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1.
Medicine (Baltimore) ; 99(35): e21488, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871870

RESUMO

BACKGROUND: Celiac disease is an autoimmune enteropathy characterized by an aberrant immune response to ingested gluten in genetically predisposed individuals. Studies have pointed to a rising prevalence of celiac disease in recent decades. Changes in diet and use of medication that may impact the gut microbiome have been suggested as potential contributors. Exposure to protein pump inhibitors (PPIs) was recently found to be associated with an increased risk for subsequent diagnosis of celiac disease. We aimed to investigate potential mechanisms for this link by examining the relationship between PPI use and gluten-related immune responses in the context of changes in gut microbiome. METHODS: We performed a post hoc analysis of blood and fecal samples from a recent randomized trial in order to assess the potential association between PPI use and development of celiac disease serology in conjunction with alterations in gastrointestinal microbial composition. The study included 12 healthy participants who were administered a PPI (Omeprazole; 40 mg twice daily) for 4 or 8 weeks. RESULTS: The analysis did not reveal an overall significant change in levels of serologic markers of celiac disease for the study cohort in response to PPI treatment. However, one individual developed a marked increase in the celiac disease-specific autoantibody response to transglutaminase 2 in conjunction with enhanced immune reactivity to gluten during the trial. Genotyping revealed positivity for the celiac disease-associated HLA-DQ2 and -DQ8 alleles. Furthermore, the observed elevation in antibody responses was closely associated with a sharp increase in fecal abundance of bacteria of the order Actinomycetales. CONCLUSIONS: The results of this exploratory analysis support further investigation of molecular mechanisms involved in the contribution of PPIs to celiac disease risk through the potential enhancement of gluten immunopathology and changes in gut microbial population.


Assuntos
Doença Celíaca/sangue , Doença Celíaca/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Omeprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Actinomycetales/crescimento & desenvolvimento , Adulto , Alelos , Doença Celíaca/epidemiologia , Doença Celíaca/metabolismo , Fezes/microbiologia , Feminino , Proteínas de Ligação ao GTP/sangue , Proteínas de Ligação ao GTP/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Genótipo , Glutens/efeitos adversos , Glutens/imunologia , Antígenos HLA-DQ/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/uso terapêutico , Prevalência , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Transglutaminases/sangue , Transglutaminases/efeitos dos fármacos
4.
J Cancer Res Clin Oncol ; 146(10): 2693-2697, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32449002

RESUMO

PURPOSE: Sorafenib is an oral tyrosine kinase inhibitor (TKI) and first-line treatment option for advanced hepatocellular carcinoma (HCC). Preliminary evidence indicates proton pump inhibitors (PPI) may affect the absorption of TKIs through decreased gut dissolution. This study aims to evaluate the impact of PPI use on the survival outcomes of advanced HCC patients treated with sorafenib. METHODS: The study was a secondary analysis of individual-participant data from the phase III clinical trial NCT00699374. Cox proportional hazard analysis was used to evaluate the association between baseline PPI use and survival outcomes. Overall survival (OS) was the primary outcome with progression-free survival (PFS) secondary. RESULTS: In a cohort of 542 advanced HCC patients initiating sorafenib treatment, 122 were concomitantly using a PPI at baseline. No significant associations between baseline PPI use and OS were identified on univariable (HR [95% CI]; 1.01 [0.80-1.28], P = 0.93) and adjusted (1.10 [0.82-1.41], P = 0.62) analysis. Furthermore, no significant associations between baseline PPI use and PFS were identified on univariable (0.96 [0.76-1.21], P = 0.73) and adjusted (1.11 [0.86-1.44], P = 0.41) analysis. CONCLUSION: In a large high-quality dataset, PPI use was not observed to compromise the survival outcomes of advanced HCC patients initiated on sorafenib.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , Sorafenibe/administração & dosagem , Sorafenibe/farmacocinética , Carcinoma Hepatocelular/mortalidade , Ensaios Clínicos Fase III como Assunto , Estudos de Coortes , Sinergismo Farmacológico , Absorção Gastrointestinal/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Taxa de Sobrevida
5.
Lancet Infect Dis ; 20(8): 964-975, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32275867

