RESUMEN
AIMS: Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo. METHODS: Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo. RESULTS: Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. CONCLUSIONS: These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.
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Subfamilia B de Transportador de Casetes de Unión a ATP , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Lansoprazol , Lisosomas , Ratones Desnudos , Inhibidores de la Bomba de Protones , Ensayos Antitumor por Modelo de Xenoinjerto , Lansoprazol/farmacología , Animales , Humanos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones , Inhibidores de la Bomba de Protones/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Simulación del Acoplamiento Molecular , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Proteínas de NeoplasiasRESUMEN
BACKGROUND: The mechanism by which proton pump inhibitors (PPIs) alter gut microbiota remains to be elucidated. We aimed to learn whether PPI induced gut microbiota alterations by promoting oral microbial translocation. METHODS: Healthy adult volunteers were randomly assigned: PP group (n=8, 40 mg esomeprazole daily for seven days) and PM group (n=8, 40 mg esomeprazole along with chlorhexidine mouthwash after each meal for seven days). Fecal and saliva samples were analysed using 16S ribosomal RNA sequencing. Mouse models were introduced to confirm the findings in vivo, while the effect of pH on oral bacteria proliferation activity was investigated in vitro. RESULTS: Taxon-based analysis indicated that PPI administration increased Streptococcus abundance in gut microbiota (P<0.001), and the increased species of Streptococcus were found to be from the oral site or oral/nasal sites, in which Streptococcus anginosus was identified as the significantly changed species (P<0.004). Microbial source tracker revealed that PPI significantly increased the contribution of oral bacteria to gut microbiota (P=0.026), and no significant difference was found in PM group (P=0.467). Compared to the baseline, there was a 42-fold increase in gut abundance of Streptococcus anginosus in PP group (P=0.002), and the times decreased to 16-fold in PM group (P=0.029). Mouse models showed that combination of PPI and Streptococcus anginosus significantly increased the gut abundance of Streptococcus anginosus compared with using PPI or Streptococcus anginosus only. Furthermore, Streptococcus anginosus cannot survive in vitro at a pH lower than 5. CONCLUSIONS: PPIs altered gut microbiota by promoting oral-originated Streptococcus translocation into gut.
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Esomeprazol , Heces , Microbioma Gastrointestinal , Inhibidores de la Bomba de Protones , Saliva , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Adulto Joven , Traslocación Bacteriana/efectos de los fármacos , Clorhexidina/farmacología , Esomeprazol/farmacología , Heces/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Voluntarios Sanos , Concentración de Iones de Hidrógeno , Boca/microbiología , Antisépticos Bucales/farmacología , Estudios Prospectivos , Inhibidores de la Bomba de Protones/farmacología , ARN Ribosómico 16S , Saliva/microbiología , Streptococcus anginosus/efectos de los fármacos , Streptococcus anginosus/aislamiento & purificaciónRESUMEN
INTRODUCTION: Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett's cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett's oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids. METHODS: 15 BO patients had endoscopy with biopsies of Barrett's metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1α was knocked down with siRNA or shRNA. RESULTS: At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1α, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1α activation, which decreased miR-200a&b while increasing VEGF, ZEB1 and motility; HIF-1α knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1α, increased VEGF and decreased miR-200a&b. CONCLUSIONS: In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1α signalling in Barrett's metaplasia. In Barrett's cells, ABS trigger EMP via HIF-1α signalling. Thus, HIF-1α appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO. TRIAL REGISTRATION NUMBER: NCT02579460.
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Esófago de Barrett , Transición Epitelial-Mesenquimal , Subunidad alfa del Factor 1 Inducible por Hipoxia , Inhibidores de la Bomba de Protones , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esófago de Barrett/patología , Esófago de Barrett/metabolismo , Esófago de Barrett/genética , Movimiento Celular , Esofagitis Péptica/patología , Esofagitis Péptica/metabolismo , Esofagitis Péptica/etiología , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genéticaRESUMEN
BACKGROUND: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment. PATIENTS AND METHODS: This multicenter, retrospective, observational study, conducted across 4 medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio. RESULTS: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival period was 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% CI, 0.70-2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61-2.47). Consistent results were obtained for subgroups receiving palbociclib (nâ =â 177) and abemaciclib (nâ =â 63) without propensity score matching. Adverse event incidence and severity were similar in both groups. CONCLUSION: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.
