RESUMEN
PURPOSE: Gastritis, one of the most common clinically diagnosed conditions, is defined as the infiltration of inflammatory cells into the gastric mucosa. Drugs for gastritis include histamine-2 receptor antagonists and proton pump inhibitors (PPIs), which reduce acidity in the stomach, and antacids, which neutralize acid. Esomeprazole is a PPI for gastroesophageal reflux disease and gastric and duodenal ulcers that has been shown to be safe and effective at a 10 mg dose. Dual-release drugs have not yet been approved for the treatment of gastritis domestically or internationally. In this study, a dual delayed-release (DR) esomeprazole (10 mg), was compared to famotidine (20 mg) to determine its effectiveness in the treatment of gastritis. METHODS: This study was a randomized, open-label, multiple-dose, 2-treatment, 2-period, 2-sequence crossover study with a 7-day washout between periods. In each period, the subjects were administered one dose of esomeprazole (10 mg) or famotidine (20 mg) for 7 days at each period. The 24-hour gastric pH was recorded after single and multiple doses. The percentage of time (duration%) that the pH was maintained above 4 in the 24 hours after 7 days of repeated dosing was evaluated. FINDINGS: The mean percentages of time that the gastric pH was above 4 after multiple doses over 7 days of a dual DR esomeprazole (10 mg) and famotidine (20 mg) was 47.31% ± 14.85% and 23.88% ± 10.73%. IMPLICATIONS: Multiple doses of a dual DR esomeprazole (10 mg) showed effective gastric acid secretion suppression compared to famotidine with comparable safety and tolerability. These results provide evidence supporting the clinical use of a dual DR esomeprazole (10 mg) to treat gastritis. CLINICALTRIALS: gov identifier: NCT04967014.
Asunto(s)
Estudios Cruzados , Preparaciones de Acción Retardada , Esomeprazol , Famotidina , Gastritis , Esomeprazol/administración & dosificación , Esomeprazol/farmacología , Humanos , Famotidina/administración & dosificación , Masculino , Adulto , Femenino , Adulto Joven , Gastritis/tratamiento farmacológico , República de Corea , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/farmacología , Concentración de Iones de Hidrógeno , Voluntarios Sanos , Determinación de la Acidez Gástrica , Ácido Gástrico/metabolismo , Antiulcerosos/administración & dosificación , Antiulcerosos/farmacología , Antiulcerosos/farmacocinéticaRESUMEN
OBJECTIVE: This study investigated the raft-forming suspension of famotidine as an anti-reflux formulation to improve the oral bioavailability of narrow absorption window drugs by enhancing gastric residence time (GRT) and preventing gastro-esophageal reflux disease (GERD). METHOD: Various combinations of raft-forming agents, such as Tragacanth gum (TG), guar gum (GG), and xanthan gum (XG), were evaluated alongside sodium alginate (SA) to develop an effective raft. Preformulation studies and preliminary screening were conducted to identify the most suitable raft-forming agent, and GG was chosen due to its mucilaginous properties. The formulation was optimized using a 32 full factorial design, with the quantities of GG and SA as independent factors and apparent viscosity and in-vitro drug release (%) as dependent factors. The in vivo floating behavior study was performed for optimized and stabilized formulation. RESULTS: Among the tested batches, F6 was selected as the optimized formulation. It exhibited desirable characteristics such as adequate raft weight for extended floating in gastric fluid, improved apparent viscosity, and a significant percentage of drug release at 12 h. A mathematical model was applied to the in-vitro data to gain insights into the drug release mechanism of the formulation. The stability of the suspension was assessed under accelerated conditions, and it demonstrated satisfactory stability. The formulation remains floating in the Rabbit stomach for more than 12 h. CONCLUSION: It concludes that the developed formulation has enhanced bioavailability in the combination of GG and SA. The floating layer of the raft prevents acid reflux, and the famotidine is retained for an extended period of time in the gastric region, preventing excess acid secretion. The developed formulations are effective for stomach ulcers and GERD, with the effect of reducing acid secretion by H2 receptor antagonists.
