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1.
BMC Pharmacol Toxicol ; 23(1): 9, 2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-35039078

RESUMO

BACKGROUND: This study aimed to evaluate incidence risk and adverse clinical outcomes in COVID-19 disease among short-term users of acid-suppressants in South Korea. METHODS: This retrospective cohort study, conducted using a nationwide claims database for South Korea, used data from patients with COVID-19 tested between January 1 and May 15, 2020. Patients aged over 18 years and prescribed proton pump inhibitors (PPI) or histamine-2 receptor antagonist (H2RA) for more than 7 days were identified. Primary outcome was COVID-19 while secondary outcomes were all-cause mortality, hospitalization with respiratory disease, or intensive respiratory intervention. Large-scale propensity scores were used to match patients, while the Cox proportional hazard model was utilized to evaluate any association between exposure and outcome(s). The risk estimates were calibrated by using 123 negative control outcomes. RESULTS: We identified 26,166 PPI users and 62,117 H2RA users. After propensity score matching, compared to H2RA use, PPI use was not significantly associated with lower risk of COVID-19 (calibrated hazard ratio [HR], 0.81 [95% confidence interval (CI), 0.30-2.19]); moreover, PPI use was not associated with adverse clinical outcomes in COVID-19, namely, hospitalization with respiratory disease (calibrated HR, 0.88 [95% CI, 0.72-1.08]), intensive respiratory interventions (calibrated HR, 0.92 [95% CI, 0.46-1.82]), except for all-cause mortality (calibrated HR, 0.54 [95% CI, 0.31-0.95]). CONCLUSIONS: In this study, we found that the PPI user was not associated with risk of COVID-19 compared to H2RA users. There was no significant relationship between severe clinical outcomes of COVID-19 and exposure to PPI compared with H2RA, except for all-cause mortality.


Assuntos
COVID-19/epidemiologia , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , SARS-CoV-2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/terapia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
2.
Gut ; 71(1): 111-118, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210775

RESUMO

OBJECTIVE: To determine whether proton pump inhibitors (PPIs) are associated with an increased risk of colorectal cancer, compared with histamine-2 receptor antagonists (H2RAs). DESIGN: The United Kingdom Clinical Practice Research Datalink was used to identify initiators of PPIs and H2RA from 1990 to 2018, with follow-up until 2019. Cox proportional hazards models were fit to estimate marginal HRs and 95% CIs of colorectal cancer. The models were weighted using standardised mortality ratio weights using calendar time-specific propensity scores. Prespecified secondary analyses assessed associations with cumulative duration, cumulative dose and time since treatment initiation. The number needed to harm was calculated at five and 10 years of follow-up. RESULTS: The cohort included 1 293 749 and 292 387 initiators of PPIs and H2RAs, respectively, followed for a median duration of 4.9 years. While the use of PPIs was not associated with an overall increased risk of colorectal cancer (HR: 1.02, 95% CI 0.92 to 1.14), HRs increased with cumulative duration of PPI use (<2 years, HR: 0.93, 95% CI 0.83 to 1.04; 2-4 years, HR: 1.45, 95% CI 1.28 to 1.60; ≥4 years, HR: 1.60, 95% CI 1.42 to 1.80). Similar patterns were observed with cumulative dose and time since treatment initiation. The number needed to harm was 5343 and 792 for five and 10 years of follow-up, respectively. CONCLUSION: While any use of PPIs was not associated with an increased risk of colorectal cancer compared with H2RAs, prolonged use may be associated with a modest increased risk of this malignancy.