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Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidores de la Bomba de Protones , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/administración & dosificación , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Piperazinas/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/farmacología , Piperazinas/administración & dosificación , Aminopiridinas/uso terapéutico , Aminopiridinas/farmacología , Aminopiridinas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/uso terapéutico , Piridinas/farmacología , Piridinas/efectos adversos , Piridinas/administración & dosificación , Bencimidazoles/uso terapéutico , Bencimidazoles/farmacología , Bencimidazoles/efectos adversos , Adulto , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Proton-pump inhibitors (PPIs) prevent aspirin-associated gastric and duodenal mucosal damage. However, long-term use of PPIs can lead to various adverse reactions, such as gastric polyps and enterochromaffin-like cell hyperplasia. Current research indicates that the abovementioned adverse reactions are mainly related to hypergastrinemia. We investigated whether low-frequency administration of omeprazole could effectively repair aspirin-induced mucosal damage and reduce the increase in gastrin levels associated with long-term use of PPIs. METHODS: SpragueâDawley rats were divided into four treatment groups: daily aspirin, daily aspirin and omeprazole once every day (qd), daily aspirin and omeprazole once every other day (qod), and daily aspirin and omeprazole once every three days (1/d3). After 15 days of feeding, blood samples were collected, and the stomachs of sacrificed rats were subjected to macroscopic, histological, and immunohistochemical studies. Moreover, in clinical practice, patients with peptic ulcers caused by aspirin took a standard dose of omeprazole (20 mg) every other day. Two months later, gastroscopy was performed to examine the healing of the ulcers. RESULTS: Both the omeprazole qd and omeprazole qod administrations effectively prevented aspirin-induced gastric peptic ulcers, with no significant difference between the two groups in the inhibition of parietal cell secretion of gastric acid and cell apoptosis. However, omeprazole 1/d3 failed to completely prevent aspirin-induced gastric mucosal injury. Notably, the gastrin levels, cell proliferation ability and cholecystokinin B receptor expression of the omeprazole qd group were significantly higher than those of the omeprazole qod group. In clinical work, patients with peptic ulcers caused by aspirin were given a standard dose of omeprazole every other day, and their ulcers healed after 2 months, as observed by gastroscopy. CONCLUSIONS: Omeprazole administration once every other day can effectively prevent aspirin-induced peptic ulcers and reduce hypergastrinemia, which may reduce the long-term adverse effects of PPI treatment.
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Aspirina , Mucosa Gástrica , Gastrinas , Omeprazol , Inhibidores de la Bomba de Protones , Ratas Sprague-Dawley , Animales , Aspirina/efectos adversos , Aspirina/administración & dosificación , Omeprazol/farmacología , Omeprazol/administración & dosificación , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/administración & dosificación , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Gastrinas/sangre , Masculino , Ratas , Esquema de Medicación , Humanos , Úlcera Péptica/prevención & control , Úlcera Péptica/inducido químicamente , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Úlcera Gástrica/prevención & control , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patologíaRESUMEN
OBJECTIVE: This study evaluates the impact of a representative proton pump inhibitor (PPI) (omeprazole), administered simultaneously or staggered, on the pharmacokinetics of levothyroxine (LT4) solution (Tirosint-SOL). METHODS: This was a randomized, 3-way crossover, comparative bioavailability study in 36 healthy adults under fasting conditions. Omeprazole 40 mg delayed-release capsule was administered once daily from Day 1 to 6 (mornings, Treatment-A; evenings, Treatment-B; none, Treatment-C) to increase and stabilize gastric pH. In the morning of Day 5, a single dose of LT4 solution 600 mcg was administered. Blood samples were collected 0 to 48 hours post-LT4 administration. Noncompartmental pharmacokinetic parameters were calculated for total serum thyroxine using baseline-corrected data. Maximum concentration (Cmax) and area under the concentration-time curve (AUC0-48) were included in an analysis of variance to obtain geometric mean ratios and 90% confidence intervals. RESULTS: For both comparisons (A/C and B/C), geometric mean ratios and 90% confidence intervals for all parameters were within the equivalence boundaries (80%-125%), indicating bioequivalence: for A/C, AUC0-48 98.98% [94%-104%], and Cmax 91.68% [87%-97%]; for B/C, AUC0-48 98.94% [95%-103%], and Cmax 94.90% [90%-100%]. Median Tmax (time associated with Cmax) was similar across treatments. CONCLUSION: This study demonstrated that Tirosint-SOL bioavailability is unaffected by coadministration of a representative PPI, given simultaneously or staggered by about 12 hours, compared to administration of LT4 solution alone. For hypothyroid patients on PPI therapy, administration of LT4 solution may reduce variations in thyroid stimulating hormone levels related to intermittent use of acid-reducing drugs and consequently the need for dose adjustments.
