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1.
Drug Res (Stuttg) ; 70(10): 484-488, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32877948

RESUMO

Although the major therapeutic uses of the proton pump inhibitors are in gastric-acid related diseases, evidences are suggestive of a pleiotropic nature of the compounds. We comment on the probable pathways and cellular machineries via which proton pump inhibitors could show beneficial therapeutic effects against SARS-CoV-2 based on the existing evidences. Proton pump inhibitors have shown antiviral potencies in various in vivo and in vitro studies. Some of the major possible ways through which they can act against SARS-CoV-2 are by exerting anti-inflammatory and anti-fibrotic effects, via vacuolar ATPase pumps leading to raised endolysosomal pH and by targeting endosomal complexes. The current pandemic has put forward a challenge to find treatment options. Although the potential roles of proton pump inhibitors against SARS-CoV-2 have been discussed in recent publications, the clinical evidences for their real-world effectiveness do not point towards a beneficial effect clearly yet. We suggest that although proton pump inhibitors should strongly be considered as potential therapeutic options for COVID-19, larger studies in the form of randomized controlled trials would be required to arrive at a definite conclusion.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Inibidores da Bomba de Prótons/farmacologia , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/virologia
2.
PLoS One ; 15(8): e0228002, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764831

RESUMO

Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid tumors, but only 13-32% of patients respond to the therapy. Now, it is understood that the rapid rate of topoI degradation in response to irinotecan causes irinotecan resistance. We have published that the deregulated DNA-PKcs kinase cascade ensures rapid degradation of topoI and is at the core of the drug resistance mechanism of topoI inhibitors, including irinotecan. We also identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary upstream regulator of DNA-PKcs in response to topoI inhibitors. Previous reports showed that rabeprazole, a proton pump inhibitor (PPI) inhibits CTDSP1 activity. The purpose of this study was to confirm the effects of rabeprazole on CTDSP1 activity and its impact on irinotecan-based therapy in colon cancer. Using differentially expressing CTDSP1 cells, we demonstrated that CTDSP1 contributes to the irinotecan sensitivity by preventing topoI degradation. Retrospective analysis of patients receiving irinotecan with or without rabeprazole has shown the effects of CTDSP1 on irinotecan response. These results indicate that CTDSP1 promotes sensitivity to irinotecan and rabeprazole prevents this effect, resulting in drug resistance. To ensure the best chance at effective treatment, rabeprazole may not be a suitable PPI for cancer patients treated with irinotecan.


Assuntos
Neoplasias Colorretais/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Rabeprazol/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/fisiopatologia , DNA , DNA Topoisomerases Tipo I/fisiologia , Proteína Quinase Ativada por DNA/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Irinotecano/metabolismo , Irinotecano/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/metabolismo , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol/farmacologia , Estudos Retrospectivos , Inibidores da Topoisomerase I/farmacologia
3.
PLoS One ; 15(7): e0235163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730257

RESUMO

OBJECTIVES: The purpose of this study was to reconfirm the association between the risk of fracture and proton pump inhibitor use and to establish evidence for defining a high-risk group of patients among proton pump inhibitor users. METHODS: A nested case-control study was performed using data from the National Health Insurance Sharing Service database from the period January 2007 to December 2017. The study population included elderly women aged ≥65 years with claims for peptic ulcer or gastro-esophageal reflux disease. The cases were all incidental osteoporotic fractures, and up to two controls were matched to each case by age, osteoporosis, and Charlson comorbidity index. Conditional logistic regression was used to calculate the adjusted odds ratio and 95% confidence interval (CI). RESULTS: A total of 21,754 cases were identified, and 43,508 controls were matched to the cases. The adjusted odds ratio of osteoporotic fractures related to the use of proton pump inhibitors was 1.15 (95% CI: 1.11-1.20). There was a statistically significant interaction between proton pump inhibitor and bisphosphonate use (p<0.01). The risk of fracture in patients using proton pump inhibitors was 1.15 (95% CI: 1.08-1.92) in bisphosphonate users and 1.11 (95% CI: 1.03-1.20) in bisphosphonate non-users. CONCLUSION: Concomitant use of bisphosphonates and proton pump inhibitors will likely increase the risk of osteoporotic fractures in women aged 65 and over, and caution should be exercised in this high-risk group of patients.