Asunto(s)
Sistemas de Liberación de Medicamentos , Famotidina , Galactanos , Famotidina/administración & dosificación , Famotidina/farmacocinética , Animales , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Alginatos , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/metabolismo , Disponibilidad Biológica , Mananos/administración & dosificación , Gomas de Plantas , Viscosidad , Masculino , Conejos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/efectos de los fármacos , Polisacáridos Bacterianos , Estabilidad de Medicamentos , Administración OralRESUMEN
OBJECTIVE: Visual analog scale (VAS) can be used to evaluate multiple parameters. There have been no reports on the verification of order effects or reproducibility of the VAS method for overall palatability of oral dosage forms. The purpose of this study was to assess the validity of a method for evaluating the palatability of orally disintegrating tablets (ODTs) using a 100-mm VAS. MATERIALS AND METHODS: We conducted clinical trials to evaluate the overall palatability, taste, and scent of 3 ODTs (F1, F2, F3) that contained famotidine (20, 10, and 5 mg, respectively). The study protocol was approved by the Research Ethics Committee of the University of Shizuoka, Japan (No. 21 - 36). To investigate the intergroup reproducibility of the VAS evaluation, 40 participants were divided into three groups, and each group underwent human gustatory sensation test of F1, F2, and F3, performed using a crossover design with 6 different tasting sequences. To evaluate intragroup reproducibility of the VAS evaluation, the participants assessed the same ODTs twice. RESULTS: The VAS scores for overall palatability followed the same order (F3>F2>F1) in all groups. The VAS scores for the overall palatability of F1, F2, and F3 did not significantly differ between the first and second evaluations. The Kruskal-Wallis test indicated a minimal impact of the assessment order on ODT evaluations. We confirm the reliability and reproducibility of the VAS method for evaluating ODT palatability. CONCLUSION: The VAS method for assessing ODT palatability provides accurate information and can contribute to the design and manufacture of patient-friendly pharmaceutical products.
Asunto(s)
Estudios Cruzados , Comprimidos , Gusto , Escala Visual Analógica , Humanos , Administración Oral , Reproducibilidad de los Resultados , Masculino , Adulto , Femenino , Famotidina/administración & dosificación , Adulto JovenRESUMEN
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.
Asunto(s)
Disponibilidad Biológica , Preparaciones de Acción Retardada , Famotidina , Famotidina/farmacocinética , Famotidina/administración & dosificación , Famotidina/química , Famotidina/farmacología , Animales , Ratas , Masculino , Excipientes/química , Suspensiones , Cápsulas , Liberación de Fármacos , Resinas Acrílicas/química , Antagonistas de los Receptores H2 de la Histamina/farmacocinética , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Antagonistas de los Receptores H2 de la Histamina/farmacología , Antagonistas de los Receptores H2 de la Histamina/química , Adhesividad , Composición de Medicamentos , AcrilatosRESUMEN
In this study, a new gastro-floating sustained-release tablet (GFT) with a combination of Etoricoxib (ET) and Famotidine (FM) was successfully developed. GFTs were prepared by using a combination of hydrophilic swellable natural/semi-synthetic polymers as a controlled-release layer. Through a 24 full factorial statistical experimental design, the effects of formulation factors on the release of GFTs were conducted. The ideal floating tablet (FT) comprised konjac-gum (150 mg), guar-gum (26.57 mg), xanthan-gum (54.17 mg), and HPMC-K15-M (69.25 mg). The ideal FT exhibited a high swelling index (SI) (297.7%) and rapid FLT (around 50 s) in 0.1 N HCl as well as controlled release of ET (22.43% in 1 h and 77.47% in 8 h) and FM (24.89% in 1 h and 93.82% in 8 h) with the absence of any drug-excipient interactions. The AUC0â¼72 (ng h/mL) of ET and FM in the GFTs were approximately double-fold of the market, respectively. The relative bioavailability was (207.48 ± 12.02% and 208.51 ± 13.11%) compared with commercial tablets. The X-ray imaging showed a promising buoyancy ability for approximately 8 h. These findings revealed the successful preparation of the sustained-release floating tablet with improved dual drug delivery.