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Disponibilidad Biológica , Estudios Cruzados , Omeprazol , Inhibidores de la Bomba de Protones , Tiroxina , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Interacciones Farmacológicas , Omeprazol/farmacocinética , Omeprazol/administración & dosificación , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/farmacocinética , Inhibidores de la Bomba de Protones/farmacología , Tiroxina/farmacocinética , Tiroxina/administración & dosificación , Tiroxina/sangreRESUMEN
This systematic review and meta-analysis evaluated the efficacy of dexlansoprazole (a proton pump inhibitor-PPI) in resolving heartburn, reflux, and other symptoms and complications resulting from gastroesophageal reflux disease (GERD). The study followed PRISMA 2020 and was registered in PROSPERO (CRD42020206513). The search strategy used MeSH and free terms appropriately adapted for each database. Only randomized clinical trials (RCTs) were included. The Cochrane tool (RoB 2.0) was used to assess the risk of bias, and the certainty of evidence was rated using GRADE. Ten RCTs were included. Dexlansoprazole outperformed the placebo and other PPIs in the resolution of heartburn and reflux symptoms in patients with GERD, with benefits during and after treatment, especially in those with moderate and severe symptoms. The meta-analyses indicated that dexlansoprazole at doses of 30 and 60 mg had more 24 h heartburn-free days and nights compared to the placebo medications; no difference was reported between dexlansoprazole at doses of 30 and 60 mg in heartburn-free nights. A low bias risk and a moderate certainty of evidence were observed. This review confirms the therapeutic effect of dexlansoprazole (placebo-controlled) and its improvements in GERD symptoms compared to another PPI. However, the interpretation of the results should be carried out cautiously due to the small number of included studies and other reported limitations.
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Dexlansoprazol , Reflujo Gastroesofágico , Inhibidores de la Bomba de Protones , Humanos , Dexlansoprazol/uso terapéutico , Reflujo Gastroesofágico/tratamiento farmacológico , Pirosis/inducido químicamente , Pirosis/tratamiento farmacológico , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Resultado del TratamientoRESUMEN
Pazopanib exhibits pH-dependent solubility and its absorption depends primarily on the stomach pH. Significant decrease of pazopanib absorption by coadministration with proton pump inhibitors in clinical situation need to be overcome. Thus, the purpose of this study is firstly to investigate the effect of acidic beverages and sodium citrate buffer on the solubility of pazopanib and secondly to examine the effect of sodium citrate buffer on pazopanib absorption in a rat model with esomeprazole-mediated gastric acid suppression. Pazopanib solubility decreased with increasing pH of sodium citrate buffer in vitro. Interestingly, its solubility in some acidic beverages was significantly lower than that in sodium citrate buffer of the same pH. The AUC0-24h of pazopanib administered in tap water to rats treated with esomeprazole (ESP rats) was 66 % lower than that in the control rats treated with saline. However, AUC0-24h was 4.8 times higher in ESP rats that received pazopanib with sodium citrate buffer (pH 2.3) compared to ESP rats that received pazopanib with tap water. Our results indicate that the drug-drug interactions between pazopanib and proton pump inhibitors can be overcome, at least in part, by suspending pazopanib in sodium citrate buffer.
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Esomeprazol , Indazoles , Inhibidores de la Bomba de Protones , Pirimidinas , Sulfonamidas , Ratas , Animales , Inhibidores de la Bomba de Protones/farmacología , Esomeprazol/farmacología , Citrato de Sodio , Solubilidad , Ácido Gástrico , Sodio , Agua , Concentración de Iones de HidrógenoRESUMEN
Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D2 receptor (D2R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D2R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD.
