RESUMEN
The mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently used in IBD to counteract two pivotal processes of intestinal fibrosis, the differentiation of intestinal fibroblasts to activated myofibroblasts using CCD-18Co cells, and the epithelial-to-mesenchymal transition (EMT) of intestinal epithelial cells using Caco-2 cells (IEC), both being processes induced by transforming growth factor-ß1 (TGF-ß1). The drugs tested included mesalamine, azathioprine, methotrexate, prednisone, methylprednisolone, budesonide, infliximab, and adalimumab. The expression of fibrosis and EMT markers (collagen-I, α-SMA, pSmad2/3, occludin) was assessed by Western blot analysis and by immunofluorescence. Of the drugs used, only prednisone, methylprednisolone, budesonide, and adalimumab were able to antagonize the pro-fibrotic effects induced by TGF-ß1 on CCD-18Co cells, reducing the fibrosis marker expression. Methylprednisolone, budesonide, and adalimumab were also able to significantly counteract the TGF-ß1-induced EMT process on Caco-2 IEC by increasing occludin and decreasing α-SMA expression. This is the first study that evaluates, using in vitro cellular models, the direct antifibrotic effects of drugs currently used in IBD, highlighting which drugs have potential antifibrotic effects.
Asunto(s)
Budesonida , Transición Epitelial-Mesenquimal , Fibrosis , Enfermedades Inflamatorias del Intestino , Factor de Crecimiento Transformador beta1 , Humanos , Células CACO-2 , Transición Epitelial-Mesenquimal/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Budesonida/farmacología , Adalimumab/farmacología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Metilprednisolona/farmacología , Mesalamina/farmacología , Prednisona/farmacología , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Antiinflamatorios/farmacología , Infliximab/farmacología , Infliximab/uso terapéutico , Azatioprina/farmacología , Metotrexato/farmacología , Intestinos/efectos de los fármacos , Intestinos/patología , Diferenciación Celular/efectos de los fármacosRESUMEN
PURPOSE: To evaluate the therapeutic efficacy of intravenous amoxicillin clavulanate potassium combined with nebulized budesonide and ambroxol hydrochloride in pediatric community-acquired pneumonia (CAP) and its impact across various microbial strains and clinical symptoms. The primary objective of this study is to evaluate the efficacy of intravenous amoxicillin-clavulanate combined with nebulized budesonide and ambroxol hydrochloride in the treatment of pediatric community-acquired pneumonia (CAP), and to analyze their impact on different microbial strains and clinical symptoms. Secondary objectives include assessing the treatment's effect on the improvement of clinical symptoms, hospital stay duration, and the levels of inflammatory markers. DESIGN: Prospective, single-center study. METHODS: Fifty-six children with CAP, aged under 6 years, from Affiliated Maternity and Child Health Care Hospital of Nantong University were included. Patients were treated with conventional therapy and the study medication. Clinical characteristics, microbiological data, symptom improvement, and hospitalization times were analyzed. FINDINGS: Young children, particularly under 1 year, exhibited a higher incidence of multiple microbial infections and severe clinical manifestations. Treatment with budesonide and ambroxol hydrochloride led to significant clinical improvement across all age groups, with notable efficacy against various pathogens. CONCLUSIONS: Nebulized budesonide and ambroxol hydrochloride are effective in treating pediatric CAP, offering a promising therapeutic option, particularly for young children with severe presentations.
Asunto(s)
Ambroxol , Budesonida , Infecciones Comunitarias Adquiridas , Nebulizadores y Vaporizadores , Humanos , Ambroxol/administración & dosificación , Ambroxol/uso terapéutico , Budesonida/administración & dosificación , Budesonida/uso terapéutico , Femenino , Masculino , Preescolar , Lactante , Estudios Prospectivos , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Resultado del Tratamiento , Administración por Inhalación , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Niño , Neumonía/tratamiento farmacológico , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Expectorantes/administración & dosificación , Expectorantes/uso terapéutico , Biomarcadores/sangre , Quimioterapia Combinada , Tiempo de InternaciónRESUMEN
BACKGROUND: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count - focusing on blood EOS count 100 to < 300 cells/mm3 - as a function of exacerbation history and COPD severity. METHODS: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12-24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. RESULTS: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. CONCLUSIONS: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).