RESUMO

BACKGROUND: (+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. METHODS: The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safety, tolerability, and pharmacokinetics of SJ733, and identification of an SJ733 dose to test in the induced blood-stage malaria model. The phase 1b was a single-centre, open-label, volunteer infection study using the induced blood-stage malaria model in which fasted participants were intravenously infected with blood-stage P falciparum and subsequently treated with a single dose of SJ733. Phase 1b took place at Q-Pharm (Herston, QLD, Australia) and was initiated only after phase 1a showed that exposure exceeding the threshold minimum exposure could be safely achieved in humans. Participants were inoculated on day 0 with P falciparum-infected human erythrocytes (around 2800 parasites in the 150 mg dose cohort and around 2300 parasites in the 600 mg dose cohort), and parasitaemia was monitored before malaria inoculation, after inoculation, immediately before SJ733 dosing, and then post-dose. Participants were treated with SJ733 within 24 h of reaching 5000 parasites per mL or at a clinical score higher than 6. Phase 1b primary endpoints were calculation of a parasite reduction ratio (PRR48) and parasite clearance half-life, and safety and tolerability of SJ733 (incidence, severity, and drug-relatedness of adverse events). In both phases of the trial, SJ733 hydrochloride salt was formulated as a powder blend in capsules containing 75 mg or 300 mg for oral administration. Healthy men and women (of non-childbearing potential) aged 18-55 years were eligible for both studies. Both studies are registered with ClinicalTrials.gov (NCT02661373 for the phase 1a and NCT02867059 for the phase 1b). FINDINGS: In the phase 1a, 23 healthy participants were enrolled and received one to three non-consecutive doses of SJ733 between March 14 and Dec 7, 2016. SJ733 was safe and well tolerated at all doses and in fasted and fed conditions. 119 adverse events were recorded: 54 (45%) were unrelated, 63 (53%) unlikely to be related, and two (2%) possibly related to SJ733. In the phase 1b, 17 malaria-naive, healthy participants were enrolled. Seven participants in the 150 mg dose cohort were inoculated and dosed with SJ733. Eight participants in the 600 mg dose cohort were inoculated, but two participants could not be dosed with SJ733. Two additional participants were subsequently inoculated and dosed with SJ733. SJ733 exposure increased proportional to the dose through to the 600 mg dose, then was saturable at higher doses. Fasted participants receiving 600 mg exceeded the target area under the concentration curve extrapolated to infinity (AUC0-∞) of 13 000 µg × h/L (median AUC0-∞ 24 283 [IQR 16 135-31 311] µg × h/L, median terminal half-life 17·4 h [IQR 16·1-24·0], and median timepoint at which peak plasma concentration is reached 1·0 h [0·6-1·3]), and this dose was tested in the phase 1b. All 15 participants dosed with SJ733 had at least one adverse event. Of the 172 adverse events recorded, 128 (74%) were mild. The only adverse event attributed to SJ733 was mild bilateral foot paraesthesia that lasted 3·75 h and resolved spontaneously. The most common adverse events were related to malaria. Based on parasite clearance half-life, the derived log10PRR48 and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0-2·5) and 6·47 h (95% CI 5·88-7·18) for 150 mg, and 4·1 (3·7-4·4) and 3·56 h (3·29-3·88) for 600 mg. INTERPRETATION: The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy. FUNDING: Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities.


Assuntos
Antimaláricos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Isoquinolinas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Inibidores da Bomba de Prótons/uso terapêutico , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Estudos de Casos e Controles , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Feminino , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , Resultado do Tratamento , Adulto Jovem
6.
Surgery ; 168(1): 67-71, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32276736

