RESUMO
BACKGROUND AND AIM: Bismuth and non-bismuth quadruple therapy are the guideline-recommended first-line therapy in children with Helicobacter pylori infection in areas with high antibiotic resistance. However, their efficacy in children is uncertain and there are few well-designed studies. Here, we evaluated the eradication rates of standard triple therapy, bismuth-based quadruple therapy and sequential therapy in children with H. pylori infection. METHODS: A randomised controlled trial was conducted in children infected with H. pylori in West China Second Hospital. They were randomly assigned to 14-day standard triple therapy (omeprazole + amoxicillin + clarithromycin), 14-day bismuth quadruple therapy (bismuth + omeprazole + amoxicillin + clarithromycin) and 10-day sequential therapy (omeprazole + amoxicillin for 5 days followed by omeprazole + clarithromycin + metronidazole for 5 days). The eradication rate was assessed by a 13C-urea breath test 4 to 6 weeks after therapy completion. Symptom improvement and adverse events were compared among the groups. RESULTS: In total, 132 patients were enrolled. The eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy were 70.0%, 78.9% and 50.0% in per-protocol analysis and 63.6%, 68.2% and 43.2% in intention-to-treat analysis, respectively. Symptom improvement and adverse drug event rates were similar in the three groups. CONCLUSION: The three therapeutic regimens evaluated in this study are equally not recommendable for H. pylori infection treatment due to unsatisfactory eradication rates. The high prevalence of clarithromycin resistance makes the use of clarithromycin-based quadruple therapy not advisable, even in combination with amoxicillin and bismuth salts.
Assuntos
Amoxicilina , Antibacterianos , Bismuto , Claritromicina , Quimioterapia Combinada , Infecções por Helicobacter , Helicobacter pylori , Metronidazol , Omeprazol , Humanos , Infecções por Helicobacter/tratamento farmacológico , Feminino , Masculino , Criança , Omeprazol/administração & dosagem , Omeprazol/uso terapêutico , Metronidazol/administração & dosagem , Metronidazol/uso terapêutico , Amoxicilina/administração & dosagem , Claritromicina/administração & dosagem , Claritromicina/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Bismuto/administração & dosagem , Bismuto/uso terapêutico , Adolescente , Resultado do Tratamento , Esquema de Medicação , Pré-Escolar , Testes Respiratórios , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
Currently, Biopharmaceutics Classification System (BCS) classes I and III are the only biological exemptions of immediate-release solid oral dosage forms eligible for regulatory approval. However, through virtual bioequivalence (VBE) studies, BCS class II drugs may qualify for biological exemptions if reliable and validated modeling is used. Here, we sought to establish physiologically based pharmacokinetic (PBPK) models, in vitro-in vivo relationship (IVIVR), and VBE models for enteric-coated omeprazole capsules, to establish a clinically-relevant dissolution specification (CRDS) for screening BE and non-BE batches, and to ultimately develop evaluation criteria for generic omeprazole enteric-coated capsules. To establish omeprazole's IVIVR based on the PBPK model, we explored its in vitro dissolution conditions and then combined in vitro dissolution profile studies with in vivo clinical trials. The predicted omeprazole pharmacokinetics (PK) profiles and parameters closely matched the observed PK data. Based on the VBE results, the bioequivalence study of omeprazole enteric-coated capsules required at least 48 healthy Chinese subjects. Based on the CRDS, the capsules' in vitro dissolution should not be < 28%-54%, < 52%, or < 80% after two, three, and six hours, respectively. Failure to meet these dissolution criteria may result in non-bioequivalence. Here, PBPK modeling and IVIVR methods were used to bridge the in vitro dissolution of the drug with in vivo PK to establish the BE safety space of omeprazole enteric-coated capsules. The strategy used in this study can be applied in BE studies of other BCS II generics to obtain biological exemptions and accelerate drug development.