Assuntos
Difosfonatos/farmacologia , Refluxo Gastroesofágico/tratamento farmacológico , Fraturas por Osteoporose/epidemiologia , Úlcera Péptica/tratamento farmacológico , Inibidores da Bomba de Prótons/farmacologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Difosfonatos/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Fraturas por Osteoporose/prevenção & controle , Inibidores da Bomba de Prótons/uso terapêutico , República da Coreia/epidemiologia , Fatores de Risco
4.
Toxicology ; 440: 152487, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32418911

RESUMO

Renal toxicity is the primary factor that limits clinical use of cisplatin (CP). A previous study showed that omeprazole (OME) protected against CP-induced toxicity in human renal tubular HK-2 cells and rat kidneys. However, the protective mechanisms of OME have not been characterized. We evaluated the ability of OME to inhibit CP-induced inflammation, and characterized the pathways responsible for this effect. Rats were randomly divided into five groups (n = 10/group). The OME groups were intraperitoneally injected with 1.8 or 3.6 mg OME /kg body weight once daily for 5 days. One hour after final administration of vehicle or OME, all rats (except those in control group and OME alone group) were intraperitoneally injected with 15 mg/kg CP. Twenty-four hours after CP injection, the surgery was applied. The time points and dosing of OME and CP were calculated based on previous studies and the therapeutic dose for patients. Omeprazole attenuated CP-induced apoptosis and damage in vivo and in vitro, as evidenced by increased cell viability and prevention of structural damage. Omeprazole ameliorated CP-induced renal injury through inhibition of NF-κB activation and IκBα degradation, and down-regulation of toll-like receptor 4 (TLR4) and Nod-like receptor protein 3 (NLRP3). Lipopolysaccharide, a TLR4 agonist, was used to verify this mechanism. The results indicated that OME inhibited CP-induced expression of inflammatory proteins, and this effect was blunted by co-treatment with LPS in HK-2 cells. These findings suggested that the protective effects of OME against CP-induced kidney damage may occur through inhibition of the TLR4/NF-κB/NLRP3 signaling pathway. This study provided evidence that OME may be a promising agent to inhibit CP-induced nephrotoxicity.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/prevenção & controle , Antineoplásicos , Cisplatino , NF-kappa B/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Proteínas I-kappa B/efeitos dos fármacos , Testes de Função Renal , Masculino , Ratos , Ratos Sprague-Dawley , Cicatrização/efeitos dos fármacos
5.
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
6.
Bull Cancer ; 107(4): 458-464, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32057465

RESUMO

Proton pump inhibitors, a major progress in gastro-enterology, are globally among the most widely prescribed drugs. But, due to their strong gastric acid inhibition, they can be responsible for side effects, particularly in cancer patients. They are involved in renal function impairment, bone fractures, digestive bacterial overgrowth, particularlyclostridium difficile infections, anemia and hypomagnesemia. Long term use can increase the risks of gastric, pancreatic and liver cancers. They decrease absorption of weak bases drugs, particularly tyrosine kinase inhibitors and capecitabine and are responsible for a poorer prognosis if taken concomitantly with erlotinib, gefitinib and pazopanib. Modification of cyclin dependent kinases is also possible as well as decrease of efficacy of immune check point inhibitors (microbiome modifications). Absoption and efficacy of capecitabine seem also poorer with negative prognosis effect on treatment of gastric and colon cancer. Their long term use, particularly in cancer patients, should probably be avoided.