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Trastorno Obsesivo Compulsivo , Inhibidores de la Bomba de Protones , Ratones , Animales , Quinpirol/farmacología , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/etiología , Neuronas , Concentración de Iones de HidrógenoRESUMEN
Abomasal ulcers are recognized in sheep of all ages, but research regarding therapeutic interventions is limited. Proton Pump Inhibitors (PPIs) such as pantoprazole, are clinically used with a paucity of evidence regarding efficacy in mature sheep. Intravenous and subcutaneously administered pantoprazole dosed at 1.0 mg/kg in adult sheep will increase the pH of abomasal fluid compared to pre-administration baseline. The objectives were to assess the effect of pantoprazole, after single and multiple administration, on abomasal fluid pH in adult sheep. A third objective was to describe the pharmacokinetic parameters of IV and SC pantoprazole. Four clinically healthy adult Southdown ewes previously fitted with a gastrostomy tube in the abomasum were utilized in this randomized, 2-way cross-over trial. Ewes received pantoprazole (1.0 mg/kg) as a single and 3-dose regimen (every 24 hours). After a 10 day washout period the reverse treatment was applied. Blood for analysis of pantoprazole concentration was collected intermittently for 24 hours, and abomasal fluid pH was measured at intervals for a 96-hour period. The pH of the abomasal fluid was higher in pantoprazole treatments for up to 24 hours after dosing. Following intravenous administration of pantoprazole to study ewes, elimination half-life, volume of distribution, and clearance of pantoprazole was estimated as 3.29 hours, 0.35 L/kg, and 65.26 mL/hr/kg respectively. After subcutaneous dosing, maximum concentration, time to maximum concentration, half-life of elimination, and volume of distribution, were estimated as 2604 ng/mL, 0.55 hours, 2.48 hours, and 0.37 L/kg. Additionally, the bioavailability was estimated as 83.33%. Pantoprazole administered IV or SC may be useful for treatment or prevention of abomasal ulcers in adult sheep.
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Pantoprazol , Animales , Pantoprazol/farmacocinética , Pantoprazol/administración & dosificación , Ovinos , Femenino , Inyecciones Subcutáneas , Concentración de Iones de Hidrógeno , Inhibidores de la Bomba de Protones/farmacocinética , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/farmacología , Abomaso/efectos de los fármacos , Administración Intravenosa , Estudios Cruzados , Inyecciones IntravenosasRESUMEN
Introduction: Azole resistance has been increasingly reported and become an issue for clinical managements of invasive mycoses. New strategy with combination therapy arises as a valuable and promising alternative option. The aim of the present study is to investigate the in vitro combinational effect of proton pump inhibitors (PPIs) and azoles against pathogenic fungi. Methods: In vitro interactions of PPIs including omeprazole (OME), lansoprazole (LAN), pantoprazole (PAN), and rabeprazole (RAB), and commonly used azoles including itraconazole (ITC), posaconazole (POS), voriconazole (VRC) and fluconazole (FLC), were investigated via broth microdilution chequerboard procedure adapted from the CLSI M27-A3 and M38-A2. A total of 67 clinically isolated strains, namely 27 strains of Aspergillus spp., 16 strains of Candida spp., and 24 strains of dematiaceous fungi, were studied. C. parapsilosis (ATCC 22019) and A. flavus (ATCC 204304) was included to ensure quality control. Results: PPIs individually did not exert any significant antifungal activity. The combination of OME with ITC, POS, or VRC showed synergism against 77.6%, 86.6%, and 4% strains of tested pathogenic fungi, respectively, while synergism of OME/FLC was observed in 50% strains of Candida spp. Synergism between PAN and ITC, POS, or VRC was observed against 47.8%, 77.6% and 1.5% strains of tested fungi, respectively, while synergism of PNA/FLC was observed in 50% strains of Candida spp. Synergism of LAN with ITC, POS, or VRC was observed against 86.6%, 86.6%, and 3% of tested strains, respectively, while synergism of LAN/FLC was observed in 31.3% strains of Candida spp. Synergy of the combination of RAB with ITC, POS, or VRC was observed against 25.4%, 64.2%, and 4.5% of tested strains, respectively, while synergism of RAB/FLC was observed in 12.5% of Candida spp.. Among PPIs, synergism was least observed between RAB and triazoles, while among triazoles, synergism was least observed between VRC and PPIs. Among species, synergy was much more frequently observed in Aspergillus spp. and dematiaceous fungi as compared to Candida spp. Antagonism between PPIs with ITC or VRC was occasionally observed in Aspergillus spp. and dematiaceous fungi. It is notable that PPIs combined with azoles showed synergy against azole resistant A. fumigatus, and resulted in category change of susceptibility of ITC and POS against Candida spp. Discussion: The results suggested that PPIs combined with azoles has the potential to enhance the susceptibilities of azoles against multiple pathogenic fungi and could be a promising strategy to overcome azole resistance issues. However, further investigations are warranted to study the combinational efficacy in more isolates and more species, to investigate the underlying mechanism of interaction and to evaluate the potential for concomitant use of these agents in human.