RESUMO

BACKGROUND: Marginal ulcer is a well-known complication after pancreatoduodenectomy. In light of increasing long-term survival after pancreatoduodenectomy, the identification of risk factors and preventive strategies are of utmost importance. We assessed the incidence, clinical impact, and potential risk factors of marginal ulcer after pancreatoduodenectomy. METHODS: A prospectively maintained database of patients undergoing pancreatoduodenectomy was analyzed retrospectively. Univariate and bivariate competing-risk Cox regression analyses were performed to identify risk factors for marginal ulcer. RESULTS: Two hundred and fifty-five consecutive patients underwent pancreatoduodenectomy. The median follow-up was 35.7 months. Marginal ulcer was diagnosed in 19 patients (7.5%), and the median time from pancreatoduodenectomy to marginal ulcer diagnosis was 450 days. Thirteen of these 19 patients presented with abdominal pain, melena, or anemia. In all these 13 patients, marginal ulcer resolved with proton pump inhibitor therapy and endoscopic surveillance. Six patients with marginal ulcer presented with an acute abdomen and underwent emergency laparotomy for marginal ulcer perforation and peritonitis. There was no marginal ulcer-related mortality. Univariate and bivariate competing-risk analyses showed an increased risk for marginal ulcer with discontinuation of proton pump inhibitor therapy, smoking, alcohol intake, and the use of non-steroidal anti-inflammatory drugs. Discontinuation of proton pump inhibitor therapy was an independent risk factor for marginal ulcer development. CONCLUSION: Marginal ulcer is a relevant long-term complication after pancreatoduodenectomy that occurs more frequently after proton pump inhibitor therapy is discontinued. Based on our data, permanent use of proton pump inhibitor after pancreatoduodenectomy is strongly recommended especially for those patients who smoke, consume alcohol, or use non-steroidal anti-inflammatory drugs.


Assuntos
Pancreaticoduodenectomia/efeitos adversos , Úlcera Péptica/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Inibidores da Bomba de Prótons/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/epidemiologia , Úlcera Péptica/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Adulto Jovem
7.
Anticancer Res ; 40(4): 2209-2217, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234916

RESUMO

AIM: To investigate potential association between administration of corticosteroids, antibiotics, probiotics, proton pump inhibitors, non-steroidal anti-inflammatory drugs (NSAID), statins and metformin and outcome in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. PATIENTS AND METHODS: A total of 224 patients with advanced NSCLC treated at nine comprehensive cancer centers were analyzed in this national retrospective study. Survival statistics were evaluated using Kaplan-Meier method and Cox analysis. RESULTS: Only corticosteroid use had a significant negative effect on the objective response rate. In the univariate analysis, there was no significant effect of the studied concomitant medications on the efficacy of nivolumab. In a subsequent multifactorial analysis, a possible positive effect of the concomitant use of NSAID at the initiation of nivolumab treatment was revealed. CONCLUSION: The results of the present retrospective exploratory analysis underscore the importance of knowing the exact type of concomitant medication, the route of administration, the dose of medication, and the region of the ongoing study. The present data indicated a significantly higher rate of progression in patients treated with corticosteroids and the possible positive effect of NSAID use at the initiation of nivolumab treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/métodos , Corticosteroides/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Probióticos/administração & dosagem , Modelos de Riscos Proporcionais , Inibidores da Bomba de Prótons/administração & dosagem , Estudos Retrospectivos
8.
Medicine (Baltimore) ; 99(11): e19520, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176102

RESUMO

Proton pump inhibitors (PPIs) have been the first line treatment for gastroesophageal reflux disease (GERD). The aim of this study was to evaluate the efficacy of vonoprazan (VPZ), a potassium-competitive acid blocker for reflux esophagitis (RE), nonerosive reflux disease (NERD), and PPI-resistant GERD patients.An open-label, single-center, observational study in our hospital was performed from August 2016 to August 2017. All patients diagnosed with GERD were asked to self-report a questionnaire of frequency scale for the symptoms of GERD (FSSG) and rate their degree of satisfaction with the treatment of GERD during outpatient visit. A total of 200 (RE 47, NERD 49, PPI-resistant GERD 104) patients were included in the present study. The primary endpoint was the change of FSSG and the proportion of degree of satisfaction with the treatment at the end of the initial therapy. A percentage of improvement (improvement rate) and resolution (resolution rate) at the end of the initial therapy were evaluated. Secondary endpoint included the proportion of patients with symptomatic relapse in the 24-week maintenance phase.FSSG and the degree of satisfaction were significantly improved after the initial therapy in every group. Improvement and resolution rate after the initial therapy were 83.0% and 67.0% in RE, 66.7% and 60.4% in NERD, and 76.0% and 60.4% in PPI-resistant group. There was no significance between after the initial therapy and 24 weeks in improvement and resolution rate. Thirty-two of the total 48 patients did not take VPZ at 24 weeks. Total FSSG score in each group was 1.67 ±â€Š1.97, 2.71 ±â€Š4.91, and 4.0 ±â€Š4.93. The nonrelapse rate at 24 weeks in each group was 66.7%, 60.0%, and 50.0%. The resolution rate at 24 weeks in each group was 38.9%, 45.0%, and 30.0%.The VPZ therapy is effective for initial and maintenance therapy and improves heartburn and patient's satisfaction significantly in all 3 groups. Among patients who stopped taking VPZ during the maintenance period, 42.0% of RE and NERD group and 30% of PPI-resistant group experience complete remission from GERD at 24 weeks by introduction of VPZ.