Assuntos
Neoplasias/complicações , Inibidores da Bomba de Prótons/efeitos adversos , Antineoplásicos/farmacocinética , Infecções Bacterianas/induzido quimicamente , Capecitabina/farmacocinética , Contraindicações de Medicamentos , Interações Medicamentosas , Disbiose/induzido quimicamente , Cloridrato de Erlotinib/administração & dosagem , Fraturas Ósseas/induzido quimicamente , Absorção Gastrointestinal/efeitos dos fármacos , Neoplasias Gastrointestinais/induzido quimicamente , Gefitinibe/administração & dosagem , Humanos , Rim/efeitos dos fármacos , Prognóstico , Proteínas Tirosina Quinases/antagonistas & inibidores , Inibidores da Bomba de Prótons/farmacologia , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem
7.
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
8.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G375-G389, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928220

RESUMO

Mixed acidic-alkaline refluxate is a major pathogenic factor in chronic esophagitis progressing to Barrett's esophagus (BE). We hypothesized that epidermal growth factor (EGF) can interact with COX-2 and peroxisome proliferator-activated receptor-γ (PPARγ) in rats surgically prepared with esophagogastroduodenal anastomosis (EGDA) with healthy or removed salivary glands to deplete salivary EGF. EGDA rats were treated with 1) vehicle, 2) EGF or PPARγ agonist pioglitazone with or without EGFR kinase inhibitor tyrphostin A46, EGF or PPARγ antagonist GW9662 respectively, 3) ranitidine or pantoprazole, and 4) the selective COX-2 inhibitor celecoxib combined with pioglitazone. At 3 mo, the esophageal damage and the esophageal blood flow (EBF) were determined, the mucosal expression of EGF, EGFR, COX-2, TNFα, and PPARγ mRNA and phospho-EGFR/EGFR protein was analyzed. All EGDA rats developed chronic esophagitis, esophageal ulcerations, and intestinal metaplasia followed by a fall in the EBF, an increase in the plasma of IL-1ß, TNFα, and mucosal PGE2 content, the overexpression of COX-2-, and EGF-EGFR mRNAs, and proteins, and these effects were aggravated by EGF and attenuated by pioglitazone. The rise in EGF and COX-2 mRNA was inhibited by pioglitazone but reversed by pioglitazone cotreated with GW9662. We conclude that 1) EGF can interact with PG/COX-2 and the PPARγ system in the mechanism of chronic esophagitis; 2) the deleterious effect of EGF involves an impairment of EBF and the overexpression of COX-2 and EGFR, and 3) agonists of PPARγ and inhibitors of EGFR may be useful in the treatment of chronic esophagitis progressing to BE.NEW & NOTEWORTHY Rats with EGDA exhibited chronic esophagitis accompanied by a fall in EBF and an increase in mucosal expression of mRNAs for EGF, COX-2, and TNFα, and these effects were exacerbated by exogenous EGF and reduced by removal of a major source of endogenous EGF with salivectomy or concurrent treatment with tyrphostin A46 or pioglitazone combined with EGF. Beneficial effects of salivectomy in an experimental model of BE were counteracted by PPARγ antagonist, whereas selective COX-2 inhibitor celecoxib synergistically with pioglitazone reduced severity of esophageal damage and protected esophageal mucosa from reflux. We propose the cross talk among EGF/EGFR, PG/COX-2, and proinflammatory cytokines with PPARγ pathway in the mechanism of pathogenesis of chronic esophagitis progressing to BE and EAC.


Assuntos
Esôfago de Barrett/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Mucosa Esofágica/metabolismo , Esofagite/metabolismo , PPAR gama/metabolismo , Animais , Esôfago de Barrett/tratamento farmacológico , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/patologia , Esofagite/tratamento farmacológico , Esofagite/genética , Esofagite/patologia , Interleucina-1beta/metabolismo , Masculino , PPAR gama/agonistas , PPAR gama/genética , Pioglitazona/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Ratos Wistar , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
Eur J Med Chem ; 188: 112027, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923859

