RESUMO
To develop a new kind of famotidine-resin microcapsule for gastric adhesion sustained release by screening out suitable excipients and designing reasonable prescriptions to improve patient drug activities to achieve the expected therapeutic effect. The famotidine drug resin was prepared using the water bath method with carbomer 934 used as coating material. Microcapsules were prepared using the emulsified solvent coating method and appropriate excipients were used to prepare famotidine sustained release suspension. Pharmacokinetics of the developed microcapsules were studied in the gastrointestinal tract of rats. The self-made sustained-release suspension of famotidine hydrochloride effectively reduced the blood concentration and prolonged the action time. The relative bioavailability of the self-made suspension of the famotidine hydrochloride to the commercially available famotidine hydrochloride was 146.44%, with an average retention time of about 5h longer, which indicated that the new suspension had acceptable adhesion properties. The findings showed that the newly developed famotidine-resin microcapsule increased the bioavailability of the drug with a significant sustained-release property.
Assuntos
Disponibilidade Biológica , Preparações de Ação Retardada , Famotidina , Famotidina/farmacocinética , Famotidina/administração & dosagem , Famotidina/química , Famotidina/farmacologia , Animais , Ratos , Masculino , Excipientes/química , Suspensões , Cápsulas , Liberação Controlada de Fármacos , Resinas Acrílicas/química , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/farmacologia , Antagonistas dos Receptores H2 da Histamina/química , Adesividade , Composição de Medicamentos , AcrilatosRESUMO
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 & AIMS: Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs are associated with an increased risk of gastric cancer (GC) after Helicobacter pylori (Hp) eradication, it is uncertain whether PCABs carry the same risk. METHODS: Using a population-based claims database in Japan, we identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018. Patients who failed this regimen and those diagnosed with GC before or within 1 year after Hp eradication were excluded. We compared GC incidence between PCAB users and histamine type-2 receptor antagonist (H2RA) users, matching them on the basis of propensity scores calculated with considerations for age, sex, smoking, alcohol consumption, comorbidities, and co-administered medications. PCABs included only vonoprazan in this study. RESULTS: Among 54,055 patients, 568 (1.05%) developed GC during the follow-up period (mean, 3.65 years). The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in PCAB users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. The use of PCABs was associated with a higher GC risk (matched hazard ratio, 1.92; 95% confidence interval, 1.13-3.25; P = .016). Longer PCAB use and high-dose PCAB use were significantly associated with higher incidence of GC. Sensitivity analyses showed the risk of GC incidence among PCAB users was comparable with that of PPI users. CONCLUSIONS: The use of PCABs was associated with an increased risk of GC among Hp-eradicated patients, with duration/dose response effects.
Assuntos
Infecções por Helicobacter , Inibidores da Bomba de Prótons , Pirróis , Neoplasias Gástricas , Sulfonamidas , Humanos , Masculino , Feminino , Neoplasias Gástricas/epidemiologia , Infecções por Helicobacter/complicações , Pessoa de Meia-Idade , Japão/epidemiologia , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Idoso , Incidência , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Helicobacter pylori , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Estudos Retrospectivos , Adulto , Medição de Risco , Fatores de Risco , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêuticoRESUMO
Proton pump inhibitor (PPI) use may be associated with renal dysfunction. Renal dysfunction in PPI users requires evaluation of development and progression risks simultaneously, using estimated glomerular filtration rate (eGFR) slope, which indicates changes in eGFR per year. To the best of our knowledge, no studies have evaluated eGFR slope in PPI users. This study investigated the association between PPI use and renal dysfunction using eGFR slope. A single-center cohort study was conducted using the health records data at Hamamatsu University Hospital in Japan. Participants were defined as first users of acid-suppressing drugs (PPIs or Histamine H2 receptor antagonists (H2RAs)) from 2010 to 2021 and continuously prescribed for ≥ 90 days. The H2RA group was used for the propensity-score matching (PSM) to the PPI group to minimize the effects of confounders. The eGFR slope was estimated using a linear mixed effects model. Participants were stratified by baseline eGFR and age, respectively, as subgroup analyses. A total of 4,649 acid-suppressing drug users met the inclusion criteria, including 950 taking H2RAs and 3,699 PPIs. After PSM, 911 patients were assigned to each group. The eGFR slopes of the PPI and H2RA users were -4.75 (95% CI: -6.29, -3.20) and -3.40 (-4.38, -2.42), respectively. The difference between the groups was not significant. Significant declines in eGFR were observed with PPIs with baseline eGFR ≥ 90 and age < 65. PPI use for ≥ 90 days may hasten eGFR decline compared to H2RA use, especially in patients with eGFR ≥ 90 or age < 65.