Assuntos
Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Feminino , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Inquéritos e Questionários , Resultado do Tratamento
9.
Am J Gastroenterol ; 115(5): 706-715, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32205645

RESUMO

INTRODUCTION: Proton pump inhibitors (PPIs) are commonly used for gastrointestinal disorders; given they increase the systemic levels of gastrin, a trophic hormone, there is a concern about their carcinogenicity. This study evaluated the association between PPI use and gastrointestinal cancers. METHODS: We performed a nested case-control study in a large, community-based integrated healthcare setting. Cases were adults with gastric (n = 1,233), colorectal (n = 18,595), liver (n = 2,329), or pancreatic cancers (n = 567). Each case was matched with up to 10 controls by age, sex, race/ethnicity, medical facility, and enrollment duration. The primary exposure was defined as ≥2-year cumulative PPI supply. Data were obtained from pharmacy, cancer registry, and electronic medical record databases. Associations were evaluated using conditional logistic regression and adjusted for multiple confounders. We also evaluated the cancer risks separately by PPI dose, duration of use, and dose and duration. RESULTS: PPI use of ≥2-years was not associated with the risks of gastric (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.81-1.42), colorectal (OR: 1.05, 95% CI: 0.99-1.12), liver (OR: 1.14, 95% CI: 0.91-1.43), or pancreatic cancers (OR: 1.22, 95% CI: 0.89-1.67), compared to non-users. In exploratory analyses, elevated cancer risks were primarily restricted to those with ≥10 years of PPI use, but no consistent associations were found for increasing PPI dose and/or duration of use. DISCUSSION: PPI use of ≥2 years was not associated with increased risks of gastrointestinal cancers. The cancer risks associated with PPI use of ≥10 years requires further study.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Inibidores da Bomba de Prótons/administração & dosagem , Neoplasias Gástricas/epidemiologia , Idoso , California/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Sistema de Registros , Fatores de Risco
10.
Helicobacter ; 25(2): e12683, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32074663

RESUMO

BACKGROUND/AIMS: Conventional second-line, bismuth-containing quadruple therapy is administered four times a day. We aimed to evaluate the efficacy and safety of twice a day administration compared to the four times a day therapy. METHODS: Medical records of consecutive patients with positive 13 C-urea breath tests (UBTs) after first-line eradication were reviewed. From December 2018 to June 2019, 100 consecutive 13 C-UBT-positive patients received tetracycline 1 g, metronidazole 750 mg, bismuth subcitrate 300 mg, and pantoprazole 20 mg twice a day for one week. The same number of consecutive13 C-UBT-positive patients before December 2018 was included as controls. The control group received tetracycline 500 mg and bismuth subcitrate 300 mg four times a day, metronidazole 500 mg three times a day, and pantoprazole 20 mg twice a day for one week. Eradication was confirmed based on a 13 C-UBT performed in the 5th week after taking quadruple therapy. RESULTS: Ninety-eight patients from the twice a day group and 99 patients from the four times a day group were analyzed. The eradication rate did not differ between the twice a day group (92/98, 93.9%) and the four times a day group (92/99, 92.9%). Adverse drug effects were found in 36 patients from the twice a day group and 50 patients from the four times a day group (P = .051). Abdominal pain, discomfort, and distention were more common with four times a day intake (13.1%) than with twice a day intake (4.1%; P = .024). CONCLUSIONS: We determined for the first time that twice a day intake of bismuth-containing quadruple therapy using 2 g/d of tetracycline, 1.5 g/d of metronidazole, and 600 mg/d of bismuth subcitrate for one week is effective and safe as the conventional four times a day therapy. Twice a day intake decreased abdominal pain, discomfort, and distention.