Assuntos
Neoplasias Colorretais/induzido quimicamente , Inibidores da Bomba de Prótons/efeitos adversos , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Bases de Dados Factuais , Feminino , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Reino Unido/epidemiologia
3.
Gut ; 71(1): 16-24, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34226290

RESUMO

OBJECTIVE: To determine whether new users of proton pump inhibitors (PPIs) are at an increased risk of gastric cancer compared with new users of histamine-2 receptor antagonists (H2RAs). DESIGN: Using the UK Clinical Practice Research Datalink, we conducted a population-based cohort study using a new-user active comparator design. From 1 January 1990 to 30 April 2018, we identified 973 281 new users of PPIs and 193 306 new users of H2RAs. Cox proportional hazards models were fit to estimate HRs and 95% CIs of gastric cancer, and the number needed to harm was estimated using the Kaplan-Meier method. The models were weighted using standardised mortality ratio weights using calendar time-specific propensity scores. Secondary analyses assessed duration and dose-response associations. RESULTS: After a median follow-up of 5.0 years, the use of PPIs was associated with a 45% increased risk of gastric cancer compared with the use of H2RAs (HR 1.45, 95% CI 1.06 to 1.98). The number needed to harm was 2121 and 1191 for five and 10 years after treatment initiation, respectively. The HRs increased with cumulative duration, cumulative omeprazole equivalents and time since treatment initiation. The results were consistent across several sensitivity analyses. CONCLUSION: The findings of this large population-based cohort study indicate that the use of PPIs is associated with an increased risk of gastric cancer compared with the use of H2RAs, although the absolute risk remains low.


Assuntos
Inibidores da Bomba de Prótons/efeitos adversos , Neoplasias Gástricas/induzido quimicamente , Estudos de Coortes , Feminino , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias Gástricas/epidemiologia , Reino Unido/epidemiologia
4.
PLoS One ; 16(11): e0259514, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34735523

RESUMO

INTRODUCTION: Famotidine is a competitive histamine H2-receptor antagonist most commonly used for gastric acid suppression but thought to have potential efficacy in treating patients with Coronavirus disease 2019 (COVID-19). The aims of this systematic review and meta-analysis are to summarize the current literature and report clinical outcomes on the use of famotidine for treatment of hospitalized patients with COVID-19. METHODS: Five databases were searched through February 12, 2021 to identify observational studies that reported on associations of famotidine use with outcomes in COVID-19. Meta-analysis was conducted for composite primary clinical outcome (e.g. rate of death, intubation, or intensive care unit admissions) and death separately, where either aggregate odds ratio (OR) or hazard ratio (HR) was calculated. RESULTS: Four studies, reporting on 46,435 total patients and 3,110 patients treated with famotidine, were included in this meta-analysis. There was no significant association between famotidine use and composite outcomes in patients with COVID-19: HR 0.63 (95% CI: 0.35, 1.16). Across the three studies that reported mortality separated from other endpoints, there was no association between famotidine use during hospitalization and risk of death-HR 0.67 (95% CI: 0.26, 1.73) and OR 0.79 (95% CI: 0.19, 3.34). Heterogeneity ranged from 83.69% to 88.07%. CONCLUSION: Based on the existing observational studies, famotidine use is not associated with a reduced risk of mortality or combined outcome of mortality, intubation, and/or intensive care services in hospitalized individuals with COVID-19, though heterogeneity was high, and point estimates suggested a possible protective effect for the composite outcome that may not have been observed due to lack of power. Further randomized controlled trials (RCTs) may help determine the efficacy and safety of famotidine as a treatment for COVID-19 patients in various care settings of the disease.


Assuntos
COVID-19/tratamento farmacológico , Famotidina/uso terapêutico , Hospitalização , Adulto , Idoso , Gerenciamento de Dados , Feminino , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Razão de Chances , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco , SARS-CoV-2
5.
Sci Rep ; 11(1): 20987, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34697319

RESUMO

Acid suppressants are widely-used classes of medications linked to increased risks of aerodigestive infections. Prior studies of these medications as potentially reversible risk factors for COVID-19 have been conflicting. We aimed to determine the impact of chronic acid suppression use on COVID-19 infection risk while simultaneously evaluating the influence of social determinants of health to validate known and discover novel risk factors. We assessed the association of chronic acid suppression with incident COVID-19 in a 1:1 case-control study of 900 patients tested across three academic medical centers in California, USA. Medical comorbidities and history of chronic acid suppression use were manually extracted from health records by physicians following a pre-specified protocol. Socio-behavioral factors by geomapping publicly-available data to patient zip codes were incorporated. We identified no evidence to support an association between chronic acid suppression and COVID-19 (adjusted odds ratio 1.04, 95% CI 0.92-1.17, P = 0.515). However, several medical and social features were positive (Latinx ethnicity, BMI ≥ 30, dementia, public transportation use, month of the pandemic) and negative (female sex, concurrent solid tumor, alcohol use disorder) predictors of new infection. These findings demonstrate the value of integrating publicly-available databases with medical data to identify critical features of communicable diseases.