Assuntos
Taxa de Filtração Glomerular , Antagonistas dos Receptores H2 da Histamina , Inibidores da Bomba de Prótons , Humanos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Estudos de Coortes , Japão , Idoso de 80 Anos ou mais , AdultoRESUMO
PURPOSE: Paclitaxel is associated with hypersensitivity reactions (HSRs). Intravenous premedication regimens have been devised to decrease the incidence and severity of HSRs. At our institution oral histamine 1 receptor antagonists (H1RA) and histamine 2 receptor antagonists (H2RA) were adopted as standard. Standardizations were implemented for consistent premedication use in all disease states. The purpose of this retrospective study was to compare the incidence and severity of HSRs before and after standardization. METHODS: Patients who received paclitaxel from 20 April 2018 to 8 December 2020 having an HSR were included in analysis. An infusion was flagged for review if a rescue medication was administered after the start of the paclitaxel infusion. The incidences of all HSR prior to and post-standardization were compared. A subgroup analysis of patients receiving paclitaxel for the first and second time was performed. RESULTS: There were 3499infusions in the pre-standardization group and 1159infusions in the post-standardization group. After review, 100 HSRs pre-standardization and 38 HSRs post-standardization were confirmed reactions. The rate of overall HSRs was 2.9% in the pre-standardization group and 3.3% in the post-standardization group (p = 0.48). HSRs, during the first and second doses of paclitaxel, occurred in 10.2% of the pre-standardization and 8.5% of the post-standardization group (p = 0.55). CONCLUSIONS: This retrospective interventional study demonstrated that same-day intravenous dexamethasone, oral H1RA, and oral H2RA are safe premedication regimens for paclitaxel. No change in the severity of reactions was seen. Overall, better adherence to premedication administration was seen post-standardization.
Assuntos
Antineoplásicos Fitogênicos , Hipersensibilidade a Drogas , Antagonistas dos Receptores Histamínicos H1 , Antagonistas dos Receptores H2 da Histamina , Paclitaxel , Humanos , Dexametasona/uso terapêutico , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/prevenção & controle , Hipersensibilidade a Drogas/tratamento farmacológico , Histamina , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Paclitaxel/uso terapêutico , Pré-Medicação/efeitos adversos , Estudos Retrospectivos , Antagonistas dos Receptores H2 da Histamina/administração & dosagemRESUMO
PURPOSE: Findings from large observational studies on whether the use of acid suppressants increases the risk of dementia have been inconsistent. Since proton pump inhibitors (PPI) and histamine-2 receptor antagonists (H2RA) are the most commonly used acid suppressants in clinical practice, we performed a meta-analysis to examine the influence of PPI and H2RA on the risk of dementia. METHODS: A systematic search was performed on the PubMed, EMBASE, and Cochrane Library databases to identify studies published up to April, 2021. Studies that reported adjusted hazard ratio (HR) with 95% confidence intervals (CI) for the associations of interest were included. Data in the included studies were pooled using the random-effects model for meta-analysis. Statistical analysis was performed using Stata version 12.0 software. RESULTS: Seventeen studies involving 1,251,562 participants were included. It was found that PPI users were not likely to develop dementia compared with those not taking PPI (HR = 0.98, 95% CI: 0.85-1.13). Subgroup analysis based on publication year, location, mean age, duration of PPI use, and female proportion also revealed no association between PPI use and dementia risk. Similarly, H2RA use was not associated with the risk of dementia, as indicated by the pooled HR of 1.20 (95% CI: 0.98-1.47). CONCLUSION: Results of this meta-analysis suggest that PPI and H2RA do not increase the risk of dementia. These results may be used to inform the clinical application of acid suppressants. However, further randomized controlled trials are needed to confirm the present conclusions.