Assuntos
Cápsulas , Liberação Controlada de Fármacos , Modelos Biológicos , Omeprazol , Equivalência Terapêutica , Omeprazol/farmacocinética , Omeprazol/administração & dosagem , Omeprazol/química , Humanos , Masculino , Adulto , Solubilidade , Adulto Jovem , Administração Oral , Inibidores da Bomba de Prótons/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/química , Feminino , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/normas , Medicamentos Genéricos/química , Estudos Cross-OverRESUMO
Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM) was developed based on gefapixant physicochemical properties and clinical pharmacokinetics to aid formulation selection, bioequivalence safe space assessment and dissolution specification settings. In vitro dissolution profiles of different free base and citrate salt formulations were used as an input to the model. The model was validated against the results of independent studies, which included a bioequivalence and a relative bioavailability study, as well as a human ADME study, all meeting acceptance criteria of prediction errors ≤ 20% for both Cmax and AUC. PBBM was also applied to evaluate gastric pH-mediated drug-drug-interaction potential with co-administration of a proton pump inhibitor (PPI), omeprazole. Model results showed good agreement with clinical data in which omeprazole lowered gefapixant exposure for the free base formulation but did not significantly alter gefapixant pharmacokinetics for the citrate based commercial drug product. An extended virtual dissolution bioequivalence safe space was established. Gefapixant drug product batches are anticipated to be bioequivalent with the clinical reference batch when their dissolution is > 80% in 60 minutes. PBBM established a wide dissolution bioequivalence space as part of assuring product quality.
Assuntos
Modelos Biológicos , Solubilidade , Equivalência Terapêutica , Humanos , Inibidores da Bomba de Prótons/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/química , Disponibilidade Biológica , Biofarmácia/métodos , Liberação Controlada de Fármacos , Omeprazol/farmacocinética , Omeprazol/administração & dosagem , Omeprazol/química , Administração Oral , Concentração de Íons de Hidrogênio , Comprimidos , Interações Medicamentosas , Química Farmacêutica/métodos , Estudos Cross-Over , Composição de Medicamentos/métodosRESUMO
Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC-1 study. Cytokines, especially interleukin (IL)-6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL-6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL-6 kinetics profiles were assessed, the mean IL-6 profile with a maximum concentration (Cmax) of IL-6 (21 pg/mL) and the IL-6 profile of the patient presenting the highest IL-6 Cmax (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC-1. For the mean IL-6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87-1.20). For the maximum IL-6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90-2.23), and minimal for caffeine and s-warfarin (mean AUC ratios 0.82-1.25). Maximum change in exposure for these substrates occurred 3-4 days after step-up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL-6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step-up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS.
Assuntos
Síndrome da Liberação de Citocina , Interações Medicamentosas , Interleucina-6 , Modelos Biológicos , Humanos , Interleucina-6/sangue , Síndrome da Liberação de Citocina/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/metabolismo , Área Sob a Curva , Ciclosporina/farmacocinética , Ciclosporina/administração & dosagem , Midazolam/farmacocinética , Midazolam/administração & dosagem , Omeprazol/farmacocinética , Omeprazol/administração & dosagem , Sinvastatina/farmacocinética , Sinvastatina/administração & dosagemRESUMO
BACKGROUND: Antisecretory drugs are commonly prescribed with clopidogrel-based dual antiplatelet therapy (DAPT) to prevent gastrointestinal bleeding in high-risk patients after percutaneous coronary intervention (PCI). However, omeprazole and esomeprazole (inhibiting proton pump inhibitors [PPIs]) may increase cardiovascular event rates on co-administration with clopidogrel. This study aimed to examine trends in the use of antisecretory agents in patients administered clopidogrel-based DAPT and the concomitant use of clopidogrel and inhibiting PPIs. METHODS: We used National Inpatient Sample data compiled by the Health Insurance Review & Assessment Service from 2009 to 2020. Further, we identified patients who were prescribed clopidogrel-based DAPT after PCI and investigated the concomitant use of antisecretory agents with clopidogrel. To verify the annual trend of drug utilization, we used the Cochran-Armitage trend test. RESULTS: From 2009 to 2020, the percentage of H2 receptor antagonist users decreased steadily (from 82.5% in 2009 to 25.3% in 2020); instead, the percentage of PPI users increased (from 23.7% in 2009 to 82.0% in 2020). The use of inhibiting PPI also increased (from 4.2% in 2009 to 30.7% in 2020). Potassium competitive acid blockers (P-CABs) were rarely used before 2019; however, in 2020, it accounted for 7.8% of the antisecretory users. CONCLUSIONS: Our study demonstrates that the use of inhibiting PPIs increased steadily in patients administered clopidogrel-based DAPT therapy. This is a major concern since the concomitant use of inhibiting PPIs with clopidogrel could increase the risk of cardiovascular events.