Assuntos
COVID-19/epidemiologia , COVID-19/terapia , Refluxo Gastroesofágico/complicações , Determinantes Sociais da Saúde , Idoso , Comportamento , COVID-19/psicologia , California , Estudos de Casos e Controles , Biologia Computacional/métodos , Bases de Dados Factuais , Feminino , Gastroenterologia , Refluxo Gastroesofágico/tratamento farmacológico , Geografia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Inibidores da Bomba de Prótons/farmacologia , Fatores de Risco , Classe Social
7.
Tohoku J Exp Med ; 255(1): 41-48, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34526429

RESUMO

Effective Helicobacter pylori (H. pylori) eradication is a major public health concern; however, eradication failure rates with the standard triple therapy remain high. We aimed to investigate the effectiveness and tolerability of ranitidine bismuth citrate (RBC) pretreatment before standard triple therapy for H. pylori eradication. A prospective, randomized, controlled, and open-label clinical trial was conducted from June to December 2019. H. pylori eradication rate, safety, and tolerability were compared between the standard treatment group (esomeprazole, amoxicillin, and clarithromycin for 7 days) and RBC pretreatment group (RBC for 2 weeks before standard triple therapy). This trial ended earlier than estimated owing to the N-nitrosodimethylamine concerns with ranitidine. Success rates of H. pylori eradication were 80.9% and 67.3% in the RBC pretreatment (n = 47) and standard treatment (n = 52) (p = 0.126) groups, respectively. Our trial was discontinued earlier than planned; however, a statistical significance would be achieved by expansion of our data (p = 0.031) if patient enrollment numbers reached those initially planned. Adverse event rates were comparable between groups (25.5% in the pretreatment group vs. 28.8% in the standard treatment group), without serious event. Tolerability was excellent in both groups, recorded as 97.9% and 100% in the pretreatment and standard treatment groups, respectively. Compared with the standard triple regimen, RBC pretreatment for 2 weeks may achieve higher H. pylori eradication rates, with excellent safety and tolerability. However, this study necessitates further validation as it was discontinued early owing to the N-nitrosodimethylamine issues of ranitidine.


Assuntos
Bismuto/administração & dosagem , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Ranitidina/análogos & derivados , Adulto , Idoso , Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Carga Bacteriana/efeitos dos fármacos , Claritromicina/administração & dosagem , Esquema de Medicação , Quimioterapia Combinada , Esomeprazol/administração & dosagem , Feminino , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ranitidina/administração & dosagem , Falha de Tratamento , Resultado do Tratamento
8.
Calcif Tissue Int ; 109(6): 696-705, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34213594

RESUMO

Proton pump inhibitors (PPIs) have been associated with an increased risk of fragility fractures in pharmaco-epidemiological studies. The mechanism is unclear, but it has been speculated that by neutralising gastric acid, they may reduce intestinal calcium absorption, causing secondary hyperparathyroidism and bone loss. Here we investigated that hypothesis that the skeletal effects of PPI might be mediated by inhibitory effects on the bone-specific phosphatase PHOSPHO1. We found that the all PPIs tested inhibited the activity of PHOSPHO1 with IC50 ranging between 0.73 µM for esomeprazole to 19.27 µM for pantoprazole. In contrast, these PPIs did not inhibit TNAP activity. We also found that mineralisation of bone matrix in primary osteoblast cultures was inhibited by several PPIs in a concentration dependent manner. In contrast, the histamine-2 receptor antagonists (H2RA) nizatidine, famotidine, cimetidine and ranitidine had no inhibitory effects on PHOSPHO1 activity. Our experiments show for the first time that PPIs inhibit PHOSPHO1 activity and matrix mineralisation in vitro revealing a potential mechanism by which these widely used drugs are associated with the risk of fractures.