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Azoles , Inhibidores de la Bomba de Protones , Humanos , Azoles/farmacología , Inhibidores de la Bomba de Protones/farmacología , Hongos , Antifúngicos/farmacología , Triazoles/farmacología , Voriconazol/farmacología , Fluconazol/farmacología , Candida , Aspergillus , Candida parapsilosis , Pruebas de Sensibilidad Microbiana , Farmacorresistencia FúngicaRESUMEN
We elucidated the efficacy of gut microbiome-altering drugs on pembrolizumab efficacy in patients with metastatic urothelial carcinoma (mUC). Clinical data were analyzed retrospectively from 133 patients with mUC who received second-line pembrolizumab therapy between January 2018 and January 2021, following failed platinum-based chemotherapy. We evaluated the effects of gut microbiome-altering drugs (proton pump inhibitors [PPI]/potassium-competitive acid blockers [P-CAB], H2 blockers, antibiotics, non-steroidal anti-inflammatory drugs [NSAIDs], metformin, antipsychotics, steroids, and opioids), taken by patients within 30 days before/after pembrolizumab treatment, on progression-free survival (PFS) and overall survival (OS). Fifty-one patients received PPI/P-CAB (37/14, respectively); H2 blockers, 7; antibiotics, 35; NSAIDs, 22; antipsychotics, 8; metformin, 3; steroids, 11; and opioids, 29. Kaplan-Meier curves revealed PPI or P-CAB users showed shorter PFS than non-PPI-P-CAB users (p = 0.001, p = 0.005, respectively). Multivariate analysis highlighted PPI/P-CAB use as the only independent prognostic factor for disease progression (hazards ratio: 1.71, 95% confidence interval: 1.14-2.07, p = 0.010) but not death (p = 0.177). Proton pump inhibitors/potassium-competitive acid blockers may decrease the efficacy of pembrolizumab therapy for mUC, possibly via gut microbiome modulation.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Células Transicionales , Metformina , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/patología , Antibacterianos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Esteroides/uso terapéutico , Metformina/uso terapéuticoRESUMEN
Ulcer disorders including the oral mucosa, large intestine, and stomach mucosa, cause significant global health burdens. Conventional treatments such as non-steroid anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), histamine H2 receptor antagonists (H2RAs), and cytoprotective agents have drawbacks like mucosal injury, diminish gastric acid secretion, and interact with concurrent medications. Therefore, alternative therapeutic approaches are needed to tackle this health concern. Plants are rich in active metabolites in the bark, roots, leaves, fruits, and seeds, and have been utilized for medicinal purposes since ancient times. The use of herbal therapy is crucial, and regulations are necessary to ensure the quality of products, particularly in randomized studies, to assess their efficacy and safety in treating ulcer disorders. This study aims to explore the anti-ulcer activity of medicinal plants in treating peptic ulcer disease, ulcerative colitis, and aphthous ulcers. Articles were searched in Scopus and PubMed, and filtered for publication from 2013 to 2023, resulting in a total of 460 from Scopus and 239 from PubMed. The articles were further screened by title and abstract and resulted in 55 articles. Natural products, rich in active metabolites, were described to manage ulcer disease by protecting the mucosa, reducing ulcer effects, inhibiting pro-inflammatory factors, and reducing bacterial load, thus improving patients' quality of life. Natural extracts have proven effective in managing other health problems, including ulcers by reducing pain and decreasing lesions. This review provides an overview of preclinical and clinical studies on medicinal plants, focusing on their effectiveness in treating conditions like peptic ulcers, ulcerative colitis, and aphthous ulcers.