RESUMO

Genetic rearrangements of the mixed lineage leukemia (MLL) leading to oncogenic MLL-fusion proteins (MLL-FPs). MLL-FPs occur in about 10% of acute leukemias and are associated with dismal prognosis and treatment outcomes which emphasized the need for new therapeutic strategies. In present study, by a cell-based screening in-house compound collection, we disclosed that Rabeprazole specially inhibited the proliferation of leukemia cells harboring MLL-FPs with little toxicity to non-MLL cells. Mechanism study showed Rabeprazole down-regulated the transcription of MLL-FPs related Hox and Meis1 genes and effectively inhibited MLL1 H3K4 methyltransferase (HMT) activity in MV4-11 cells bearing MLL-AF4 fusion protein. Displacement of MLL1 probe from WDR5 protein suggested that Rabeprazole may inhibit MLL1 HMT activity through disturbing MLL1-WDR5 protein-protein interaction. Moreover, other proton pump inhibitors (PPIs) also indicated the inhibition activity of MLL1-WDR5. Preliminary SARs showed the structural characteristics of PPIs were also essential for the activities of MLL1-WDR5 inhibition. Our results indicated the drug reposition of PPIs for MLL-rearranged leukemias and provided new insight for further optimization of targeting MLL1 methyltransferase activity, the MLL1-WDR5 interaction or WDR5.


Assuntos
Antineoplásicos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucemia/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia/metabolismo , Leucemia/patologia , Estrutura Molecular , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Ligação Proteica/efeitos dos fármacos , Inibidores da Bomba de Prótons/síntese química , Inibidores da Bomba de Prótons/química , Rabeprazol/síntese química , Rabeprazol/química , Relação Estrutura-Atividade
10.
Acta Pharm ; 70(2): 179-190, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31955147

RESUMO

Breast cancer is the most common cancer and is the leading cause of cancer deaths among women worldwide. Despite the availability of numerous therapeutics for breast cancer management, cytotoxicity and emergence of drug resistance are major challenges that limit their benefits. The acidic microenvironment surrounding tumor cells is a common feature inducing cancer cell invasiveness and chemoresistance. Proton pump inhibitors (PPIs) are one of the most commonly prescribed drugs for the treatment of acid-related conditions. PPIs have been reported to exhibit antitumorigenic effects in many cancer types. In this study, the anti-proliferative and anti-migratory effects of PPIs in three breast cancer cell lines; MCF-7, T47D, and MDA-MB-231 cells, have been investigated. In addition, the combined effects of PPIs with anticancer drugs, as well as the mechanism of PPI-mediated anti-proliferative activity were evaluated. The anti-proliferative and combined effects of PPIs were evaluated by MTT assay. Cell migration was assessed using the wound-healing assay. The mechanism of cell death was assessed using annexin V-FITC/propidium iodide staining flow cytometry method. Our results indicated that PPIs treatment significantly inhibited the growth of breast cancer cells in a dose-dependent manner. The antiproliferative activity of PPIs was significantly induced by apoptosis in all tested cell lines. The combined treatment of PPIs with doxorubicin resulted in a synergistic effect in all cell lines, whereas the combined treatment with raloxifene exhibited synergistic effect in T47D cells only and additive effects in MDA-MB-231 and MCF-7 cells. In addition, PPIs treatment significantly reduced cell migration in MDA-MB-231 cells. In conclusion, the addition of PPIs to the treatment regimen of breast cancer appears to be a promising strategy to potentiate the efficacy of chemotherapy and may suppress cancer metastasis.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Inibidores da Bomba de Prótons/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Microambiente Tumoral/efeitos dos fármacos
11.
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
12.
J Laryngol Otol ; 134(1): 68-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31918788

RESUMO

OBJECTIVE: To determine whether patients would have equivalent or improved outcomes when receiving non-surgical management versus surgical removal for vocal process granulomas. METHODS: A chart review was performed for 53 adults with vocal process granulomas. All patients received baseline anti-reflux treatment consisting of twice-daily proton pump inhibitors and vocal hygiene education. Further treatment approaches were divided into non-surgical (i.e. inhaled corticosteroids, voice therapy, botulinum toxin injections) and surgical groups. Subjective parameters (Voice Handicap Index 10 and Reflux Symptom Index) and outcomes were tabulated and statistically compared. Cause of granuloma was also analysed to determine if this influenced outcomes. RESULTS: Of 53 patients, 47 (89 per cent) experienced reduction in granuloma size, while 37 (70 per cent) experienced complete resolution. The rate of complete granuloma resolution after initial treatment strategy alone was significantly higher in non-surgical compared to surgical patients (67 and 30 per cent, respectively; p = 0.039). No difference in outcome was seen between iatrogenic and idiopathic granulomas. CONCLUSION: Non-surgical patients were more likely to experience initial treatment success than those who underwent surgical removal. Continued emphasis should be placed on conservative treatment options prior to surgery for patients with this condition.