Asunto(s)
Preparaciones de Acción Retardada , Liberación de Fármacos , Etoricoxib , Famotidina , Comprimidos , Famotidina/administración & dosificación , Famotidina/farmacocinética , Famotidina/química , Etoricoxib/administración & dosificación , Etoricoxib/farmacocinética , Etoricoxib/química , Animales , Masculino , Conejos , Excipientes/química , Disponibilidad BiológicaRESUMEN
Cilofexor is a nonsteroidal farnesoid X receptor agonist being developed in combination with firsocostat/semaglutide for the treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated the effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of cilofexor (100- or 30-mg fixed-dose combination with firsocostat) in healthy participants. Cohorts 1 (n = 20, 100 mg) and 2 (n = 30, 30 mg) followed a 3-period, 2-sequence crossover design and evaluated effects of light-fat and high-fat meals. Cohort 3 (n = 30, 100 mg fasting) followed a 2-period, 2-sequence crossover design and evaluated the effects of a 40-mg single dose of famotidine. Cohort 4 (n = 18, 100 mg) followed a 3-period, 2-sequence crossover design and evaluated the effects of a 40-mg once-daily regimen of omeprazole administered under fasting conditions or following a light-fat meal. Administration with light-fat or high-fat meals resulted in no change and an â¼35% reduction in cilofexor AUC, respectively, relative to the fasting conditions. Under fasting conditions, famotidine increased cilofexor AUC by 3.2-fold and Cmax by 6.1-fold, while omeprazole increased cilofexor AUC by 3.1-fold and Cmax by 4.8-fold. With a low-fat meal, omeprazole increased cilofexor exposure to a lesser extent (Cmax 2.5-fold, AUC 2.1-fold) than fasting conditions. This study suggests that caution should be exercised when cilofexor is administered with ARAs under fed conditions; coadministration of cilofexor (100 or 30 mg) with ARAs under fasting conditions is not recommended with the current clinical trial formulations.
Asunto(s)
Estudios Cruzados , Interacciones Alimento-Droga , Receptores Citoplasmáticos y Nucleares , Humanos , Masculino , Receptores Citoplasmáticos y Nucleares/agonistas , Adulto , Femenino , Adulto Joven , Persona de Mediana Edad , Comidas , Famotidina/farmacocinética , Famotidina/administración & dosificación , Ayuno/metabolismo , Combinación de Medicamentos , Voluntarios Sanos , Grasas de la Dieta/administración & dosificación , Área Bajo la CurvaRESUMEN
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.
Asunto(s)
Cimetidina/farmacología , Famotidina/farmacología , Traumatismos por Radiación/mortalidad , Irradiación Corporal Total/efectos adversos , Administración Oral , Animales , Cimetidina/administración & dosificación , Quimioterapia Combinada , Famotidina/administración & dosificación , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Antagonistas de los Receptores H2 de la Histamina/farmacología , Masculino , Ratones , Traumatismos por Radiación/tratamiento farmacológico , Traumatismos por Radiación/etiología , Tasa de SupervivenciaRESUMEN
AIM: The present research was aimed to develop thiolated polyacrylic acid (TPA) based microspheres (MSPs) containing famotidine (FX) and clarithromycin (CLX). METHODS: TPA was synthesised from polyacrylic acid and l-cysteine in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC). The prepared TPA was characterised using FT-IR (Fourier transform-infra red), 1H-NMR (proton nuclear magnetic resonance) spectroscopy, P-XRD (powder X ray diffraction) method, and zeta potential. The analytical tools have supported the formation of TPA. The thiolated microspheres were prepared by emulsion solvent evaporation method using 0.75% w/v polymer concentration and stirring at 400 rpm for 8 hr. RESULTS: The average particle size and zeta potential of optimised formulation was found to be 25.2 ± 1.87 µm and -26.68 mV, respectively. The entrapment efficiency of the optimised formulation was obtained 67.20% for FX and 70.20% for CLX. The developed microspheres were swelled only in 4 h from 0.5 to 0.9. The in vitro mucoadhesive study and in vitro drug release studies demonstrated that microspheres showed mucoadhesive property. In in vitro drug release studies, the release of FX and CLX were observed to be 58.68% and 60.48%, respectively from microspheres in 8 h. The thiolated microspheres showed higher adhesion time (7.0 ± 0.8 h) in comparison to the plain microspheres (2.6 ± 0.4 h). CONCLUSION: The prepared TPA based mucoadhesive microspheres can be utilised as carriers for the treatment of peptic ulcer caused by Helicobacter pylori which will offer enhanced residence time for the rational drug combination in the gastric region.