Assuntos
Demência/epidemiologia , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco , Fatores SexuaisRESUMO
PURPOSE: Several observational studies have presented conflicting results on the association between the use of proton pump inhibitors (PPIs) or histamine H2 receptor antagonist (H2RA) and the risk of coronavirus disease 2019 (COVID-19). This systematic review and meta-analysis aimed to examine this association. METHODS: In July 2021, PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for articles investigating the relationship between the two main acid suppressants and COVID-19. Studies showing the effect estimates as hazard ratio (HR) for severe outcomes or incidence of COVID-19 were evaluated using a random-effects model. RESULTS: A total of 15 retrospective cohort studies with 18,109 COVID-19 cases were included in the current meta-analysis. PPI use was significantly associated with severe outcomes of COVID-19 (hazard ratio [HR] = 1.53; 95% confidence interval [CI]: 1.20-1.95) but not with the incidence of COVID-19, whereas H2RA use was significantly associated with decreased incidence (HR = 0.86, 95% CI: 0.76-0.97). For subgroup analyses of PPIs, increased severe outcomes of COVID-19 were observed in < 60 years, active use, in-hospital use, and Asians. For subgroup analyses of H2RAs, decreased severe outcomes of COVID-19 were observed in > 60 years, while in-hospital use and use in Asia were associated with higher disease severity. CONCLUSIONS: Close observation can be considered for COVID-19 patients who use PPIs to prevent severe outcomes. However, caution should be taken because of substantial heterogeneity and plausible protopathic bias.
Assuntos
COVID-19/epidemiologia , COVID-19/patologia , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Fatores Etários , Humanos , Incidência , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores Sexuais , Fatores SociodemográficosRESUMO
BACKGROUND: Acid-suppressive drugs (ASDs) are being used by increasing number of children and young adults. However, evidence for a relationship between ASD use and the risk of fracture in these groups of patients is conflicting. We conducted a meta-analysis to evaluate the risk of fracture in children and young adults exposed to ASDs. METHODS: A literature search was performed using the PUBMED, EMBASE, and Cochrane Library databases from inception to November 2020. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated to determine the relationship of ASD use with fracture risk in children and young adults. RESULTS: Six studies reporting the outcomes of more than 900,000 children and young adults with ASD use were included in the meta-analysis. The pooled RR for fracture with the use of proton pump inhibitors (PPIs) versus non-use of these medications was 1.17 (95% CI = 1.1-1.25; P < 0.001) in children and 1.2 (95% CI = 0.87-1.65; P = 0.272) in young adults. By contrast, the use of histamine H2-receptor antagonists (H2RAs) was not significantly associated with fracture risk in children (RR, 1.08, 95% CI = 0.99-1.17; P = 0. 083) or young adults (RR, 1.08, 95% CI = 0.82-1.42; P = 0.589). Significant statistical and clinical heterogeneity among studies were determined for the main analysis and most of the subgroup analyses. CONCLUSIONS: Our study provides evidence linking PPI use to an increased risk of fracture in children. Thus, the use of PPIs in these patients should be carefully considered. However, randomized controlled studies are needed to determine causality and the role of unmeasured/residual confounding factors in this association.
Assuntos
Fraturas Ósseas/epidemiologia , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Masculino , Estudos Observacionais como Assunto , Inibidores da Bomba de Prótons/efeitos adversos , Medição de Risco , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: The discovery that ranitidine is contaminated with N-nitrosodimethylamine, a suspected human carcinogen, raises the hypothesis of a gastrointestinal carcinogenic effect; however, evidence remains inconclusive. METHODS: We used the nationwide Danish Prescription Registry to identify a cohort of incident ranitidine users and two active comparator cohorts comprising users of other histamine-2 receptor blockers (H2RB) and users of proton pump inhibitors (PPI). All Danish adults with a first prescription of ranitidine, other H2RBs, or PPIs in 1996 through 2008 were followed virtually completely through 2018 for incidence of esophageal, stomach, liver, and pancreatic cancers. We used Cox regression with propensity-score weighting to calculate hazard ratios and 10-year cumulative risk with 95% confidence intervals. RESULTS: We ascertained 276 newly diagnosed esophageal, 342 stomach, 133 hepatocellular, and 517 pancreatic cancers among ranitidine users during follow-up (median 14 years). In comparison with use of other H2RBs or PPIs, we found no consistent evidence of increased HRs or excess 10-year cumulative risk of any upper gastrointestinal cancer following ranitidine use. We observed no association after restriction to subjects with at least 5 or 10 prescriptions or those with 10 prescriptions and at least 10 years of follow-up. CONCLUSIONS: Our large prospective study using high-quality prescription and cancer incidence data, with two active comparator groups, provides no compelling evidence that ranitidine increases the risk of upper gastrointestinal cancers. IMPACT: Our results, which do not support any carcinogenic effect on esophagus, stomach, liver or pancreas, should be reassuring for millions of concerned past users of ranitidine.