Assuntos
Clopidogrel , Hemorragia Gastrointestinal , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Inibidores da Bomba de Prótons , Humanos , Clopidogrel/administração & dosagem , Clopidogrel/uso terapêutico , Clopidogrel/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/prevenção & controle , Terapia Antiplaquetária Dupla/métodos , Esomeprazol/administração & dosagem , Esomeprazol/uso terapêutico , Omeprazol/administração & dosagem , Omeprazol/uso terapêutico , Omeprazol/efeitos adversos , Interações Medicamentosas , Quimioterapia Combinada , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/uso terapêuticoRESUMO
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.
Assuntos
Aspirina , Mucosa Gástrica , Gastrinas , Omeprazol , Inibidores da Bomba de Prótons , Ratos Sprague-Dawley , Animais , Aspirina/efeitos adversos , Aspirina/administração & dosagem , Omeprazol/farmacologia , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/administração & dosagem , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Gastrinas/sangue , Masculino , Ratos , Esquema de Medicação , Humanos , Úlcera Péptica/prevenção & controle , Úlcera Péptica/induzido quimicamente , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Úlcera Gástrica/prevenção & controle , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologiaRESUMO
Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.
Assuntos
Citocromo P-450 CYP2C19 , Fígado , Omeprazol , Inibidores da Bomba de Prótons , Humanos , Sistemas de Notificação de Reações Adversas a Medicamentos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/sangue , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Bases de Dados Factuais , População do Leste Asiático , Japão , Fígado/metabolismo , Fígado/efeitos dos fármacos , Modelos Biológicos , Omeprazol/farmacocinética , Omeprazol/efeitos adversos , Omeprazol/sangue , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacocinética , Inibidores da Bomba de Prótons/sangueRESUMO
As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.
Assuntos
Dextrometorfano , Interações Medicamentosas , Leucemia Mieloide Aguda , Midazolam , Síndromes Mielodisplásicas , Pioglitazona , Piridinas , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia Mieloide Aguda/tratamento farmacológico , Feminino , Idoso , Síndromes Mielodisplásicas/tratamento farmacológico , Midazolam/farmacocinética , Pioglitazona/farmacocinética , Pioglitazona/farmacologia , Dextrometorfano/farmacocinética , Dextrometorfano/administração & dosagem , Piridinas/farmacocinética , Piridinas/administração & dosagem , Flurbiprofeno/farmacocinética , Flurbiprofeno/administração & dosagem , Flurbiprofeno/análogos & derivados , Triazinas/farmacocinética , Triazinas/uso terapêutico , Triazinas/administração & dosagem , Adulto , Omeprazol/farmacocinética , Omeprazol/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Recidiva , Idoso de 80 Anos ou mais , AminopiridinasRESUMO
Chronic use of omeprazole has been linked to central effects alongside with the global concern of increasing appearance of neuropsychiatric disorders. This study aimed to identifying behavioral, inflammatory, and oxidative stress alterations after long-term administration of omeprazole. C57BL/6 mice were divided in groups: OME and Sham, each received either solutions of omeprazole or vehicle, administered for 28 days by gavage. Results observed in the omeprazole-treated mice: Decrease in the crossing parameter in the open field, no change in the motor performance assessed by rotarod, an immobility time reduction in the forced swimming test, improved percentage of correct alternances in the Ymaze and an exploration time of the novel object reduction in the novel object recognition. Furthermore, a reduced weight gain and hippocampal weight were observed. There was an increase in the cytokine IL1-ß levels in both prefrontal cortex (PFC) and serum, whereas TNF-α increased only in the PFC. Nitrite levels increased in the hippocampus (HP) and PFC, while malondialdehyde (MDA) and glutathione (GSH) levels decreased. These findings suggest that omeprazole improves depressive-like behavior and working memory, likely through the increase in nitrite and reduction in MDA levels in PFC and HP, whereas, the impairment of the recognition memory is more likely to be related to the reduced hippocampal weight. The diminished weight gain might be associated with the IL-1ß increased levels in the peripheral blood. Altogether, omeprazole showed to have the potential to impact at central level and inflammatory and oxidative parameters might exert a role between it.
Assuntos
Comportamento Animal , Hipocampo , Camundongos Endogâmicos C57BL , Omeprazol , Estresse Oxidativo , Animais , Estresse Oxidativo/efeitos dos fármacos , Omeprazol/farmacologia , Omeprazol/administração & dosagem , Masculino , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Camundongos , Glutationa/metabolismo , Malondialdeído/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/administração & dosagem , Nitritos/sangueRESUMO
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.