Assuntos
Antagonistas dos Receptores H2 da Histamina , Inibidores da Bomba de Prótons , Calcificação Fisiológica , Pantoprazol , Monoéster Fosfórico Hidrolases , Inibidores da Bomba de Prótons/farmacologia
10.
Am J Gastroenterol ; 116(6): 1211-1219, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074826

RESUMO

INTRODUCTION: Proton pump inhibitors (PPIs) are commonly prescribed medications. Long-term use of PPIs has been suspected to have a provocative effect on gastric cancer. This study was to determine the association between PPI vs histamine 2 receptor antagonist (H2RA) use and the risk of gastric cancer in a region where the risk of this malignancy is high. METHODS: A population-based cohort study using the Korean National Health Insurance Services Database. The participants with first prescription of PPIs and H2RA with normal esophagogastroduodenoscopy finding from 2004 through 2015 were collected. Among them, 50% of participants were systematic stratified randomly sampled. There were 122,118 users of PPIs or H2RAs who use medication more than cumulative defined daily dose of 180 days. The users were followed up from long-term use threshold until gastric cancer, death from non-gastric cancer cause, gastric surgery, or study end (December 2017). RESULTS: After calculating propensity score weights, we included 39,799 PPI and 38,967 H2RA users. Among the new PPI and H2RA users, we identified 411 cases of incident gastric cancer from 182,643 person-years of follow-up observation and 397 cases from 178,846 person-years of follow-up observation, respectively. Compared with H2RA users, PPI users did not experience significantly different gastric cancer incidence (adjusted hazard ratio, 1.01; 95% confidence interval, 0.88-1.16; P = 0.89). Sensitivity analyses confirmed that gastric cancer incidence did not differ between PPI and H2RA users. DISCUSSION: In this large study, long-term treatment with PPIs vs H2RAs did not show higher risk of gastric cancer even in a high-risk region.


Assuntos
Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Neoplasias Gástricas/epidemiologia , Adulto , Idoso , Endoscopia do Sistema Digestório , Determinação de Ponto Final , Feminino , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Inibidores da Bomba de Prótons/efeitos adversos , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/induzido quimicamente
11.
JAMA ; 326(3): 240-249, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34180947

RESUMO

Importance: In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption. Objective: To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020. Interventions: Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA. Main Outcome and Measure: Twenty-four-hour urinary excretion of NDMA. Results: Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, -6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, -1.1 [IQR, -9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported. Conclusions and Relevance: In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population. Trial Registration: ClinicalTrials.gov Identifier: NCT04397445.


Assuntos
Dimetilnitrosamina/urina , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Ranitidina/farmacocinética , Administração Oral , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Masculino , Placebos/farmacocinética , Ranitidina/administração & dosagem
12.
J Int Med Res ; 49(6): 3000605211025130, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34182815

RESUMO

OBJECTIVE: We aimed to compare the efficacy and risks of proton pump inhibitor (PPI) versus histamine-2 receptor blocker (H2B) use for stress ulcer prophylaxis (SUP) in critically ill patients with sepsis and risk factors for gastrointestinal bleeding (GIB). METHODS: In this retrospective cohort study, we used the Medical Information Mart for Intensive Care III Clinical Database to identify critically ill adult patients with sepsis who had at least one risk factor for GIB and received either an H2B or PPI for ≥48 hours. Propensity score matching (PSM) was conducted to balance baseline characteristics. The primary outcome was in-hospital mortality. RESULTS: After 1:1 PSM, 1056 patients were included in the H2B and PPI groups. The PPI group had higher in-hospital mortality (23.8% vs. 17.5%), GIB (8.9% vs. 1.6%), and pneumonia (49.6% vs. 41.6%) rates than the H2B group. After adjusting for risk factors of GIB and pneumonia, PPI use was associated with a 1.28-times increased risk of in-hospital mortality, 5.89-times increased risk of GIB, and 1.32-times increased risk of pneumonia. CONCLUSIONS: Among critically ill adult patients with sepsis at risk for GIB, SUP with PPIs was associated with higher in-hospital mortality and higher risk of GIB and pneumonia than H2Bs.


