A, Akazawa, Y, Takeda, T, Matsumoto, K, Matsumoto, K, Asaoka, D, Hojo, M, Yao, T, et al
The Journal of international medical research. 2019;(4):1441-1452
Abstract
BACKGROUND/AIMS: Vonoprazan is a new a potassium-competitive acid blocker (P-CAB) that was recently developed in Japan. However, vonoprazan's efficacy in healing gastric ulcers after endoscopic submucosal dissection (ESD) remains controversial. This study aimed to compare the efficacy of P-CABs and proton pump inhibitors (PPIs) in healing post-ESD ulcers. MATERIALS AND METHODS This prospective randomized controlled trial (UMIN000017386) enrolled 40 patients with gastric neoplasia, who underwent ESD at our hospital from April 2015 to January 2016. Before ESD, patients were randomly divided into the following two groups: group V, vonoprazan 20 mg/day; or group R, rabeprazole 10 mg/day. Medications were taken 1 day before to 4 weeks after ESD. The ESD-induced artificial ulcer size was measured just after ESD and 4 weeks after ESD to calculate the reduction rate as follows: (ulcer area 4 weeks after ESD)/(ulcer area just after ESD) × 100. RESULTS Eighteen patients in group V and 15 patients in group R were analyzed. The mean reduction rate was significantly different in groups V and R (93.3% vs 96.6%, respectively). Post-ESD bleeding was observed in two patients in group R and drug-induced hepatic injury in one patient in group R. CONCLUSION Rabeprazole facilitated the healing process post-ESD.
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A Phase 1 Pharmacokinetic Study of Cysteamine Bitartrate Delayed-Release Capsules Following Oral Administration with Orange Juice, Water, or Omeprazole in Cystinosis.
Armas, D, Holt, RJ, Confer, NF, Checani, GC, Obaidi, M, Xie, Y, Brannagan, M
Advances in therapy. 2018;(2):199-209
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INTRODUCTION Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR. METHODS This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences. RESULTS All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC0-t, AUC0-∞, and Cmax were all within the 80-125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated. CONCLUSION Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water). FUNDING Horizon Pharma, Inc.