Assuntos
Disponibilidade Biológica , Estudos Cross-Over , Omeprazol , Inibidores da Bomba de Prótons , Tiroxina , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Interações Medicamentosas , Omeprazol/farmacocinética , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacocinética , Inibidores da Bomba de Prótons/farmacologia , Tiroxina/farmacocinética , Tiroxina/administração & dosagem , Tiroxina/sangueRESUMO
BACKGROUND: We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed. METHODS: In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses. RESULTS: Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration-time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined. CONCLUSION: This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation. CLINICAL TRIAL REGISTRATION: EudraCT number: 2021-006643-39.
Assuntos
Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Interações Medicamentosas , Inibidores do Fator Xa , Voluntários Saudáveis , Piridonas , Ritonavir , Humanos , Ritonavir/administração & dosagem , Ritonavir/farmacocinética , Ritonavir/farmacologia , Masculino , Adulto , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Piridonas/farmacocinética , Piridonas/administração & dosagem , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C19/genética , Administração Oral , Feminino , Rivaroxabana/farmacocinética , Rivaroxabana/administração & dosagem , Adulto Jovem , Piridinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacologia , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Tiazóis/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Midazolam/farmacocinética , Midazolam/administração & dosagem , Omeprazol/farmacocinética , Omeprazol/administração & dosagem , Omeprazol/farmacologiaRESUMO
INTRODUCTION: The optimal proton pump inhibitor (PPI) regimen for eosinophilic esophagitis (EoE) is unclear. We compared histologic response rates of different dosing combinations. METHODS: A total of 305 patients with newly diagnosed EoE received standard (omeprazole 20 mg daily), once-daily moderate (40 mg daily), twice-daily moderate (20 mg twice daily), or high (40 mg twice daily) dose PPI for ≥8 weeks. RESULTS: Approximately 42.3% achieved histologic response to PPI, with higher rates for twice-daily (moderate 52.8%/high 54.3%) than once-daily (standard 11.8%/moderate 10%) dosing ( P < 0.0001). On multivariable analysis, twice-daily moderate (adjusted odds ratio 6.75, confidence interval 2.53-18.0, P = 0.0008) and high (adjusted odds ratio 12.8, confidence interval 4.69-34.8, P < 0.0001) doses independently predicted histologic response. DISCUSSION: Twice-daily PPI is associated with higher EoE histologic response rates than once-daily regimen.
Assuntos
Esquema de Medicação , Esofagite Eosinofílica , Inibidores da Bomba de Prótons , Humanos , Inibidores da Bomba de Prótons/administração & dosagem , Esofagite Eosinofílica/tratamento farmacológico , Esofagite Eosinofílica/patologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Resultado do Tratamento , Indução de Remissão , Adulto Jovem , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: Omega-3 fatty acid and alpha-tocopherol supplementation reduces gastric ulcer formation in humans and rodents; however, efficacy of prevention in horses is unknown. Equine Omega Complete (EOC) is an oral supplement containing omega-3 fatty acids and alpha-tocopherol. HYPOTHESIS/OBJECTIVE: Determine if EOC supplementation prevents gastric ulcers and increases serum alpha-tocopherol concentrations in healthy horses. ANIMALS: Nine thoroughbred geldings; 5-13 years old. METHODS: Prospective randomized block design, repeated in crossover model. Horses were administered EOC, omeprazole, or water PO for 28 days. Horses underwent an established gastric ulcer induction protocol from days 21-28 via intermittent feed deprivation. Gastroscopies were performed on days 0, 21, and 28. Serum alpha-tocopherol concentrations were measured on days 0 and 28. The effects of treatment and time on ulcer grades were assessed with ordinal logistic regression, with significance at P-value <.05. RESULTS: Ulcer grades increased during ulcer induction in control and EOC but not omeprazole groups (P = .02). Grades increased in EOC-treated horses after ulcer induction from a median of 1 [95% confidence interval 0-2.5] (day 0) to 2.5 [1.5-3.5] (day 28) and were similar to the control group (P = .54). Serum alpha-tocopherol increased in EOC-treated horses from day 0 to day 28 (mean 2.2 ± 0.43 µg/mL to 2.96 ± 0.89 µg/mL; P < .001) with high individual variation; this increase was not different from omeprazole or control groups. CONCLUSION AND CLINICAL IMPORTANCE: Supplementation with EOC for 28 days did not prevent gastric ulcer formation nor increase alpha-tocopherol concentrations relative to the control group.