Asunto(s)
Antibacterianos/administración & dosificación , Antiulcerosos/administración & dosificación , Claritromicina/administración & dosificación , Famotidina/administración & dosificación , Resinas Acrílicas , Adhesivos , Quitosano , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Emulsiones , Excipientes , Mucosa Gástrica , Microesferas , Tamaño de la Partícula , Material ParticuladoRESUMEN
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.
Asunto(s)
Famotidina/farmacocinética , Ácido Gástrico/metabolismo , Antagonistas de los Receptores H2 de la Histamina/farmacocinética , Antagonistas de los Receptores de Orexina/farmacocinética , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Adulto , Método Doble Ciego , Interacciones Farmacológicas/fisiología , Famotidina/administración & dosificación , Femenino , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Humanos , Masculino , Antagonistas de los Receptores de Orexina/administración & dosificación , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: The COVID-19 pandemic due to SARS-CoV-2 infection can produce Acute Respiratory Distress Syndrome as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria, and might reduce the histamine-mediated pulmonary cytokine storm in COVID-19. Can a combination of Histamine-1 and Histamine-2 receptor blockers improve COVID-19 inpatient outcomes? METHODS: A physician-sponsored cohort study of cetirizine and famotidine was performed in hospitalized patients with severe to critical pulmonary symptoms. Pulmonologists led the inpatient care in a single medical center of 110 high-acuity patients that were treated with cetirizine 10 mg b.i.d. and famotidine 20 mg b.i.d. plus standard-of-care. RESULTS: Of all patients, including those with Do Not Resuscitate directives, receiving the dual-histamine receptor blockade for at least 48 h, the combination drug treatment resulted in a 16.4% rate of intubation, a 7.3% rate of intubation after a minimum of 48 h of treatment, a 15.5% rate of inpatient mortality, and 11.0 days duration of hospitalization. The drug combination exhibited beneficial reductions in inpatient mortality and symptom progression when compared to published reports of COVID-19 inpatients. Concomitant medications were assessed and hydroxychloroquine was correlated with worse outcomes. CONCLUSIONS: This physician-sponsored cohort study of cetirizine and famotidine provides proof-of-concept of a safe and effective method to reduce the progression in symptom severity, presumably by minimizing the histamine-mediated cytokine storm. Further clinical studies in COVID-19 are warranted of the repurposed off-label combination of two historically-safe histamine receptor blockers.
Asunto(s)
Cetirizina/administración & dosificación , Infecciones por Coronavirus/tratamiento farmacológico , Famotidina/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Neumonía Viral/tratamiento farmacológico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus/aislamiento & purificación , COVID-19 , Estudios de Cohortes , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/fisiopatología , Neumonía Viral/virología , Infecciones del Sistema Respiratorio/fisiopatología , SARS-CoV-2 , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine's pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Famotidina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Administración Intravenosa , Antivirales/administración & dosificación , Antivirales/farmacocinética , COVID-19 , Simulación por Computador , Reposicionamiento de Medicamentos , Famotidina/administración & dosificación , Famotidina/farmacocinética , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Pandemias , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Replicación Viral/efectos de los fármacosRESUMEN
OBJECTIVE: Treatment options for non-hospitalised patients with coronavirus disease 2019 (COVID-19) to reduce morbidity, mortality and spread of the disease are an urgent global need. The over-the-counter histamine-2 receptor antagonist famotidine is a putative therapy for COVID-19. We quantitively assessed longitudinal changes in patient reported outcome measures in non-hospitalised patients with COVID-19 who self-administered high-dose famotidine orally. DESIGN: Patients were enrolled consecutively after signing written informed consent. Data on demographics, COVID-19 diagnosis, famotidine use, drug-related side effects, temperature measurements, oxygen saturations and symptom scores were obtained using questionnaires and telephone interviews. Based on a National Institute of Health (NIH)-endorsed Protocol to research Patient Experience of COVID-19, we collected longitudinal severity scores of five symptoms (cough, shortness of breath, fatigue, headaches and anosmia) and general unwellness on a four-point ordinal scale modelled on performance status scoring. All data are reported at the patient level. Longitudinal combined normalised symptom scores were statistically compared. RESULTS: Ten consecutive patients with COVID-19 who self-administered high-dose oral famotidine were identified. The most frequently used famotidine regimen was 80 mg three times daily (n=6) for a median of 11 days (range: 5-21 days). Famotidine was well tolerated. All patients reported marked improvements of disease related symptoms after starting famotidine. The combined symptom score improved significantly within 24 hours of starting famotidine and peripheral oxygen saturation (n=2) and device recorded activity (n=1) increased. CONCLUSIONS: The results of this case series suggest that high-dose oral famotidine is well tolerated and associated with improved patient-reported outcomes in non-hospitalised patients with COVID-19.