Asunto(s)
Broncodilatadores , Budesonida , Eosinófilos , Fumarato de Formoterol , Glicopirrolato , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Masculino , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Glicopirrolato/administración & dosificación , Femenino , Anciano , Persona de Mediana Edad , Broncodilatadores/administración & dosificación , Budesonida/administración & dosificación , Eosinófilos/efectos de los fármacos , Fumarato de Formoterol/administración & dosificación , Método Doble Ciego , Progresión de la Enfermedad , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Administración por Inhalación , Resultado del Tratamiento , Antagonistas Muscarínicos/administración & dosificación , Volumen Espiratorio Forzado/efectos de los fármacos , Volumen Espiratorio Forzado/fisiologíaRESUMEN
BACKGROUND: Fractional exhaled nitric oxide (FeNO) is used for the diagnosis and monitoring of asthma, although its utility to guide treatment and its correlation with other tools is still under discussion. We study the possibility to withdraw inhaled corticosteroid treatment in atopic patients with mild asthma based on the FeNO level, as well as to study its correlation with other clinical control tools. METHODS: Prospective and randomized study including atopic patients aged 18 to 65 with mild asthma, stable, on low-dose inhaled corticosteroid (ICS) treatment, who had their treatment withdrawn based on a FeNO level of 40 ppb. Patients were randomized into two groups: control group (treatment with ICS was withdrawn regardless of FeNO level) and experimental group (according to the FeNO levels, patients were assigned to one of two groups: FeNO > 40 ppb on treatment with budesonide 200 mcg every 12 h and SABA on demand; FeNO ≤ 40 ppb only with SABA on demand). Follow-up was conducted for one year, during which medical assessment was performed with FeNO measurements, asthma control test (ACT), lung function tests (FEV1, FEV1/FVC, PEF, and RV/TLC), and recording of the number of exacerbations. RESULTS: Ninety-two patients were included, with a mean age of 39.92 years (SD 13.99); 46 patients were assigned to the control group, and 46 patients to the experimental group. The number of exacerbations was similar between the groups (p = 0.301), while the time to the first exacerbation was significantly shorter in the control group (30.86 vs. 99.00 days), p < 0.001, 95% CI (43.332-92.954). Lung function tests (FEV1, FEV1/FVC, PEF, and RV/TLC) showed no differences between the groups (p > 0.05). Both FeNO and ACT showed significant changes in the groups in which ICS was withdrawn (p < 0.05 for both parameters). A significant negative correlation was observed between FeNO and ACT (r = -0.139, p = 0.008). CONCLUSIONS: In atopic patients with mild asthma, withdrawal of ICS based on an FeNO of 40 ppb led to worsened symptoms but without changes in lung function tests or an increase in exacerbations. There was a negative correlation between FeNO values and symptomatic control measured by the ACT. TRIAL REGISTRATION: Clinical Trial Number: 2012-000372-42. Start Date: 2012-07-23. Trial registered prospectively ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-000372-42 ). This study adheres to CONSORT guidelines of randomised control trials.