Assuntos
Doenças dos Cavalos , Úlcera Gástrica , alfa-Tocoferol , Animais , Masculino , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/sangue , Estudos Cross-Over , Suplementos Nutricionais , Doenças dos Cavalos/sangue , Doenças dos Cavalos/prevenção & controle , Cavalos , Omeprazol/administração & dosagem , Estudos Prospectivos , Úlcera Gástrica/sangue , Úlcera Gástrica/prevenção & controle , Úlcera Gástrica/veterináriaRESUMO
OBJECTIVES: This mixed-methods feasibility study aimed to explore parents' and medical practitioners' views on the acceptability and design of a clinical trial to determine whether routine prophylactic proton pump inhibitors (PPI) reduce the incidence of anastomotic stricture in infants with oesophageal atresia (OA). DESIGN: Semi-structured interviews with UK parents of an infant with OA and an online survey, telephone interviews and focus groups with clinicians. Data were analysed using reflexive thematic analysis and descriptive statistics. PARTICIPANTS AND SETTING: We interviewed 18 parents of infants with OA. Fifty-one clinicians (49 surgeons, 2 neonatologists) from 20/25 (80%) units involved in OA repair completed an online survey and 10 took part in 1 of 2 focus groups. Interviews were conducted with two clinicians whose survey responses indicated they had concerns about the trial. OUTCOME MEASURES: Parents and clinicians ranked the same top four outcomes ('Severity of anastomotic stricture', 'Incidence of anastomotic stricture', 'Need for treatment of reflux' and 'Presence of symptoms of reflux') as important to measure for the proposed trial. RESULTS: All parents and most clinicians found the use, dose and duration of omeprazole as the intervention medication, and the placebo control, as acceptable. Parents stated they would hypothetically consent to their child's participation in the trial. Concerns of a few parents and clinicians about infants suffering with symptomatic reflux, and the impact of this for study retention, appeared to be alleviated through the symptomatic reflux treatment pathway. Hesitant clinician views appeared to change through discussion of parental support for the study and by highlighting existing research that questions current practice of PPI treatment. CONCLUSIONS: Our findings indicate that parents and most clinicians view the proposed Treating Oesophageal Atresia with prophylactic proton pump inhibitors to prevent STricture (TOAST) trial to be feasible and acceptable so long as infants can be given PPI if clinicians deem it clinically necessary. This insight into parent and clinician views and concerns will inform pilot phase trial monitoring, staff training and the development of the trial protocol.
Assuntos
Atresia Esofágica , Estenose Esofágica , Omeprazol , Inibidores da Bomba de Prótons , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Recém-Nascido , Constrição Patológica/etiologia , Constrição Patológica/prevenção & controle , Atresia Esofágica/complicações , Atresia Esofágica/cirurgia , Estudos de Viabilidade , Refluxo Gastroesofágico/etiologia , Refluxo Gastroesofágico/prevenção & controle , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Estenose Esofágica/etiologia , Estenose Esofágica/prevenção & controle , Quimioprevenção , Pesquisas sobre Atenção à Saúde , Pais , Médicos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Omeprazol/administração & dosagem , Omeprazol/uso terapêutico , Aceitação pelo Paciente de Cuidados de Saúde , Atitude do Pessoal de Saúde , AdultoRESUMO
Heartburn occurs in 75% of patients with digestive discomfort of any origin and is one of the main symptoms of gastroesophageal reflux disease. Treatment focuses on lifestyle modification and symptomatology management with various drugs; when heartburn is moderate to severe, a proton pump inhibitor is more suitable. Omeprazole (OMZ) combined with sodium bicarbonate (BC) has demonstrated significant and sustained suppression of acid secretion. The objective was to compare the effect of sequential OMZ/BC therapy compared to OMZ monotherapy for the improvement of heartburn in Mexican individuals. The study was a double-blind, randomized, controlled, multicenter clinical study including 277 subjects with moderate to severe heartburn. Patients received 7 days of OMZ/BC and 7 days of OMZ (OMZ/BC7) or 14 days of OMZ (OMZ14). The primary endpoint was defined as the change in the number of days a week that the patient has heartburn, it was evaluated at 14 days. Both treatments reduced time (days) with heartburn by less than 4 days (OMZ14 3.9 vs. 4.2 days OMZ/BC7), as well as duration, number of events and intensity of heartburn. The treatments improved the quality of life, and the control of the symptoms. The proportion of adverse events was lower with OMZ/BC. The non-inferiority of OMZ/BC7 with respect to OMZ14 was verified.