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Antiulcerosos , Colitis Ulcerosa , Úlcera Péptica , Estomatitis Aftosa , Humanos , Úlcera , Colitis Ulcerosa/tratamiento farmacológico , Estomatitis Aftosa/tratamiento farmacológico , Calidad de Vida , Úlcera Péptica/tratamiento farmacológico , Antiulcerosos/farmacología , Antiulcerosos/uso terapéutico , Antagonistas de los Receptores H2 de la Histamina , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéuticoRESUMEN
Gastroesophageal reflux disease (GERD) and Helicobacter pylori (H. pylori) infection are different disease states that are united by the core role of acid suppression in their management. In GERD, proton pump inhibitors (PPIs) have long been standard therapy based on abundant positive clinical trial data supporting their efficacy and safety. In H. pylori, PPIs are also a critical element of therapy in combination with 1 or more antibiotics to achieve and maintain a pH that maximizes the efficacy of therapy. Despite the considerable clinical success and widespread use of PPIs, room remains for agents with differentiated pharmacokinetic and pharmacodynamic profiles. The potassium-competitive acid blockers (PCABs) are mechanistically distinct from PPIs but are acid-stable and do not require activation of the proton pump by coadministration of food. In pharmacodynamic studies, these agents have shown greater durations of acid suppression above the critical threshold of pH 4 (for GERD) and pH 6 (for H. pylori), which have been shown to optimize therapeutic efficacy in these settings. These results have translated in clinical studies to similar and, in some cases, improved outcomes relative to PPIs in these disease states. This review summarizes current knowledge on the physiology of acid secretion, pathophysiology and management of GERD and H. pylori, and key characteristics and clinical trial data for PPIs and PCABs.
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Reflujo Gastroesofágico , Infecciones por Helicobacter , Helicobacter pylori , Inhibidores de la Bomba de Protones , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Helicobacter pylori/efectos de los fármacos , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/farmacología , Infecciones por Helicobacter/tratamiento farmacológico , Ácido Gástrico/metabolismo , Concentración de Iones de Hidrógeno , Antibacterianos/uso terapéutico , Antibacterianos/farmacologíaRESUMEN
BACKGROUND: Acid suppressant drugs (ASDs) are commonly used to decrease gastric acid production, but some evidence exists that ASDs exert immunomodulatory effects. Such an effect has not been investigated in dogs for which ASDs are routinely prescribed. HYPOTHESIS: Compared to naïve subjects, dogs treated with ASDs will exhibit differences in leukocyte ratios after treatment. ANIMALS: Fifty-one dogs with mast cell tumors (MCTs). MATERIALS AND METHODS: Dogs with MCT that were either AS naïve or treated with ASDs (i.e., histamine-2-receptor antagonists [H2RA] or proton pump inhibitors [PPI]) were included in this retrospective study. Subjects were categorized into 3 treatment groups (AS naïve, H2RA treated, and PPI treated), and leukocyte ratios (neutrophil:eosinophil, lymphocyte:monocyte, and neutrophil:lymphocyte [NLR]) were calculated before and after treatment. A mixed effects analysis of variance on ranks was used to assess differences in ratios between treatments, between pre- and post-treatment time points, and between pre- and post-time points for each treatment. Concurrent administration of antihistamines, corticosteroids, and chemotherapeutic drugs was assessed as a confounding factor. RESULTS: Famotidine (n = 14/14) and omeprazole (n = 12/12) were the only H2RA and PPI used, respectively. Dogs receiving famotidine had a significant increase in median NLR from pre- to post-treatment (3.429; range, 1.417-15 to 5.631; range, 2.654-92; P < 0.01) compared to PPI treated or AS naïve dogs. No differences existed in chemotherapeutic drug or corticosteroid use between groups. CONCLUSIONS: A significant difference in NLR was identified in famotidine treated dogs compared with omeprazole treated or AS naïve dogs.
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Enfermedades de los Perros , Famotidina , Antagonistas de los Receptores H2 de la Histamina , Omeprazol , Inhibidores de la Bomba de Protones , Animales , Perros , Enfermedades de los Perros/tratamiento farmacológico , Estudios Retrospectivos , Famotidina/uso terapéutico , Famotidina/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Femenino , Masculino , Omeprazol/uso terapéutico , Omeprazol/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/farmacología , Recuento de Leucocitos/veterinaria , Mastocitoma/veterinaria , Mastocitoma/tratamiento farmacológicoRESUMEN
Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25-2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38⯵M. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.