Asunto(s)
Asma , Budesonida , Óxido Nítrico , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Administración por Inhalación , Corticoesteroides/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Pruebas Respiratorias , Budesonida/uso terapéutico , Prueba de Óxido Nítrico Exhalado Fraccionado , Óxido Nítrico/análisis , Estudios Prospectivos , Pruebas de Función RespiratoriaRESUMEN
The aim of this study was the evaluation of suitability of novel mucoadhesive hydrogel platforms for the delivery of therapeutics useful for the management of disorders related to the gastrointestinal tract (GI). At this purpose, here we describe the preparation, the physicochemical characterization and drug delivery behaviour of novel hydrogels, based on self-assembling lipopeptides (MPD02-09), obtained by covalently conjugating lauric acid (LA) to SNA's peptide derivatives gotten by variously combining D- and L- amino acid residues. LA conjugation was aimed at improving the stability of the precursor peptides, obtaining amphiphilic structures, and triggering the hydrogels formation through the self-assembling. Budesonide (BUD), an anti-inflammatory drug, was selected as model because of its use in the treatment in GI disorders. Preliminary studies were performed to correlate the chemical structure of the conjugates with the key physicochemical properties of the materials for drug delivery. Two lipopeptides, MPD03 and MPD08, were found to form hydrogels (MPD03h and MPD08h, respectively) with characteristics suitable for drug delivery. These materials showed mucoadhesiveness of about 60 %. In vitro studies carried out with BUD loaded hydrogels showed about 70 % drug release within 6 h. Wound healing assessed in Caco-2 and HaCaT cells, showed reduction of cell-free area to values lower than 10 %. Taking together these results MPD03h and MPD08h have been shown to be excellent candidates for BUD delivery.
Asunto(s)
Budesonida , Preparaciones de Acción Retardada , Liberación de Fármacos , Hidrogeles , Hidrogeles/química , Humanos , Células CACO-2 , Budesonida/química , Budesonida/administración & dosificación , Cicatrización de Heridas/efectos de los fármacos , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Lipopéptidos/química , Lipopéptidos/administración & dosificación , Ácidos Láuricos/química , Sistemas de Liberación de Medicamentos/métodos , Células HaCaT , Péptidos/química , Péptidos/administración & dosificaciónRESUMEN
This study aimed to investigate the amorphous stabilization of BCS Class II drugs using mesoporous silica as a carrier to produce amorphous solid dispersions. Ibuprofen, fenofibrate, and budesonide were selected as model drugs to evaluate the impact of molecular weight and partition coefficient on the solid state of drug-loaded mesoporous silica (MS) particles. The model drugs were loaded into three grades of MS, SYLYSIA SY730, SYLYSIA SY430, and SYLYSIA SY350, with pore diameters of 2.5 nm, 17 nm, and 21 nm, respectively, at 1:1, 2:1, and 3:1, carrier to drug ratios, and three different loading concentrations using solvent immersion and spray drying techniques. Differential scanning calorimetry (DSC) thermograms of SY430 and SY350 samples exhibited melting point depressions indicating constricted crystallization inside the pores, whereas SY730 samples with melting points matching the pure API may be a result of surface crystallization. Powder x-ray diffraction (PXRD) diffractograms showed all crystalline samples matched the diffraction patterns of the pure API indicating no polymorphic transitions and all 3:1 ratio samples exhibited amorphous halo profiles. Response surface regression analysis and Classification and Regression Tree (CART) analysis suggest carrier to drug ratios, followed by molecular weight, have the most significant impact on the crystallinity of a drug loaded into MS particles.
Asunto(s)
Budesonida , Rastreo Diferencial de Calorimetría , Portadores de Fármacos , Fenofibrato , Ibuprofeno , Dióxido de Silicio , Difracción de Rayos X , Dióxido de Silicio/química , Ibuprofeno/química , Fenofibrato/química , Porosidad , Portadores de Fármacos/química , Difracción de Rayos X/métodos , Budesonida/química , Budesonida/administración & dosificación , Estabilidad de Medicamentos , Cristalización , Peso MolecularRESUMEN
OBJECTIVE: To assess the clinical effect of Qingre Bawei capsules combined with budesonide in the treatment of acute exacerbation of chronic obstructive pulmonary disease. METHODS: The retrospective study was conducted at the Baoding No.1 Central Hospital, China, and comprised data of patients with acute exacerbation of COPD admitted between June 1, 2020, and June 30, 2022. The patients were divided into two groups based on treatment methods. The group A had been treated with Qingre Bawei capsules in combination with budesonide, while the group B had been treated with budesonide alone. Both the groups had been treated for 2 consecutive weeks. The changes in blood gas indicators, inflammation indicators, and lung function indicators were compared between two groups of patients before and 24 hours after treatment. The time for clinical symptom disappearance and adverse reactions between the two groups of patients was also noted. RESULTS: Of the 120 patients, 60(50%) were in group A; 41(68.3%) males and 19(31.7%) females, with mean age 65.28±4.36 years (range: 47-78 years) and mean course of disease 31.22±4.75 hours (range: 6-65 hours). 60(50%) patients were in group B; 43(71.7%) males and 17(28.3%) females with mean age 65.31±4.31 years (range: 48-78 years) and mean course of disease 31.29±4.71 hours (range: 8-68 hours). The disappearance time of clinical symptoms in group A was better than group B (p<0.05). The levels of blood gas indicators, inflammation indicators, and lung function indicators in both groups significantly improved (p<0.05), but the degree of improvement in group A was better than group B (p<0.05); The total effective rate of group A was better than group B (p<0.05). None of the patients in either group experienced any significant adverse reaction. CONCLUSIONS: Qingre Bawei capsules combined with budesonide had a significantly better therapeutic effect on cases of acute exacerbation of chronic obstructive pulmonary disease compared to budesonide alone.