Assuntos
Granuloma/terapia , Laringite/terapia , Inibidores da Bomba de Prótons/uso terapêutico , Prega Vocal/fisiopatologia , Adulto , Idoso , Terapia Combinada , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Otorrinolaringológicos , Inibidores da Bomba de Prótons/farmacologia , Resultado do Tratamento , Prega Vocal/efeitos dos fármacos , Qualidade da Voz/efeitos dos fármacos , Treinamento da Voz
13.
BMJ ; 368: l6744, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907166

RESUMO

OBJECTIVE: To determine, in critically ill patients, the relative impact of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), sucralfate, or no gastrointestinal bleeding prophylaxis (or stress ulcer prophylaxis) on outcomes important to patients. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, trial registers, and grey literature up to March 2019. ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: We included randomised controlled trials that compared gastrointestinal bleeding prophylaxis with PPIs, H2RAs, or sucralfate versus one another or placebo or no prophylaxis in adult critically ill patients. Two reviewers independently screened studies for eligibility, extracted data, and assessed risk of bias. A parallel guideline committee (BMJ Rapid Recommendation) provided critical oversight of the systematic review, including identifying outcomes important to patients. We performed random-effects pairwise and network meta-analyses and used GRADE to assess certainty of evidence for each outcome. When results differed between low risk and high risk of bias studies, we used the former as best estimates. RESULTS: Seventy two trials including 12 660 patients proved eligible. For patients at highest risk (>8%) or high risk (4-8%) of bleeding, both PPIs and H2RAs probably reduce clinically important gastrointestinal bleeding compared with placebo or no prophylaxis (odds ratio for PPIs 0.61 (95% confidence interval 0.42 to 0.89), 3.3% fewer for highest risk and 2.3% fewer for high risk patients, moderate certainty; odds ratio for H2RAs 0.46 (0.27 to 0.79), 4.6% fewer for highest risk and 3.1% fewer for high risk patients, moderate certainty). Both may increase the risk of pneumonia compared with no prophylaxis (odds ratio for PPIs 1.39 (0.98 to 2.10), 5.0% more, low certainty; odds ratio for H2RAs 1.26 (0.89 to 1.85), 3.4% more, low certainty). It is likely that neither affect mortality (PPIs 1.06 (0.90 to 1.28), 1.3% more, moderate certainty; H2RAs 0.96 (0.79 to 1.19), 0.9% fewer, moderate certainty). Otherwise, results provided no support for any affect on mortality, Clostridium difficile infection, length of intensive care stay, length of hospital stay, or duration of mechanical ventilation (varying certainty of evidence). CONCLUSIONS: For higher risk critically ill patients, PPIs and H2RAs likely result in important reductions in gastrointestinal bleeding compared with no prophylaxis; for patients at low risk, the reduction in bleeding may be unimportant. Both PPIs and H2RAs may result in important increases in pneumonia. Variable quality evidence suggested no important effects of interventions on mortality or other in-hospital morbidity outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019126656.


Assuntos
Estado Terminal/terapia , Hemorragia Gastrointestinal , Antagonistas dos Receptores Histamínicos H2/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/prevenção & controle , Humanos , Seleção de Pacientes , Risco Ajustado/métodos
14.
Nat Commun ; 11(1): 362, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953381

RESUMO

The human gut microbiota has now been associated with drug responses and efficacy, while chemical compounds present in these drugs can also impact the gut bacteria. However, drug-microbe interactions are still understudied in the clinical context, where polypharmacy and comorbidities co-occur. Here, we report relations between commonly used drugs and the gut microbiome. We performed metagenomics sequencing of faecal samples from a population cohort and two gastrointestinal disease cohorts. Differences between users and non-users were analysed per cohort, followed by a meta-analysis. While 19 of 41 drugs are found to be associated with microbial features, when controlling for the use of multiple medications, proton-pump inhibitors, metformin, antibiotics and laxatives show the strongest associations with the microbiome. We here provide evidence for extensive changes in taxonomy, metabolic potential and resistome in relation to commonly used drugs. This paves the way for future studies and has implications for current microbiome studies by demonstrating the need to correct for multiple drug use.