Assuntos
Neoplasias Gastrointestinais/induzido quimicamente , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Ranitidina/efeitos adversos , Adulto , Estudos de Casos e Controles , Dinamarca , Dimetilnitrosamina/intoxicação , Feminino , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Ranitidina/administração & dosagem , Sistema de RegistrosRESUMO
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 TratamentoRESUMO
AIMS: The study aims at evaluating the effects of the combinatory famotidine/cimetidine diet on radiated mice's survival. MATERIALS AND METHODS: Two hundred and seventy male mice were categorized into 11 groups, a number of which were comprised of subgroups too. The groups under analysis were posed to varying doses of gamma-radiation, including 6, 7, 8, and 9 Gy, followed by treatments using various drug doses 2, 4, and 8 mg/kg, with survival fractions as long as a month after irradiation being measured and recorded. RESULTS: LD50/30 was calculated as 7.47 Gy for the group with radiation only. Following mouse treatment with a concentration of 4 and 20 mg/kg for famotidine and cimetidine, respectively, the survival fraction for the mice grew significantly compared to LD50/30. The combinatory famotidine/cimetidine diet had a higher dose-reduction factor (DRF) than single doses of the drug in radioprotection. The DRF for combinatory famotidine/cimetidine, famotidine, and cimetidine diets was 08.09, 1.1, and 1.01, respectively. CONCLUSIONS: Results imply that the combined regimen of famotidine + cimetidine in radioprotection had no significant higher DRF than with regimens including each of them separately. In addition, we did not find a synergic effect of combined oral famotidine and cimetidine on irradiated mice.
Assuntos
Cimetidina/farmacologia , Famotidina/farmacologia , Lesões por Radiação/mortalidade , Irradiação Corporal Total/efeitos adversos , Administração Oral , Animais , Cimetidina/administração & dosagem , Quimioterapia Combinada , Famotidina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/farmacologia , Masculino , Camundongos , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/etiologia , Taxa de SobrevidaRESUMO
BACKGROUND: The relationship between proton-pump inhibitor (PPI) use and chronic kidney disease (CKD) progression remains controversial. Specifically, there is a lack of data evaluating renal outcomes in established CKD patients. The aim of our study is to determine the risk of progression to end-stage kidney disease (ESKD) or death amongst CKD patients on PPI, histamine-2 receptor blocker (H2B), or no anti-acid therapy. METHODS: Using our CKD registry, we evaluated the relationship between PPI and H2B use and outcomes amongst patients with CKD (eGFR < 60), with at least 2 PCP visits in the year prior. A Cox proportional hazards model was used to evaluate the relationship between medication groups and overall mortality, while competing risks regression models were used to determine the risk of ESKD with death as a competing risk. RESULTS: 25,455 patients met inclusion criteria and were stratified according to medication group: no antacid therapy (15,961), PPI use (8646), or H2B use (848). At 4 years, the cumulative incidence of ESKD with death as a competing risk was 2.0% (95% CI: 1.7, 2.4), 1.5% (0.8, 2.8), and 1.6%(1.4, 1.9) among PPI, H2B, and no medication respectively (P = 0.22). The cumulative incidence of death with ESKD as a competing risk was 17.6% (95% CI: 16.6, 18.6), 16.7% (13.7, 19.8), and 17.3% (16.6, 18.0) (P = 0.71). CONCLUSIONS: Use of PPI in a CKD population was not associated with increased mortality or progression to ESKD when compared to H2 blocker and to no acid suppressing therapy.
Assuntos
Antagonistas dos Receptores H2 da Histamina , Falência Renal Crônica , Inibidores da Bomba de Prótons , Insuficiência Renal Crônica , Gastropatias , Comorbidade , Progressão da Doença , Feminino , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Incidência , Estimativa de Kaplan-Meier , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Resultados Negativos , Avaliação de Resultados em Cuidados de Saúde , Modelos de Riscos Proporcionais , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Sistema de Registros/estatística & dados numéricos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Medição de Risco , Gastropatias/tratamento farmacológico , Gastropatias/epidemiologia , Estados Unidos/epidemiologiaRESUMO
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 & dosagemRESUMO
BACKGROUND: Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine. METHODS: This prospective, pre-post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade ≥3. Non-inferiority was determined by checking whether the upper bound of the two-sided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin. RESULTS: In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade ≥3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference -2.7% (90% CI: -6.2 to 0.1). CONCLUSIONS: As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine. CLINICAL TRIAL REGISTRATION: www.trialregister.nl ; NL8173.