Asunto(s)
Infecciones por Coronavirus , Monitoreo de Drogas/métodos , Famotidina/administración & dosificación , Pandemias , Neumonía Viral , Evaluación de Síntomas/métodos , Adulto , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Oximetría/métodos , Medición de Resultados Informados por el Paciente , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/fisiopatología , Estudios Retrospectivos , SARS-CoV-2 , Autoadministración , Resultado del TratamientoRESUMEN
Background: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed.Results: BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.
Asunto(s)
Receptores de Esfingosina-1-Fosfato , Tetrahidronaftalenos/administración & dosificación , Adulto , Grasas de la Dieta/administración & dosificación , Método Doble Ciego , Famotidina/administración & dosificación , Ayuno/metabolismo , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Recuento de Linfocitos , Persona de Mediana Edad , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: Upper gastrointestinal (GI) ulceration and bleeding in critically ill dogs can cause severe anemia and increase morbidity. Acid suppressants using proton pump inhibitors or histamine-2 receptor blockers administered IV is commonly recommended. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy of IV administered esomeprazole, pantoprazole, and famotidine constant rate infusion (CRI) on increasing the intragastric pH of dogs. We hypothesized that esomeprazole and famotidine CRI would provide superior acid suppression compared to pantoprazole and reach pH goals for the treatment of GI bleeding. ANIMALS: Nine healthy research Beagles. METHODS: Randomized, 3-way crossover. Dogs received pantoprazole or esomeprazole at 1 mg/kg IV q12h and famotidine with a loading dose of 1 mg/kg followed by 8 mg/kg IV CRI daily for 3 consecutive days. The intragastric pH was recorded at baseline and for 72 hours of treatment. The mean pH and the mean percentage time (MPT) the intragastric pH was ≥3 or ≥4 were compared among and within treatment groups. RESULTS: Significant increases in mean pH (P < 0.0001), MPT ≥3 (P < 0.001), and MPT ≥4 (P = 0.0006) were noted over time with all 3 treatments. The time effect did not differ by treatment for mean pH, MPT ≥3, and MPT ≥4 (P = .29, .56, and .37, respectively); however, only esomeprazole and famotidine CRI achieved the goals established for the treatment of gastroduodenal ulceration in people. CONCLUSIONS AND CLINICAL IMPORTANCE: Famotidine CRI and esomeprazole might be superior acid suppressants compared to standard doses of pantoprazole for the first 72 hours of treatment.
Asunto(s)
Esomeprazol/farmacología , Famotidina/farmacología , Pantoprazol/farmacología , Animales , Antiulcerosos/administración & dosificación , Antiulcerosos/uso terapéutico , Estudios Cruzados , Perros , Esomeprazol/administración & dosificación , Famotidina/administración & dosificación , Femenino , Concentración de Iones de Hidrógeno , Inyecciones Intravenosas , Masculino , Pantoprazol/administración & dosificaciónRESUMEN
PURPOSE: The design of biorelevant conditions for in vitro evaluation of orally administered drug products is contingent on obtaining accurate values for physiologically relevant parameters such as pH, buffer capacity and bile salt concentrations in upper gastrointestinal fluids. METHODS: The impact of sample handling on the measurement of pH and buffer capacity of aspirates from the upper gastrointestinal tract was evaluated, with a focus on centrifugation and freeze-thaw cycling as factors that can influence results. Since bicarbonate is a key buffer system in the fasted state and is used to represent conditions in the upper intestine in vitro, variations on sample handling were also investigated for bicarbonate-based buffers prepared in the laboratory. RESULTS: Centrifugation and freezing significantly increase pH and decrease buffer capacity in samples obtained by aspiration from the upper gastrointestinal tract in the fasted state and in bicarbonate buffers prepared in vitro. Comparison of data suggested that the buffer system in the small intestine does not derive exclusively from bicarbonates. CONCLUSIONS: Measurement of both pH and buffer capacity immediately after aspiration are strongly recommended as "best practice" and should be adopted as the standard procedure for measuring pH and buffer capacity in aspirates from the gastrointestinal tract. Only data obtained in this way provide a valid basis for setting the physiological parameters in physiologically based pharmacokinetic models.