Asunto(s)
Budesonida , Medicamentos Herbarios Chinos , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Budesonida/administración & dosificación , Budesonida/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/efectos adversos , Estudios Retrospectivos , Quimioterapia Combinada , Cápsulas , Broncodilatadores/administración & dosificación , Broncodilatadores/uso terapéutico , Progresión de la Enfermedad , Resultado del Tratamiento , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Volumen Espiratorio Forzado/efectos de los fármacosRESUMEN
Immunoglobulin A nephropathy (IgAN) is a chronic, immune-mediated kidney disease characterized by the deposition of galactose-deficient immunoglobulin A1 (Gd-IgA1) in the kidneys. Excess Gd-IgA1 production in patients with IgAN is located within the mucosa-associated lymphoid tissue, particularly within the lamina propria in the distal ileum. Nefecon® is a targeted-release formulation of the corticosteroid budesonide, which became the first treatment approved by the US Food and Drug Administration (FDA; brand name, TARPEYO®) and European Medicines Agency (EMA; KINPEYGO®) for patients with primary IgAN at risk of rapid disease progression, after demonstrating clinically significant reduction of proteinuria in an interim analysis of the Phase III NefIgArd trial. After showing a significant reduction in estimated glomerular filtration rate decline in the full 2-year analysis of the trial, Nefecon was granted full approval by the FDA to reduce the loss of kidney function. Nefecon was specifically designed to deliver budesonide to the distal ileum, selectively targeting excess Gd-IgA1 production in the gut-associated lymphoid tissue. In this review, we describe the properties of Nefecon and the evidence to date that confirms its localized treatment effect. We also present unpublished evidence from Phase I trials investigating the pharmacokinetics and cortisol suppression effects of Nefecon in healthy participants. These studies demonstrated that Nefecon has a distinct pharmacokinetic profile from other budesonide products, allowing for targeted, localized action in the distal ileum. When considered alongside existing clinical trial data showing the effect of Nefecon on gut-associated biomarkers, available evidence indicates that Nefecon has a selective immunomodulatory mechanism of action and a direct disease-modifying effect in patients with IgAN, while having low systemic exposure and adverse effects.