La pirosis se presenta en el 75% de los pacientes con molestias digestivas de cualquier origen y es uno de los principales síntomas de la enfermedad por reflujo gastroesofágico. El tratamiento se enfoca en la modificación del estilo de vida y el manejo de la sintomatología con diversos fármacos; cuando la pirosis es moderada a severa, un inhibidor de la bomba de protones es más adecuado. El omeprazol (OMZ) combinado con bicarbonato de sodio (BC) ha demostrado supresión significativa y sostenida de la secreción ácida. El objetivo fue comparar el efecto de la terapia secuencial de OMZ/BC en comparación con el tratamiento continuo de OMZ para la mejoría de la pirosis en individuos mexicanos. Estudio clínico multicéntrico, doble ciego, controlado, aleatorizado que incluyó 277 sujetos con pirosis moderada a severa. Los pacientes recibieron 7 días de OMZ/BC y 7 días de OMZ (OMZ/BC7) o 14 días de OMZ (OMZ14). La variable primaria fue definida como el cambio del número de días a la semana que el paciente presenta pirosis, se evaluó a los 14 días. Ambos tratamientos redujeron los días con pirosis en menos 4 días (OMZ14 3,9 vs. 4,2 días OMZ/BC7), así como la duración, el número de eventos e intensidad de la pirosis. Los tratamientos mejoraron los indicadores de calidad de vida, y el control del padecimiento. La proporción de eventos adversos fue menor con OMZ/BC. Se comprobó la no-inferioridad de OMZ/BC7 respecto OMZ14.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Omeprazol/uso terapêutico , Bicarbonato de Sódio/uso terapêutico , Azia/tratamento farmacológico , Omeprazol/administração & dosagem , Omeprazol/efeitos adversos , Método Duplo-Cego , Estudos Prospectivos , Resultado do Tratamento , Bicarbonato de Sódio/administração & dosagem , Bicarbonato de Sódio/efeitos adversos , Quimioterapia CombinadaRESUMO
Pediatric upper gastrointestinal bleeding refers to an acute massive hemorrhage of the upper digestive tract and biliary tract, which is a common clinical emergency in pediatrics. This study aimed to evaluate the clinical effect of octreotide combined with omeprazole in pediatric upper gastrointestinal bleeding. Totally 84 cases of pediatric upper gastrointestinal bleeding admitted to Ningbo Women and Children's Hospital from November 2019 to April 2021 were divided into groups according to the admission order. The control group received omeprazole treatment and the observation group received octreotide plus. The total clinical effective rate of children in the observation group was higher than that of the control group. The observation group was superior to the control group with respect to the average hemostasis time, hemostasis rate, rebleeding rate and length of stay after treatment. The observation group witnessed a significantly better quality of life than the control group. For children with acute upper gastrointestinal bleeding, the combination of omeprazole and octreotide yields a promising effect in the adjustment of blood creatinine and serum urea nitrogen levels and hemostasis, which is worthy of clinical application.