Asunto(s)
Bicarbonatos/química , Ácidos y Sales Biliares/química , Líquidos Corporales/química , Líquidos Corporales/metabolismo , Tracto Gastrointestinal Superior/química , Tracto Gastrointestinal Superior/metabolismo , Tampones (Química) , Famotidina/administración & dosificación , Famotidina/metabolismo , Absorción Gastrointestinal , Humanos , Concentración de Iones de Hidrógeno , Ibuprofeno/administración & dosificación , Ibuprofeno/metabolismo , Intestino Delgado , Sales (Química)/química , EstómagoRESUMEN
Although acid suppressants are needed to attenuate gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI), pharmacodynamic interaction between clopidogrel and proton pump inhibitor (PPI) can increase the risk of high platelet reactivity (HPR). We sought to evaluate serial changes of platelet measures and influence of rabeprazole on platelet measures. After 600-mg clopidogrel loading for elective PCI, clopidogrel-sensitive patients were recruited and randomly assigned to add rabeprazole of daily 20 mg (n = 40) or famotidine of daily 40 mg (n = 40). Platelet measures were performed with light transmittance aggregometry and VASP-P assay. Primary endpoint was 5 µM ADP-induced platelet aggregation (PA) at 30-day follow-up. HPR was defined as 5 µM ADP-induced PA > 46%. Baseline platelet measures did not differ significantly between the groups. The 30-day level of 5 µM ADP-induced PA was similar between the famotidine vs. rabeprazole group (30.0 ± 16.4% vs. 30.2 ± 13.9%, P= .956). In addition, other platelet measures were comparable between the groups. At 30-day follow-up, the incidence of HPR was similar between the famotidine and rabeprazole groups (20.5% vs. 15.4%; P= .555). In conclusion, adjunctive use of rabeprazole showed the similar antiplatelet effect even in clopidogrel-sensitive patients compared with adjunctive famotidine, which may support the similar effect of rabeprazole and famotidine on the antiplatelet effect of dual antiplatelet therapy with clopidogrel plus aspirin.
Asunto(s)
Clopidogrel/farmacocinética , Famotidina/farmacología , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de la Bomba de Protones/farmacología , Rabeprazol/farmacología , Anciano , Clopidogrel/efectos adversos , Interacciones Farmacológicas , Famotidina/administración & dosificación , Famotidina/efectos adversos , Femenino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/tratamiento farmacológico , Hemorragia Gastrointestinal/etiología , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/efectos adversos , Pruebas de Función Plaquetaria , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/efectos adversos , Rabeprazol/administración & dosificación , Rabeprazol/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
PURPOSE: To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk. METHODS: Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human. RESULTS: Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt. CONCLUSIONS: The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.
Asunto(s)
Antiulcerosos/farmacocinética , Simulación por Computador , Composición de Medicamentos/métodos , Famotidina/farmacocinética , Absorción Intestinal , Modelos Biológicos , Administración Oral , Animales , Antiulcerosos/administración & dosificación , Disponibilidad Biológica , Perros , Famotidina/administración & dosificación , Femenino , Humanos , Concentración de Iones de Hidrógeno , MasculinoRESUMEN
Fanconi syndrome is a renal proximal tubulopathy characterized by excessive urinary loss of glucose, amino acids, several electrolytes, and bicarbonate. Here, we report the case of transient Fanconi syndrome in a dog following administration of firocoxib, cefadroxil, tramadol, and famotidine. A 10 mo old Maltese was presented with lethargy, anorexia, vomiting, and weight loss. Transient Fanconi syndrome without azotemia was associated with firocoxib, cefadroxil, tramadol, and famotidine treatment. The dog received supportive care including IV fluids, gastroprotectants, and oral nutritional supplements. Two months after initial diagnosis and treatment, the dog showed complete resolution of glucosuria and aminoaciduria. The unique features of Fanconi syndrome in this case emphasize the potential renal tubular toxicity of this widely used multiple-drug combination.