Asunto(s)
Budesonida , Glomerulonefritis por IGA , Humanos , Glomerulonefritis por IGA/tratamiento farmacológico , Budesonida/farmacología , Budesonida/administración & dosificación , Budesonida/uso terapéutico , Budesonida/química , Agentes Inmunomoduladores/farmacología , Agentes Inmunomoduladores/química , Agentes Inmunomoduladores/administración & dosificaciónRESUMEN
BACKGROUND: Budesonide and tixocortol pivalate as markers of contact allergy to corticosteroids have been questioned, as they are not able to detect a significant percentage of allergic patients. OBJECTIVES: To investigate the potential role of clobetasol propionate in enhancing corticosteroid sensitisation detection. METHODS: Between January 2022 and December 2023, patients who attended centres involved in the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy were tested with an extended baseline series that included budesonide, tixocortol pivalate, clobetasol propionate 0.1% in ethanol and 1% in petrolatum. RESULTS: A total of 4338 patients were tested. Twenty-four patients were allergic to budesonide (0.55%, 95% CI: 0.37-0.82); nine patients were allergic to tixocortol pivalate (0.21%, 95% CI: 0.11-0.39); and 23 patients were allergic to clobetasol (0.53%, 95% CI: 0.35-0.79). Only four of those patients allergic to clobetasol were detected by budesonide and one by tixocortol pivalate. No significant differences in the number of positive tests were found between clobetasol in petrolatum or ethanol. CONCLUSIONS: In Spain budesonide remains the main corticosteroid allergy marker whereas the role of tixocortol pivalate is questionable. The addition of clobetasol propionate to the Spanish baseline series would improve the ability to detect patients allergic to corticosteroids.
Asunto(s)
Budesonida , Clobetasol , Dermatitis Alérgica por Contacto , Humanos , Clobetasol/efectos adversos , Dermatitis Alérgica por Contacto/etiología , Dermatitis Alérgica por Contacto/diagnóstico , Budesonida/efectos adversos , España , Femenino , Masculino , Pruebas del Parche , Adulto , Persona de Mediana Edad , Glucocorticoides/efectos adversos , Hidrocortisona/análogos & derivadosRESUMEN
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent medical condition. Type 2 inflammation signs CRSwNP in western countries. Type 2 inflammation leads to nasal airflow limitation. Budesonide aqueous nasal spray (BANS) is an intranasal corticosteroid (INCS); it has been launched in the early 1980s. BANS is indicated for treating allergic rhinitis, nonallergic rhinitis, and nasal polyps (both as treatment and prevention after surgery). Consolidated evidence documented its efficacy in treating CRSwNP. In addition, BANS is safe with negligible local and systemic side effects. Recent guidelines for patients with CRSwNP recommend using INCS as the first line in many situations. In particular, patients may assess the perception of symptoms' severity using the Visual Analog Scale (VAS). A score >5/10 means uncontrolled symptoms in both diseases and requires adequate treatment. BANS could appropriately be used in patients with uncontrolled symptoms and/or moderate/severe nasal obstruction. In addition, BANS may adequately integrate surgery and biologics for CRSwNP management. In conclusion, BANS represents a valuable option in managing patients with type 2-mediated CRSwNP.
Asunto(s)
Administración Intranasal , Budesonida , Pólipos Nasales , Rociadores Nasales , Rinitis , Sinusitis , Humanos , Sinusitis/tratamiento farmacológico , Sinusitis/complicaciones , Pólipos Nasales/tratamiento farmacológico , Enfermedad Crónica , Rinitis/tratamiento farmacológico , Budesonida/uso terapéutico , Budesonida/administración & dosificación , Resultado del Tratamiento , RinosinusitisRESUMEN
Eosinophilic esophagitis (EoE) is a chronic Th2-mediated inflammatory disease of the esophagus driven by dietary or inhalant allergens which if left untreated, leads to fibrosis and poor esophageal function. Although the inflammation in the esophagus is dominated by eosinophils, there are also elevated levels of T and B cells. Blood samples from ten patients with EoE before and after treatment with orodispersible budesonide and 10 healthy controls were compared using cytometry by time-of-flight. An antibody panel was designed that covers the major immunological cell populations with a particular focus on eosinophils. The data was analyzed with multivariate methods and cluster analysis. Correlation analysis was done between immune markers and endoscopic, histological, and symptomatologic assessments. Our analysis revealed that patients with EoE had lower levels of effector memory T cells after treatment with orodispersible budesonide to the same level as healthy subjects. In addition, more suppressive eosinophils were present in the circulation of EoE patients before treatment and more immature eosinophils were present after treatment. Furthermore, levels of galectin-10+ eosinophils correlated with histological findings in esophageal tissue from EoE patients. In all patients, the peak eosinophils were decreased after treatment with orodispersible budesonide. Intriguingly, 90% of the patients had remission in the histological assessment and 50% improved in the endoscopic assessment. This study reports a detailed immune profile in patients with EoE before and after treatment with orodispersible budesonide and it is a step toward finding blood-based immune parameters that could be useful to monitor response to treatment.