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Linezolid , Trombocitopenia , Linezolid/efectos adversos , Linezolid/farmacocinética , Humanos , Trombocitopenia/inducido químicamente , Trombocitopenia/metabolismo , Células HEK293 , Animales , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Ratas , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/farmacología , Lansoprazol/farmacología , Transporte Biológico , Ratas Sprague-Dawley , Factores de Riesgo , Adulto , Transportadores de Anión Orgánico Sodio-Independiente/metabolismoRESUMEN
The study investigates the potential of lansoprazole, a proton pump inhibitor, to interfere with fungal respiration and enhance the antifungal activity of amphotericin B against multidrug-resistant Candida auris. The authors administered lansoprazole at concentrations significantly higher than typical therapeutic doses, which demonstrated promising results but also raised concerns about potential toxicity. We suggest incorporating a control group, monitoring toxicity indicators, performing pathological examinations, and conducting cellular assays to improve the study's rigor and reliability. We also highlight the need for further research into the mechanisms of lansoprazole's antifungal activity, its long-term effects on amphotericin B resistance, and potential drug-drug interactions with amphotericin B. Addressing these concerns is crucial for the clinical translation of lansoprazole as an adjuvant to amphotericin B.
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Anfotericina B , Antifúngicos , Candida auris , Farmacorresistencia Fúngica Múltiple , Sinergismo Farmacológico , Lansoprazol , Pruebas de Sensibilidad Microbiana , Lansoprazol/farmacología , Anfotericina B/farmacología , Antifúngicos/farmacología , Humanos , Candida auris/efectos de los fármacos , Candida auris/genética , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Inhibidores de la Bomba de Protones/farmacologíaRESUMEN
Helicobacter pylori (H. pylori) resistance is the most important risk factor for eradication failure. However, in most regions, antibiotic resistance rates of H. pylori in patients with different types of gastric mucosal lesions are still unclear. An 8-year clinical retrospective cohort study involving 2847 patients was performed. In this study, we first summarized and compared the resistance status of H. pylori in different years, ages, sexes, and gastric diseases. The resistance profiles of amoxicillin (AMX), clarithromycin (CLR), levofloxacin (LVX) and furazolidone (FR) and their changing trends in the clinic were described. Then, multiple antibiotic resistance in different gastric diseases and years were described and compared. The relationship between proton pump inhibitor (PPI) medication history and antibiotic resistance in H. pylori was also explored. Finally, an antibiotic resistance risk model was constructed for clinical resistance risk prediction. The overall resistance rates of AMX, CLR, LVX and FR in gastric diseases were 8.18%, 38.11%, 43.98%, and 13.73%, respectively. The mono resistance, double resistance, triple resistance, and quadruple resistance rates were 30.17%, 25.96%, 6.46%, and 0.63%, respectively. Compared with the period from 2014 to 2016, the rates of mono-resistance and multiple resistance all showed relatively downward trends in the past 5 years. Factors including age, sex, type of gastric lesions and recent PPI treatment history are associated with the antibiotic resistance rate of H. pylori. Atrophic gastritis is an important clinical feature of high-risk antibiotic resistance in H. pylori-infected patients. Patients with atrophic gastritis have higher risk of resistant strains infection. In this study, our data provide the association between antibiotic resistance of H. pylori and gastritis pattern, which indicate the higher risk of resistant strain infection if the patients with atrophic gastritis, PPI history and older age.