Assuntos
Inibidores da Bomba de Prótons , Sepse , Adulto , Histamina , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Inibidores da Bomba de Prótons/efeitos adversos , Estudos Retrospectivos , Sepse/complicações , Sepse/tratamento farmacológico , Úlcera
15.
Ars pharm ; 62(2): 144-162, abr.-jun. 2021. tab, graf
Artigo em Inglês | IBECS | ID: ibc-202441

RESUMO

INTRODUCTION: The drawbacks assosiated with oral administration of drugscan be controlled or minimized by gastro retentive formulations that remain buoyant within the stomach for an extended time by providing prolonged gastric retention and release the drug in an exceedingly extended manner thereby improving bioavailability. The current research was to develop and optimize Domperidone and Famotidine floating tablets with extended release by Quality by Design approach. METHOD: Based on QTPP (Quality Target Product Profile), CQAs (Critical Quality Attributes) were identified. Risk analysis by the evaluation of formulation and process parameters showed that optimizing the levels of polymers could reduce high risk to achieve the target profile. A 23 factor experimental design with midpoints was selected for statistical analysis and optimization. RESULTS: HPMC K100 and Carbopol 934P had a positive effect while ethyl cellulose demonstrated a negative effect on the selected responses. Drug release kinetics followed the first-order release with Higuchi diffusion and Fickian diffusion. Optimized formula satisfying all the required parameters was selected and evaluated. The predicted response values were in close agreement with experimental response values. Abdominal X-ray imaging after oral administration of the tablets on a healthy rabbit's stomach confirmed the extended floating behavior with shorter lag time. In vivo, pharmacokinetic studies in rabbits revealed that the optimized formulation exhibited prolonged drug release with enhanced Cmax, tmax, AUCo-t, and t1/2 of an optimized product when compared to the marketed product. CONCLUSIONS: It has been concluded that the application of Quality by Design in the formulation and optimization reduced the number of trials to produce a cost-effective formula


INTRODUCCIÓN: Los inconvenientes de la administración oral pueden controlarse o minimizarse mediante formulaciones gastro-retentivas que permanecen flotantes dentro del estómago durante un tiempo prolongado al proporcionar una retención gástrica prolongada y liberan el fármaco de una manera excesivamente prolongada mejorando así la biodisponibilidad. La investigación actual fue desarrollar y optimizar las tabletas flotantes de domperidona y famotidina con liberación prolongada mediante el enfoque Calidad por diseño. MÉTODO: Basado en QTPP (Perfil de producto objetivo de calidad), se identificaron CQA (Atributos críticos de calidad). El análisis de riesgos mediante la evaluación de los parámetros de formulación y proceso mostró que la optimización de los niveles de polímeros podría reducir el alto riesgo para lograr el perfil objetivo. Se seleccionó un diseño experimental de 2 factores de nivel 3 con puntos medios para el análisis estadístico y la optimización. RESULTADOS: HPMC K100, Carbopol 934P tuvo un efecto positivo y la etilcelulosa tuvo un efecto negativo sobre las respuestas seleccionadas. La cinética de liberación del fármaco siguió a la liberación de primer orden con difusión de Higuchi y difusión de Fickian. Se seleccionó y evaluó una fórmula optimizada que satisfacía todos los parámetros requeridos. Los valores de respuesta previstos estaban en estrecha concordancia con los valores de respuesta experimental. Las imágenes de rayos X abdominales después de la administración oral de las tabletas en el estómago sano del conejo confirmaron el comportamiento de flotación prolongado con un tiempo de retraso más corto. Losin vivo estudios farmacocinético sen conejos revelaron que la formulación optimizada exhibía una liberación prolongada del fármaco con una mayor Cmax, tmax, AUCo-t y t1 / 2 del producto. CONCLUSIONES: Se concluyó que la aplicación de Quality by Design en la formulación y optimización redujo el número de ensayos para producir una fórmula rentable