Asunto(s)
Budesonida , Esofagitis Eosinofílica , Eosinófilos , Humanos , Budesonida/uso terapéutico , Budesonida/administración & dosificación , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/tratamiento farmacológico , Masculino , Femenino , Eosinófilos/inmunología , Adulto , Persona de Mediana Edad , Adulto Joven , Administración Oral , Esófago/inmunología , Esófago/patología , Células Th2/inmunología , AdolescenteRESUMEN
Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of 'inhalation biopharmaceutics' i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using 'simple' Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation.
Asunto(s)
Albuterol , Budesonida , Liberación de Fármacos , Fumarato de Formoterol , Moco , Permeabilidad , Bromuro de Tiotropio , Moco/metabolismo , Administración por Inhalación , Porcinos , Animales , Budesonida/farmacocinética , Budesonida/administración & dosificación , Budesonida/química , Fumarato de Formoterol/administración & dosificación , Fumarato de Formoterol/farmacocinética , Humanos , Albuterol/administración & dosificación , Albuterol/farmacocinética , Albuterol/química , Bromuro de Tiotropio/administración & dosificación , Bromuro de Tiotropio/farmacocinética , Bromuro de Tiotropio/química , Solubilidad , Línea Celular , Broncodilatadores/administración & dosificación , Broncodilatadores/farmacocinética , Broncodilatadores/química , Pulmón/metabolismo , Composición de Medicamentos/métodosRESUMEN
BACKGROUND: Limited data exist for management strategies targeting immunotherapy-related enteritis (irEnteritis). Systemic corticosteroids are commonly used but often are limited by adverse events. Enteric corticosteroids such as budesonide offer an attractive alternative; however, the ileocolonic release of enteric-coated budesonide has limited utility for diffuse enteritis. Open-capsule budesonide (OCB) is a novel therapeutic approach that offers drug delivery throughout the small bowel. We report outcomes in patients treated with OCB for confirmed or suspected irEnteritis. METHODS: This retrospective cohort included all individuals treated with OCB for irEnteritis at Memorial Sloan Kettering from July 2018 to August 2023. Primary outcomes included clinical response, clinical remission, and corticosteroid-free remission following OCB. Secondary outcomes were OCB-related adverse events and efficacy by gastrointestinal toxicity location. RESULTS: 19 patients (53% female) with irEnteritis were treated with OCB. All patients presented with diarrhea; 15 (79%) reported anorexia with median 6 kg weight loss. 17 patients (89%) underwent esophagogastroduodenoscopy with biopsies revealing enteritis in all; 8 (42%) had concomitant colitis. 15 (79%) patients were treated previously with systemic corticosteroids: 8 (53%) were corticosteroid-dependent while 7 (47%) demonstrated non-response. 18 patients (95%) achieved clinical response, 15 (79%) attained clinical remission, and 11 (58%) had corticosteroid-free remission. Response to OCB was rapid with improvement noted after a median 4 days. 14 (74%) patients restored their pre-irEnteritis weight by OCB cessation. One mild, self-resolving adverse event was reported. CONCLUSIONS: OCB is a safe and effective therapy for irEnteritis. OCB avoids systemic immunosuppression and successfully achieves clinical response and remission even in patients previously nonresponsive to systemic corticosteroids. Future studies are needed to optimize indications and duration.