Assuntos
Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Hemorragia Gastrointestinal/tratamento farmacológico , Octreotida/uso terapêutico , Omeprazol/uso terapêutico , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/uso terapêutico , Humanos , Masculino , Octreotida/administração & dosagem , Omeprazol/administração & dosagemRESUMO
PURPOSE: To investigate the suitability of microdosed oral omeprazole for predicting CYP2C19 activity in vivo in combination with simultaneous assessment of CYP3A and CYP2D6 activity using both microdosed midazolam and yohimbine. METHODS: An open, fixed-sequence study was carried out in 20 healthy participants. Single microdosed (100 µg) and therapeutic (20 mg) doses of omeprazole were evaluated without comedication and after administration of established CYP2C19 perpetrators fluconazole (inhibition) and rifampicin (induction). To prevent degradation of the uncoated omeprazole microdose, sodium bicarbonate buffer was administered. The pharmacokinetics of omeprazole and its 5-hydroxy-metabolite were assessed as well as the pharmacokinetics of midazolam and yohimbine to estimate CYP3A4 and CYP2D6 activity. RESULTS: Calculated pharmacokinetic parameters after administration of 100 µg and 20 mg omeprazole in healthy subjects suggest dose proportionality. Omeprazole clearance was significantly decreased by fluconazole from 388 [95% CI: 266-565] to 47.2 [42.8-52.0] mL/min after 20 mg omeprazole and even further after 100 µg omeprazole (29.4 [24.5-35.1] mL/min). Rifampicin increased CYP2C19-mediated omeprazole metabolism. The omeprazole hydroxylation index was significantly related to omeprazole clearance for both doses. Both fluconazole and rifampicin altered CYP3A4 activity whereas no change of CYP2D6 activity was observed at all. CONCLUSIONS: Microdosed oral omeprazole is suitable to determine CYP2C19 activity, also during enzyme inhibition and induction. However, the administration of sodium bicarbonate buffer also had a small influence on all victim drugs used. TRIAL REGISTRATION: EudraCT: 2017-004270-34.
Assuntos
Citocromo P-450 CYP2C19 , Omeprazol , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Fluconazol/administração & dosagem , Humanos , Midazolam/administração & dosagem , Midazolam/farmacocinética , Omeprazol/administração & dosagem , Rifampina/administração & dosagem , Bicarbonato de Sódio/administração & dosagem , Ioimbina/administração & dosagemRESUMO
Givosiran (trade name GIVLAARI) is a small interfering ribonucleic acid that targets hepatic delta-aminolevulinic acid synthase 1 (ALAS1) messenger RNA for degradation through RNA interference (RNAi) that has been approved for the treatment of acute hepatic porphyria (AHP). RNAi therapeutics, such as givosiran, have a low liability for drug-drug interactions (DDIs) because they are not metabolized by cytochrome 450 (CYP) enzymes, and do not directly inhibit or induce CYP enzymes in the liver. The pharmacodynamic effect of givosiran (lowering of hepatic ALAS1, the first and rate limiting enzyme in the heme biosynthesis pathway) presents a unique scenario where givosiran could potentially impact heme-dependent activities in the liver, such as CYP enzyme activity. This study assessed the impact of givosiran on the pharmacokinetics of substrates of 5 major CYP450 enzymes in subjects with acute intermittent porphyria (AIP), the most common type of AHP, by using the validated "Inje cocktail," comprised of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). We show that givosiran treatment had a differential inhibitory effect on CYP450 enzymes in the liver, resulting in a moderate reduction in activity of CYP1A2 and CYP2D6, a minor effect on CYP3A4 and CYP2C19, and a similar weak effect on CYP2C9. To date, this is the first study evaluating the DDI for an oligonucleotide therapeutic and highlights an atypical drug interaction due to the pharmacological effect of givosiran. The results of this study suggest that givosiran does not have a large effect on heme-dependent CYP enzyme activity in the liver.
Assuntos
Acetilgalactosamina/análogos & derivados , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas/fisiologia , Ativação Enzimática/fisiologia , Fígado/metabolismo , Pirrolidinas/metabolismo , RNA Interferente Pequeno/metabolismo , 5-Aminolevulinato Sintetase/metabolismo , Acetilgalactosamina/administração & dosagem , Acetilgalactosamina/metabolismo , Adulto , Cafeína/administração & dosagem , Cafeína/metabolismo , Estudos Cross-Over , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Fígado/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Midazolam/administração & dosagem , Midazolam/metabolismo , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/metabolismo , Porfirias Hepáticas/tratamento farmacológico , Porfirias Hepáticas/metabolismo , Pirrolidinas/administração & dosagemRESUMO
INTRODUCTION: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. METHODS: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1ß, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. RESULTS: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1ß expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. CONCLUSIONS: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.
Assuntos
Omeprazol/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/administração & dosagem , Receptores de Adiponectina/agonistas , Úlcera Gástrica/tratamento farmacológico , Administração Oral , Animais , Catalase/metabolismo , Diclofenaco/efeitos adversos , Modelos Animais de Doenças , Etanol/efeitos adversos , Masculino , Camundongos , Omeprazol/farmacologia , Peroxidase/metabolismo , Piperidinas/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Superóxido Dismutase/metabolismo , Resultado do TratamentoRESUMO
Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.