Assuntos
Animais , Coelhos , Sistemas de Liberação de Medicamentos/métodos , Domperidona/farmacologia , Famotidina/farmacologia , Antieméticos/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Liberação Controlada de Fármacos , Desenho de Fármacos , Combinação de Medicamentos , Fatores de Tempo , Disponibilidade Biológica , Medição de Risco , Comprimidos/farmacologia
16.
Am J Gastroenterol ; 116(8): 1612-1619, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34028367

RESUMO

INTRODUCTION: Ranitidine has been shown to contain the carcinogen N-nitrosodimethylamine and increase urinary N-nitrosodimethylamine in humans. We investigated whether ranitidine use is associated with increased bladder cancer risk. METHODS: A nested case-control study was conducted within the Primary Care Clinical Informatics Unit Research database which contains general practice records from Scotland. Bladder cancer cases, diagnosed between 1999 and 2011, were identified and matched with up to 5 controls (based on age, sex, general practice, and date of registration). Ranitidine, other histamine-2 receptor agonists, and proton pump inhibitors were identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for comorbidities and smoking. RESULTS: There were 3,260 cases and 14,037 controls. There was evidence of an increased risk of bladder cancer in ranitidine users, compared with nonusers (fully adjusted OR = 1.22; 95% CI 1.06-1.40), which was more marked with use for over 3 years of ranitidine (fully adjusted OR = 1.43; 95% CI 1.05-1.94). By contrast, there was little evidence of any association between proton pump inhibitor use and bladder cancer risk based on any use (fully adjusted OR = 0.98; 95% CI 0.88-1.11) or over 3 years of use (fully adjusted OR = 0.98; 95% CI 0.80-1.20). DISCUSSION: In this large population-based study, the use of ranitidine particularly long-term use was associated with an increased risk of bladder cancer. Further studies are necessary to attempt to replicate this finding in other settings.


Assuntos
Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Ranitidina/efeitos adversos , Neoplasias da Bexiga Urinária/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Antagonistas dos Receptores H2 da Histamina/química , Humanos , Masculino , Pessoa de Meia-Idade , Ranitidina/química , Fatores de Risco , Escócia/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia
17.
Sci Rep ; 11(1): 9405, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931709

RESUMO

Histamine receptor 2 (H2R) blockade is commonly used in patients with gastric, duodenal ulcers or gastroesophageal reflux disease. Beyond the gastrointestinal tract, H2R is expressed by multiple immune cells, yet little is known about the immunomodulatory effects of such treatment. Clinical reports have associated H2R blockade with leukopenia, neutropenia, and myelosuppression, and has been shown to provide clinical benefit in certain cancer settings. To systematically assess effects of H2R blockade on key immune parameters, a single-center, single-arm clinical study was conducted in 29 healthy subjects. Subjects received daily high dose ranitidine for 6 weeks. Peripheral blood immunophenotyping and mediator analysis were performed at baseline, 3 and 6 weeks into treatment, and 12 weeks after treatment cessation. Ranitidine was well-tolerated, and no drug related adverse events were observed. Ranitidine had no effect on number of neutrophils, basophils or eosinophils. However, ranitidine decreased numbers of B cells and IL-2Rα (CD25) expressing T cells that remained lower even after treatment cessation. Reduced serum levels of IL-2 were also observed and remained low after treatment. These observations highlight a previously unrecognised immunomodulatory sustained impact of H2R blockade. Therefore, the immune impacts of H2R blockade may require greater consideration in the context of vaccination and immunotherapy.


Assuntos
Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Leucócitos/efeitos dos fármacos , Ranitidina/efeitos adversos , Adulto , Contagem de Linfócito CD4 , Feminino , Voluntários Saudáveis , Antagonistas dos Receptores H2 da Histamina/imunologia , Humanos , Imunomodulação , Interleucina-2/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ranitidina/imunologia , Adulto Jovem
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