Assuntos
Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Metronidazol/uso terapêutico , Compostos Organometálicos/uso terapêutico , Tetraciclina/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Antiulcerosos/administração & dosagem , Antiulcerosos/uso terapêutico , Testes Respiratórios , Quimioterapia Combinada , Feminino , Helicobacter pylori/efeitos dos fármacos , Humanos , Metronidazol/administração & dosagem , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Pantoprazol , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Tetraciclina/administração & dosagem
12.
Aliment Pharmacol Ther ; 51(5): 505-526, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31990420

RESUMO

BACKGROUND: Proton pump inhibitors (PPI) are widely used to treat acid-related disorders of the upper gastrointestinal tract. However, large observational studies have raised concerns about PPI-associated adverse events. In recent years, data from next-generation sequencing studies suggested that PPIs affect the composition of the intestinal microbiota, while a balanced gut microbiome is essential for maintaining health. AIM: To review the available evidence from next-generation sequencing studies on the effect of PPIs on the intestinal microbiome and to discuss possible implications of PPI-induced dysbiosis in health and disease. METHODS: A systematic review was conducted following the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. A PubMed query yielded 197 results. 19 publications met the prespecified eligibility criteria. RESULTS: Twelve observational study cohorts with 708 PPI users and 11 interventional cohorts with 180 PPI users were included in the review. In most studies, PPI treatment did not affect microbiological richness and diversity, but was associated with distinct taxonomic alterations: In the upper gastrointestinal tract, PPI users showed overgrowth of orally derived bacteria, mostly Streptococcaceae (findings based on six independent cohorts with 126 PPI users). In faecal samples, PPIs increased multiple taxa from the orders Bacillales (eg, Staphylococcaceae), Lactobacillales (eg, Enterococcaceae, Lactobacillaceae, Streptococcaceae) and Actinomycetales (eg, Actinomycetaceae, Micrococcaceae), the families Pasteurellaceae and Enterobacteriaceae and the genus Veillonella. Taxa decreased by PPIs include Bifidobacteriaceae, Ruminococcaceae, Lachnospiraceae and Mollicutes (findings in faecal samples based on 19 independent cohorts with 790 PPI users). CONCLUSION: PPI use is associated with moderate alterations to upper and distal gut microbiota. The available data suggest that PPI-induced hypochlorhydria facilitates colonization of more distal parts of the digestive tract by upper gastrointestinal microbiota.


Assuntos
DNA Bacteriano/análise , Disbiose/induzido quimicamente , Disbiose/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Inibidores da Bomba de Prótons/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Estudos de Coortes , DNA Bacteriano/efeitos dos fármacos , DNA Bacteriano/genética , Disbiose/epidemiologia , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Humanos , Estudos Observacionais como Assunto/estatística & dados numéricos , Inibidores da Bomba de Prótons/administração & dosagem , Análise de Sequência de DNA/métodos
13.
Aliment Pharmacol Ther ; 51(5): 534-543, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31990424

RESUMO

BACKGROUND: Vonoprazan (V), a potassium-competitive acid blocker, has a more durable acid-inhibitory effect as compared with standard-dose proton pump inhibitors (PPIs) but has not been compared with 2-4 times higher daily PPI doses administered in two divided doses. AIMS: To evaluate the acid-inhibitory effect of V 10/20 mg once-daily (OD; V10/V20) vs rabeprazole (R) 10/20 mg twice-daily (BID; R20/R40) in healthy Japanese volunteers. METHODS: This multicentre, randomised, open-label, two-period, crossover study compared V10 or V20 vs R20, or V20 vs R40 using three cohorts of 10 healthy Japanese adults. Within each cohort, subjects were randomised to receive V or R for 7 days and, following a washout period ≥7 days, the other treatment for 7 days. On day 6 of each period, 24-hours multichannel gastric impedance-pH monitoring was performed. Percent times pH ≥ 3, ≥4 and ≥5 (pH 3, 4 and 5 holding time ratios [HTRs]) in 24 hours were evaluated as primary pharmacodynamic endpoints. RESULTS: Acid-inhibitory effect (24-hours pH 3 HTR) of V20 was greater than those of R20 (91.0% vs 65.3%; P = .0049) and R40 (98.5% vs 85.9%; P = .0073). Similar results were obtained for 24-hours pH 4 and 5 HTRs. V20 also achieved greater nocturnal pH 4 (91.5% vs 73.2%; P = .0319) and 5 HTRs (78.8% vs 62.2%; P = .0325) as compared with R40. One subject (20%) developed diarrhoea while receiving R40 which was considered treatment-related. CONCLUSIONS: Compared with 2-4 times the standard daily dose of R, V20 exerts a more potent and durable acid-inhibitory effect. Trial identifier: UMIN000022198 (www.umin.ac.jp/ctr/index.htm).