Assuntos
Hipersensibilidade a Drogas/prevenção & controle , Neoplasias/tratamento farmacológico , Paclitaxel/efeitos adversos , Pré-Medicação/métodos , Ranitidina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioprevenção/efeitos adversos , Quimioprevenção/métodos , Clemastina/administração & dosagem , Dexametasona/administração & dosagem , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/patologia , Quimioterapia Combinada , Estudos de Equivalência como Asunto , Feminino , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Humanos , Infusões Intravenosas , Masculino , Futilidade Médica , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/patologia , Países Baixos/epidemiologia , Paclitaxel/administração & dosagem , Pré-Medicação/efeitos adversos , Ranitidina/administração & dosagem , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
We have previously shown that histamine (2-(1H-imidazol-4-yl)ethanamine) exerted concentration-dependent positive inotropic effects (PIE) or positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic (H2R-TG) mice that overexpress the human H2 histamine receptor (H2R) in the heart; however, the effects were not seen in their wild-type (WT) littermates. Amitriptyline, which is still a highly prescribed antidepressant drug, was reported to act as antagonist on H2Rs. Here, we wanted to determine whether the histamine effects in H2R-TG were antagonized by amitriptyline. Contractile studies were performed on isolated left and right atrial preparations, isolated perfused hearts from H2R-TG and WT mice and human atrial preparations. Amitriptyline shifted the concentration-dependent PIE of histamine (1 nM-10 µM) to higher concentrations (rightward shift) in left atrial preparations from H2R-TG. Similarly, in isolated perfused hearts from H2R-TG and WT mice, histamine increased the contractile parameters and the phosphorylation state of phospholamban (PLB) at serine 16 in the H2R-TG mice, but not in the WT mice. However, the increases in contractility and PLB phosphorylation were attenuated by the addition of amitriptyline in perfused hearts from H2R-TG. In isolated electrically stimulated human atria, the PIE of histamine that was applied in increasing concentrations from 1 nM to 10 µM was reduced by 10-µM amitriptyline. In summary, we present functional evidence that amitriptyline also acts as an antagonist of contractility at H2Rs in H2R-TG mouse hearts and in the human heart which might in part explain the side effects of amitriptyline.
Assuntos
Amitriptilina/farmacologia , Átrios do Coração/efeitos dos fármacos , Antagonistas dos Receptores H2 da Histamina/farmacologia , Receptores Histamínicos H2/efeitos dos fármacos , Amitriptilina/administração & dosagem , Animais , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/farmacologia , Relação Dose-Resposta a Droga , Átrios do Coração/metabolismo , Histamina/administração & dosagem , Histamina/metabolismo , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Camundongos , Camundongos Transgênicos , Contração Miocárdica/efeitos dos fármacos , Receptores Histamínicos H2/metabolismo , Especificidade da EspécieRESUMO
PURPOSE: Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib. METHODS: Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3-5 or 8-12 h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects. RESULTS: Median PFS in H2RA group and control group was 8.0 months and 9.0 months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60-1.48, 0.52-1.43; p = 0.82 and 0.60, respectively). CONCLUSION: This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Interações Medicamentosas , Feminino , Gefitinibe/administração & dosagem , Gefitinibe/efeitos adversos , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
A range of gastroprotective drugs are available for the treatment of esophagitis and gastroduodenal mucosal injury including acid suppressants (ie, histamine-2 receptor antagonists, proton pump inhibitors), coating agents, prostaglandin analogs, and antacids. Of these, the proton pump inhibitors are the most effective drugs for the medical treatment of upper gastrointestinal injury. However, proton pump inhibitors are not effective for all causes of upper gastrointestinal injury. The choice of gastroprotective drug should be guided by the cause and location of gastrointestinal injury and the potential for adverse effects.