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Gastritis Atrófica , Infecciones por Helicobacter , Helicobacter pylori , Gastropatías , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/epidemiología , Estudios Retrospectivos , Amoxicilina/farmacología , Claritromicina/uso terapéutico , Gastropatías/tratamiento farmacológico , Levofloxacino/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/farmacología , Furazolidona/farmacología , Furazolidona/uso terapéutico , Farmacorresistencia Bacteriana , Metronidazol/farmacologíaRESUMEN
Introduction: PPIs, or proton pump inhibitors, are the most widely prescribed drugs. There is a debate regarding the relationship between long-term PPI use and the risk of type 2 diabetes mellitus (T2DM). A potential connection between T2DM and PPIs could be an elevated gastrin concentration. This study is aimed at investigating the long-term effects of PPI omeprazole (OZ) on glucose homeostasis and pancreatic gene expression profile in mice. Methods: Healthy adult male BALB/c mice were randomly divided into three equal groups (n = 10 in each one): (1) experimental mice that received OZ 20 mg/kg; (2) control mice that received 30 µl saline per os; (3) intact mice without any interventions. Mice were treated for 30 weeks. Glucose homeostasis was investigated by fasting blood glucose level, oral glucose tolerance test (GTT), insulin tolerance test (ITT), and basal insulin resistance (HOMA-IR). Serum gastrin and insulin concentration were determined by ELISA. Expressions of Sirt1, Pparg, Nfκb1 (p105), Nfe2l2, Cxcl5, Smad3, H2a.z, and H3f3b were measured by RT-PCR. Result: The ROC analysis revealed an increase in fasting blood glucose levels in OZ-treated mice in comparison with control and intact groups during the 30-week experiment. A slight but statistically significant increase in glucose tolerance and insulin sensitivity was observed in OZ-treated mice within 30 weeks of the experiment. The mice treated with OZ exhibited significant increases in serum insulin and gastrin levels, accompanied by a rise in the HOMA-IR level. These animals had a statistically significant increase in Sirt1, Pparg, and Cxcl5 mRNA expression. There were no differences in ß-cell numbers between groups. Conclusion: Long-term OZ treatment induced hypergastrin- and hyperinsulinemia and increased expression of Sirt1, Pparg, and Cxcl5 in mouse pancreatic tissues accompanied by specific changes in glucose metabolism. The mechanism of omeprazole-induced Cxcl5 mRNA expression and its association with pancreatic cancer risk should be investigated.
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Glucemia , Gastrinas , Homeostasis , Resistencia a la Insulina , Ratones Endogámicos BALB C , Omeprazol , Animales , Omeprazol/farmacología , Omeprazol/efectos adversos , Gastrinas/sangre , Gastrinas/metabolismo , Masculino , Ratones , Homeostasis/efectos de los fármacos , Glucemia/metabolismo , Insulina/metabolismo , Insulina/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/inducido químicamente , Prueba de Tolerancia a la Glucosa , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/efectos adversos , Glucosa/metabolismoRESUMEN
INTRODUCTION: Previous studies have identified an interaction between protein kinase inhibitors (PKIs) and proton pump inhibitors (PPIs) in patients with lung cancer. This type of interaction may reduce the efficacy of PKIs. However, the effect of PKI-PPI interaction on patient mortality remains controversial. This study set out to determine the impact of PKI-PPI interaction on overall survival for lung cancer patients. MATERIALS AND METHODS: This study was conducted using data from the French National Health Care Database from January 1, 2011 to December 31, 2021. We identified patients with: (i) an age equal to or greater than 18 years; (ii) lung cancer; and (iii) at least one reimbursement for one of the following drugs: erlotinib, gefitinib, afatinib and osimertinib. Patients were followed-up between the first date of PKI reimbursement and either December 31, 2021 or if they died, the date on which death occurred. The cumulative exposure to PPI duration during PKI treatment was calculated as the ratio between the number of concomitant exposure days to PKI and PPI and the number of exposure days to PKI. A survival analysis using a Cox proportional hazards model was then performed to assess the risk of death following exposure to a PKI-PPI interaction. RESULTS: 34,048 patients received at least one reimbursement for PKIs of interest in our study: 26,133 (76.8 %) were exposed to erlotinib; 3,142 (9.2 %) to gefitinib; 1,417 (4.2 %) to afatinib; and 3,356 (9.9 %) to osimertinib. Patients with concomitant exposure to PKI-PPI interaction during 20 % or more of the PKI treatment period demonstrated an increased risk of death (HR, 1.60 [95 % CI, 1.57-1.64]) compared to other patients. When this cut-off varied from 10 % to 80 %, the estimated HR ranged from 1.46 [95 % CI, 1.43-1.50] to 2.19 [95 % CI, 2.12-2.25]. DISCUSSION/CONCLUSION: In our study, an elevated risk of death was observed in patients exposed to PKI-PPI interaction. Finally, we were able to identify a dose-dependent effect for this interaction. This deleterious effect of osimertinib and PPI was revealed for the first time in real life conditions.