Assuntos
Antiácidos/administração & dosagem , Ácido Gástrico/metabolismo , Suco Gástrico/efeitos dos fármacos , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Rabeprazol/administração & dosagem , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Antiácidos/efeitos adversos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Suco Gástrico/metabolismo , Voluntários Saudáveis , Humanos , Concentração de Íons de Hidrogênio , Japão , Masculino , Polimorfismo Genético , Inibidores da Bomba de Prótons/efeitos adversos , Pirróis/efeitos adversos , Rabeprazol/efeitos adversos , Sulfonamidas/efeitos adversos , Adulto Jovem
14.
Dig Dis ; 38(5): 408-414, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910424

RESUMO

INTRODUCTION: Suppression of gastric acid secretion with proton-pump inhibitors (PPI) is an integral part of the treatment of Helicobacter pylori infection. Esomeprazole has been shown to be superior to other PPIs when used in the context of triple therapy; however, comparative data for PPI efficacy in quadruple therapy are lacking. Current guidelines recommend H. pylori eradication with quadruple therapy in areas with high clarithromycin resistance. OBJECTIVE: To determine whether esomeprazole is more effective than other PPIs in the context of quadruple therapy for H. pylori eradication. METHODS: We retrospectively identified 25- to 60-year-old subjects with a positive 13C-urea breath test and no prior laboratory or endoscopic test for H. pylori infection. Pharmacy dispensation data were retrieved. RESULTS: A total of 7,896 subjects including 2,856 (36.2%) males, aged 40.4 ± 10.6 years, were identified. Of those, 78.1% received omeprazole, 20.1% received lansoprazole, 1.5% received esomeprazole, and 0.34% received pantoprazole together with antibiotics for H. pylori eradication. Esomeprazole was associated with a greater proportion of successful eradication (85.0 vs. 77.5%, esomeprazole vs. omeprazole, OR 1.64; 95% CI 0.99-2.72; p = 0.05). A nonsignificant trend favored esomeprazole over omeprazole among subjects receiving quadruple therapy (90.0 vs. 82.0%, respectively, OR 1.98; 95% CI 0.68-5.72; p = 0.16). Independent predictors of treatment success included older age and quadruple therapy. CONCLUSION: Esomeprazole is more beneficial than other PPIs for H. pylori eradication. Studies with larger subgroups are necessary to confirm our findings among subjects receiving quadruple therapy.


Assuntos
Infecções por Helicobacter/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Testes Respiratórios , Esquema de Medicação , Quimioterapia Combinada , Feminino , Helicobacter pylori/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , Estudos Retrospectivos , Resultado do Tratamento
15.
Einstein (Sao Paulo) ; 18: eAO4433, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31939523

RESUMO

OBJECTIVE: To describe the pharmaceutical interventions of a vertical clinical pharmacy service to promote the rational use of intravenous omeprazole. METHODS: A prospective and descriptive study carried out at a university hospital in the Midwestern Region of Brazil, from November 2014 to May 2015. The service consisted of the analysis of adequacy of the route of administration of omeprazole in relation to the clinical conditions of the patient, as well as the use of the appropriate diluent. Interventions were recorded in medical records and subsequently evaluated for acceptance. RESULTS: A total of 770 prescriptions were evaluated. Interventions related to diluent replacement were more accepted (p<0.001), and surgeons were the specialty that used the intravenous route inappropriately (p<0.001). CONCLUSION: Although partially accepted, pharmaceutical interventions could contribute to improve patient safety, since they allowed the use of a safer route of administration.