Asunto(s)
4-Butirolactona/análogos & derivados , Cefadroxilo/efectos adversos , Enfermedades de los Perros/inducido químicamente , Famotidina/efectos adversos , Síndrome de Fanconi/veterinaria , Sulfonas/efectos adversos , Tramadol/efectos adversos , 4-Butirolactona/administración & dosificación , 4-Butirolactona/efectos adversos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Animales , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antiulcerosos/administración & dosificación , Antiulcerosos/efectos adversos , Cefadroxilo/administración & dosificación , Perros , Famotidina/administración & dosificación , Síndrome de Fanconi/inducido químicamente , Glucosa , Glucosuria , Masculino , Sulfonas/administración & dosificación , Tramadol/administración & dosificaciónRESUMEN
BACKGROUND: Famotidine is sometimes administered as a continuous rate infusion (CRI) to treat gastrointestinal ulceration in critically ill dogs. However, clinical studies have not evaluated the efficacy of a famotidine CRI in dogs. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy of famotidine at raising intragastric pH when it is administered as a CRI in dogs. We hypothesized that CRI treatment with famotidine would meet clinical goals for raising intragastric pH ≥3 and 4. ANIMALS: Nine healthy Beagle dogs. METHODS: Randomized 2-way crossover. All dogs received 1.0 mg/kg IV q12h famotidine or CRI famotidine at 1.0 mg/kg IV loading dose and 8.0 mg/kg/d for 3 consecutive days. Beginning on day 0 of treatment, intragastric pH monitoring was used to continuously record intragastric pH. Mean percentage times (MPTs) for which intragastric pH was ≥3 and ≥4 were compared between groups using analysis of variance. RESULTS: There was a statistically significant difference (P < .05) in MPT ≥3 and ≥4 between the CRI and IV q12h groups on all treatment days. On days 1, 2, and 3, the MPTs ± SD for which pH was ≥3 were 92.1 ± 8.5, 96.3 ± 6.2, and 90.0 ± 15.7 for the CRI treatment group and 49.3 ± 27.3, 42.2 ± 19.6, and 45.8 ± 10.1, respectively, for the twice-daily group. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that a famotidine CRI, but not standard doses of famotidine, achieves the clinical goals established in people to promote healing of gastric tissue injury and offers an alternative to intravenous treatment with proton pump inhibitors in dogs.
Asunto(s)
Administración Intravenosa/veterinaria , Antiulcerosos/farmacología , Perros , Famotidina/farmacología , Animales , Antiulcerosos/administración & dosificación , Estudios Cruzados , Famotidina/administración & dosificación , Femenino , Determinación de la Acidez Gástrica/veterinaria , Masculino , Monitoreo Fisiológico/veterinaria , Estómago/efectos de los fármacosRESUMEN
BACKGROUND: Famotidine is commonly administered to cats. Prolonged famotidine administration results in decreased efficacy in humans, dogs, and cows, but the long-term effects in cats are unknown. OBJECTIVES: To compare the effect of 2 oral administration frequencies of famotidine, twice daily (Group 1) and twice daily every second day (Group 2), on intragastric pH and serum gastrin concentrations in cats. We hypothesized a diminished effect on intragastric pH would be observed over time in Group 1 but not Group 2. ANIMALS: Sixteen healthy cats. METHODS: Randomized, 2-factor repeated measures crossover design. Cats received 0.5-1.24 mg/kg (median, 0.87 mg/kg) famotidine twice daily or twice daily every second day for 14 consecutive days. Intragastric pH monitoring was used to record intragastric pH on treatment days 1-3 and 11-13. Mean pH and mean percentage time (MPT) intragastric pH was ≥3 and 4 were compared between and within treatment groups by analysis of variance. RESULTS: Significant treatment group by time interactions were observed for mean intragastric pH, MPT intragastric pH ≥3 and 4 (P = .009, P = .02, P = .005, respectively). Interaction post hoc tests identified significant decreases in mean intragastric pH (P = .001), MPT ≥3 (P = .001), and MPT ≥4 (P = .001) on day 13 compared to day 1 in Group 1 but not in Group 2. CONCLUSIONS AND CLINICAL IMPORTANCE: Oral famotidine administration results in a diminished effect on intragastric pH in healthy cats when given twice daily every day.