Assuntos
Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Metagenômica , Adulto , Antibacterianos/farmacologia , Antidepressivos/farmacologia , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos de Coortes , Biologia Computacional , Ecossistema , Fezes/microbiologia , Feminino , Humanos , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/microbiologia , Laxantes/farmacologia , Masculino , Metformina/farmacologia , Interações Microbianas/efeitos dos fármacos , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/farmacologia
15.
Gastroenterology ; 158(5): 1250-1261.e2, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31866243

RESUMO

BACKGROUND & AIMS: There are few data on the prevalence of gastroesophageal reflux disease (GERD) in the United States. We performed a population-based study to determine the prevalence of GERD symptoms and persistent GERD symptoms despite use of proton pump inhibitors (PPIs). METHODS: We conducted the National Gastrointestinal Survey in 2015 using MyGiHealth, an app that guides participants through National Institutes of Health gastrointestinal Patient-Reported Outcomes Measurement Information System surveys. Primary outcomes were prevalence of GERD symptoms in the past and persistence of GERD symptoms (heartburn or regurgitation 2 or more days in past week) among participants taking PPIs. Population weights were applied to the data and multivariable regression was used to adjust for confounding. RESULTS: Among 71,812 participants, 32,878 (44.1%) reported having had GERD symptoms in the past and 23,039 (30.9%) reported having GERD symptoms in the past week. We also found that 35.1% of those who had experienced GERD symptoms were currently on therapy (55.2% on PPIs, 24.3% on histamine-2 receptor blockers, and 24.4% on antacids). Among 3229 participants taking daily PPIs, 54.1% had persistent GERD symptoms. Younger individuals, women, Latino individuals, and participants with irritable bowel syndrome or Crohn's disease were more likely to have continued symptoms, even when taking PPIs. CONCLUSIONS: Using a population-based survey, we found GERD symptoms to be common: 2 of 5 participants have had GERD symptoms in the past and 1 of 3 had symptoms in the past week. We also found that half of PPI users have persistent symptoms. Given the significant effect of GERD on quality of life, further research and development of new therapies are needed for patients with PPI-refractory GERD symptoms.


Assuntos
Refluxo Gastroesofágico/epidemiologia , Inquéritos Epidemiológicos/estatística & dados numéricos , Medidas de Resultados Relatados pelo Paciente , Inibidores da Bomba de Prótons/farmacologia , Adolescente , Adulto , Estudos de Coortes , Resistência a Medicamentos , Feminino , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Inibidores da Bomba de Prótons/uso terapêutico , Qualidade de Vida , Estados Unidos/epidemiologia , Adulto Jovem
16.
Expert Opin Ther Pat ; 30(1): 15-25, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31847622

RESUMO

Introduction: Worldwide, the annual expenditure on anticancer drugs is grossly calculated to be in the order of US$100 billion, and is expected to escalate up to $150 billion by 2020. It is evident that the vast majority of the most recently devised anticancer drugs are unaffordable in economically developing nations, frequently resulting in subpar therapies. In this complex medical and economic scenario, the repurposing of older drugs for anticancer therapies becomes a necessity. The repurposing of antiacid drugs such as the proton pump inhibitors as antitumoral agents and chemosensitizers is probably one of the most recent and promising phenomenon in oncology.Areas covered: Important research articles and patents focusing on proton pump inhibitors as a potential class of therapeutics, published between the period of 2006-2019, have been covered. This review mainly focuses on the therapeutic applications, as direct anticancer agents as well as modifiers of the tumor microenvironment and modulator of chemoresistance.Expert opinion: PPIs have significant anticancer applications and are proving to be safe, effective and inexpensive. Here the authors review the current knowledge regarding the influence of PPIs on the efficacy and safety of cancer chemotherapeutics through the regulation of targets other than the H+/K+-ATPase.