Assuntos
Administração Intravenosa/métodos , Omeprazol/administração & dosagem , Serviço de Farmácia Hospitalar/normas , Inibidores da Bomba de Prótons/administração & dosagem , Adulto , Distribuição por Idade , Idoso , Brasil , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Hospitais Universitários , Humanos , Masculino , Erros de Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Prospectivos , Distribuição por Sexo
18.
Gut ; 69(2): 224-230, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31409606

RESUMO

OBJECTIVE: To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO). DESIGN: In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI -3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI -1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI -4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI -5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI -8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI -9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively. CONCLUSION: Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms. TRIAL REGISTRATION NUMBER: NCT02388724.


Assuntos
Esofagite Péptica/tratamento farmacológico , Lansoprazol/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Cicatrização
19.
Expert Opin Drug Saf ; 19(1): 59-67, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31795777

RESUMO

Introduction: The objective of this study was to review the current status of drug-induced hypomagnesemia and its adverse effects on cardiovascular disease (CVD) and hypertension. Since magnesium is a potent vasodilator, which modulates vasomotor tone, peripheral blood flow, and hypertension, its deficiency could have significant cardiovascular and blood pressure (BP) effects.Areas covered: Studies have shown that several factors can contribute to magnesium deficiency including age, diet, disease, and certain drugs such as diuretics and proton-pump inhibitors (PPIs). For an updated perspective of drug-induced hypomagnesemia, a Medline search of the English language literature was conducted between 2010 and 2019 using the terms diuretics, proton-pump inhibitors, hypomagnesemia, cardiovascular disease, hypertension, and 35 pertinent papers were retrieved.Expert opinion: The data showed that magnesium deficiency is difficult to occur since it is plentiful in green leafy vegetables, cereals, nuts, and the drinking water. However, magnesium deficiency can occur with the use of diuretics for the treatment of hypertension and heart failure, or the use of PPIs for the treatment of gastroesophageal reflux disease. Therefore, magnesium deficiency should be detected and treated to prevent the aggravation of hypertension and the onset of CVD and serious cardiac arrhythmias including torsades de points.


Assuntos
Diuréticos/efeitos adversos , Deficiência de Magnésio/induzido quimicamente , Inibidores da Bomba de Prótons/efeitos adversos , Animais , Arritmias Cardíacas/induzido quimicamente , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/fisiopatologia , Diuréticos/administração & dosagem , Humanos , Hipertensão/etiologia , Deficiência de Magnésio/complicações , Deficiência de Magnésio/diagnóstico , Inibidores da Bomba de Prótons/administração & dosagem
20.
Gastroenterology ; 158(4): 840-851, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31836530

RESUMO

Treatment of eosinophilic esophagitis has progressed from elemental formula for children and esophageal dilation for adults to selective exclusion of food triggers and swallowed topical corticosteroids. Management guidelines are available from the American Gastroenterological Association and the Joint Task Force on Allergy Immunology Practice Parameters. We cannot, however, evaluate the efficacy of treatments without a definition of response. We propose a treat-to-target approach, based on symptoms and findings from endoscopy and histology. This approach addresses dissociations between outcomes, such as symptom persistence despite normalization of histologic features and symptom resolution after esophageal dilation despite histologic features of active disease. Eosinophilic esophagitis can now be treated with biologic agents that target specific immune pathways, and findings from prospective trials have indicated that less-restrictive, empiric, elimination diets can be effective and reduce the need for repeated endoscopic assessment of disease activity during food reintroduction. We also discuss eosinophilic esophagitis subtypes, factors associated with disease, and advances in management.


Assuntos
Alérgenos/efeitos adversos , Esofagite Eosinofílica/terapia , Gastroenterologia/métodos , Administração Oral , Adolescente , Adulto , Fatores Etários , Produtos Biológicos/administração & dosagem , Criança , Terapia Combinada/métodos , Deglutição , Exposição Dietética/efeitos adversos , Dilatação/métodos , Dilatação/normas , Exposição Ambiental/efeitos adversos , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/etiologia , Esofagite Eosinofílica/patologia , Esofagoscopia , Esôfago/diagnóstico por imagem , Esôfago/patologia , Comportamento Alimentar , Gastroenterologia/normas , Glucocorticoides/administração & dosagem , Humanos , Lactente , Guias de Prática Clínica como Assunto , Inibidores da Bomba de Prótons/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
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