Assuntos
Doenças do Cão/tratamento farmacológico , Úlcera Gástrica/veterinária , Animais , Antiácidos/administração & dosagem , Antiácidos/uso terapêutico , Cães , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Úlcera Gástrica/tratamento farmacológicoRESUMO
The present study investigated the plausible modulatory role of central histaminergic transmission on the expression of nicotine withdrawal induced anxiety and somatic behavior in mice. Abrupt cessation of chronic nicotine (2 mg/kg, i.p. × 3/day) treatment for 12 days to mice, expressed increased anxiety in light & dark test and total abstinence (somatic) score at 24 h post nicotine withdrawal time. The somatic signs includes a composite score of all behaviors such as grooming, rearing, jumping, body shakes, forelimb tremors, head shakes, abdominal constrictions, scratching, empty mouth chewing or teeth chattering, genital licking, tail licking. Mice exhibited higher expression to nicotine withdrawal induced anxiety in light & dark test at 24 h post-nicotine withdrawal time on pre-treatment centrally (i.c.v) with histaminergic agents like histamine (0.1, 50 µg/mouse), histamine H3 receptor inverse agonist, thioperamide (2, 10 µg/mouse), histamine H1 receptor agonist, FMPH (2, 6.5 µg/mouse) or H2 receptor agonist amthamine (0.1, 0.5 µg/mouse) or intraperitoneally (i.p.) with histamine precursor, l-histidine (250, 500 mg/kg) as compared to control nicotine withdrawn animals. Furthermore, mice pre-treated with all these histaminergic agents except histamine H1 receptor agonist, FMPH shows exacerbated expression to post-nicotine withdrawal induced total abstinence (somatic) score in mice. On the other hand, central injection of selective histamine H1 receptor antagonist, cetirizine (0.1 µg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50 µg/mouse, i.c.v) to mice 10 min before 24 h post-nicotine withdrawal time completely alleviated the expression of nicotine withdrawal induced anxiety and somatic behavior. Thus, it can be contemplated that the blockade of central histamine H1 or H2 receptor during the nicotine withdrawal phase could be a novel approach to mitigate the nicotine withdrawal associated anxiety-like manifestations. Contribution of endogenous histamine via H1 or H2 receptor stimulation in the nicotine withdrawal induced anxiety and somatic behavior is proposed.
Assuntos
Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/etiologia , Animais , Ansiedade/fisiopatologia , Cetirizina/farmacologia , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Histidina/farmacologia , Masculino , Camundongos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Fenil-Hidrazinas/farmacologia , Piperidinas/farmacologia , Ranitidina/farmacologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Tiazóis/farmacologiaRESUMO
Lemborexant is a dual orexin receptor antagonist approved for treating insomnia. As the solubility of lemborexant is pH-sensitive, the impact of the gastric acid-reducing agent (ARA), famotidine, on lemborexant pharmacokinetics was evaluated in a Phase 1 study. Additionally, post hoc analysis of data from Phase 3 studies examined the potential effect of concomitant ARAs on patient-reported/subjective sleep onset latency (sSOL) in subjects with insomnia. Coadministration of lemborexant 10 mg with famotidine decreased the maximum observed concentration by 27% and delayed time of maximum observed concentration by 0.5 hours. Famotidine did not affect overall lemborexant exposure based on comparison of area under the concentration curves. Concomitant ARA use in the Phase 3 studies did not impact the effect of lemborexant on sSOL; the change from baseline during the last 7 nights of 1 month of treatment with lemborexant 10 mg was -17.1 minutes with vs -17.9 minutes without ARAs. Collectively, these results indicate that lemborexant can be coadministered with ARAs.
Assuntos
Famotidina/farmacocinética , Ácido Gástrico/metabolismo , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Antagonistas dos Receptores de Orexina/farmacocinética , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Adulto , Método Duplo-Cego , Interações Medicamentosas/fisiologia , Famotidina/administração & dosagem , Feminino , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Masculino , Antagonistas dos Receptores de Orexina/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Resultado do TratamentoRESUMO
H2 receptors' antagonists (H2RA) are widely used drugs and they are generally well-tolerated. Ranitidine hypersensitivity reactions (HR) are rarely reported. The article emphasizes the importance of recognizing ranitidine as a cause of anaphylaxis and the advantages and limits of allergological evaluation to establish a positive diagnose. We reviewed a series of published cases of ranitidine-induced hypersensitivity reactions, starting from a clinical case presentation. Moreover, we analyzed the ranitidine related adverse events in the Eudravigilance European database of adverse reactions. Most of the allergic reactions induced by ranitidine are type I HR with immediate onset after exposure, with variable clinical presentation. But in a few cases, there were also described delayed reactions, some after occupational exposure. The article underlines the importance of allergy evaluation to avoid future contact with the drug to reduce the risk of more severe reactions. The suspected reactions should be reported, allowing pharmacovigilance systems to analyse them and to establish further recommendations for clinicians.