Assuntos
Antineoplásicos/farmacologia , Reposicionamento de Medicamentos , Inibidores da Bomba de Prótons/farmacologia , Animais , Antineoplásicos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Patentes como Assunto , Inibidores da Bomba de Prótons/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos
17.
Int J Mol Sci ; 20(23)2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31795477

RESUMO

Gastric juice is a unique combination of hydrochloric acid (HCl), lipase, and pepsin. Acidic gastric juice is found in all vertebrates, and its main function is to inactivate microorganisms. The phylogenetic preservation of this energy-consuming and, at times, hazardous function (acid-related diseases) reflects its biological importance. Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world. Due to the reduced prevalence of Helicobacter pylori infection as well as the increased use of inhibitors of gastric acid secretion, the latter has become the most important cause of gastric hypoacidity. In the present manuscript, we review the microbiological consequences of removing gastric acidity. The resulting susceptibility to infections has not been studied extensively, and focus has mainly been restricted to bacterial and parasitic agents only. The strongest evidence concerning the relationship between hypochlorhydria and predisposition to infections relates to bacterial infections affecting the gastrointestinal tract. However, several other clinical settings with increased susceptibility to infections due to inhibited gastric acidity are discussed. We also discuss the impact of hypochlorhydria on the gut microbiome.


Assuntos
Acloridria/induzido quimicamente , Ácido Gástrico/metabolismo , Suco Gástrico/efeitos dos fármacos , Suco Gástrico/microbiologia , Inibidores da Bomba de Prótons/efeitos adversos , Acloridria/complicações , Acloridria/metabolismo , Animais , Infecções Bacterianas/etiologia , Suco Gástrico/metabolismo , Gastroenteropatias/etiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Infecções/etiologia , Inibidores da Bomba de Prótons/farmacologia
18.
Curr Gastroenterol Rep ; 21(12): 65, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31807948

RESUMO

PURPOSE OF REVIEW: Proton pump inhibitors (PPIs) are one of the most prescribed drugs in the developed world and elderly patients are particularly likely to be prescribed acid suppression. There have been reports of many diseases being associated with PPI therapy and the elderly would be particular at risk of any harms these drugs may cause. This review therefore reviews the evidence of the risks and benefits of these drugs. RECENT FINDINGS: PPIs are very effective at treating acid-related disorders. Recent randomized trials have suggested that the associations between PPI and various diseases are likely to be related to bias and residual confounding and these drugs appear to be safe apart from a possible increase risk of enteric infections. PPIs should be used at the lowest dose and for the shortest duration possible. They are still relatively safe drugs but should only be prescribed for proven indications.


Assuntos
Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/prevenção & controle , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Fatores Etários , Idoso , Interações Medicamentosas , Gastroenteropatias/etiologia , Humanos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , Medição de Risco , Fatores de Risco , Fatores de Tempo
19.
Cleve Clin J Med ; 86(12): 799-806, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31821137

RESUMO

Functional heartburn--persistent symptoms of esophageal reflux with no objective evidence of gastroesophageal reflux disease (GERD)--is the most common cause of failure of proton pump inhibitor (PPI) therapy, but it is often overlooked by internists and gastroenterologists.


Assuntos
Refluxo Gastroesofágico , Azia/diagnóstico , Administração dos Cuidados ao Paciente/métodos , Inibidores da Bomba de Prótons/farmacologia , Diagnóstico Diferencial , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/etiologia , Refluxo Gastroesofágico/fisiopatologia , Refluxo Gastroesofágico/terapia , Humanos
20.
Artigo em Inglês | MEDLINE | ID: mdl-31785730

RESUMO

Acute upper gastrointestinal bleeding (UGIB) remains a public health burden with a persistent high mortality despite advances in modern day management. Proton pump inhibitors (PPI) as medical therapy is an attractive adjuvant to endoscopic treatment in UGIB but the method and dose of PPI therapy remains controversial. This chapter aims to describe the current evidence addressing acute PPI use in the management of UGIB. It will explore the evidence behind the timing, the dosage and the mode of administration of PPI during initial UGIB management, prior to and immediately following endoscopy, as well as in the short-term following discharge.


Assuntos
Hemorragia Gastrointestinal/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Humanos , Inibidores da Bomba de Prótons/farmacologia
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