Asunto(s)
Budesonida , Enteritis , Inhibidores de Puntos de Control Inmunológico , Humanos , Femenino , Budesonida/uso terapéutico , Budesonida/farmacología , Enteritis/tratamiento farmacológico , Masculino , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , AdultoRESUMEN
OBJECTIVES: To evaluate the cost-effectiveness of budesonide/formoterol reliever and maintenance therapy compared with salmeterol/fluticasone plus salbutamol as reliever therapy for asthma patients ≥12 years from the societal perspective in China. METHODS: A Markov model was developed with three health states (non-exacerbation, exacerbation, and death) with a lifetime horizon. The exacerbation rates were obtained from a prospective cohort study conducted in Chinese asthma patients. Healthcare resources utilization data were estimated based on current clinical asthma management guidelines. Asthma-related mortality, cost input and utility values were derived from public database and literature. Model robustness was assessed with one-way sensitivity and probabilistic sensitivity analyses. RESULTS: Compared with salmeterol/fluticasone plus salbutamol, budesonide/formoterol reliever and maintenance therapy led to fewer exacerbation events (13.6 vs. 15.9) and 0.0077 quality-adjusted life years (QALY) gain at an additional cost of ¥196.38 over lifetime. The base case incremental cost-effectiveness ratio (ICER) was ¥25,409.98 per QALY gained. The variables that had most impact on the model output included drug costs and medication adherence. At a willingness-to-pay threshold of ¥257,094/QALY (3 times of gross domestic product per capita in China in 2022), the probability of budesonide/formoterol maintenance and reliever therapy being cost-effective versus salmeterol/fluticasone plus as-needed salbutamol was 83.00%. CONCLUSION: From the societal perspective, budesonide/formoterol reliever and maintenance therapy is likely to be a cost-effective option compared with salmeterol/fluticasone plus as-needed salbutamol for Chinese asthma patients ≥12 years.
Asunto(s)
Asma , Análisis Costo-Beneficio , Combinación Fluticasona-Salmeterol , Cadenas de Markov , Años de Vida Ajustados por Calidad de Vida , Humanos , Asma/tratamiento farmacológico , China , Combinación Fluticasona-Salmeterol/uso terapéutico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Budesonida/uso terapéutico , Budesonida/economía , Budesonida/administración & dosificación , Antiasmáticos/uso terapéutico , Antiasmáticos/economía , Fumarato de Formoterol/uso terapéutico , Fumarato de Formoterol/administración & dosificación , Modelos Econométricos , Niño , Adulto Joven , Estudios Prospectivos , Recursos en Salud/economía , Recursos en Salud/estadística & datos numéricos , Servicios de Salud/estadística & datos numéricos , Servicios de Salud/economía , Broncodilatadores/uso terapéutico , Broncodilatadores/economía , Broncodilatadores/administración & dosificación , Quimioterapia Combinada , Análisis de Costo-Efectividad , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Previous studies have reported reduced acute exacerbation rates and improved symptom control in asthma patients treated using inhaled corticosteroids plus formoterol maintenance and reliever therapy (MART). Fluticasone furoate (FF) and vilanterol (VIL) also provide rapid bronchodilation and sustained anti-inflammatory effects, however no studies have investigated FF/VIL as MART for asthma control. METHODS: From October 1, 2021 to September 30, 2023, this retrospective study included asthma patients classified as step 3 or 4 according to the Global Initiative for Asthma guidelines, who were then divided into two groups. One group received BUD/FOR as MART, while the other received FF/VIL as MART. Pulmonary function tests, exacerbation rates, Asthma Control Test (ACT), fractional exhaled nitric oxide (FeNO) levels, and blood eosinophil counts were measured before and after 12 months of treatment. RESULTS: A total of 161 patients were included, of whom 36 received BUD/FOR twice daily as MART, and 125 received FF/VIL once daily as MART. After 12 months of treatment, the FF/VIL group showed a significant increase in ACT scores by 1.57 (p < 0.001), while the BUD/FOR group had an increase of 0.88 (p = 0.11). In terms of FeNO levels, the BUD/FOR group experienced a decline of -0.2 ppb (p = 0.98), whereas the FF/VIL group had a mild increase of + 0.8 ppb (p = 0.7). Notably, there was a significant difference in the change of FeNO between the two groups (∆ FeNO: -0.2 ppb in BUD/FOR; + 0.8 ppb in FF/VIL, p < 0.001). There were no significant alterations observed in FEV1, blood eosinophil count, or acute exacerbation decline in either group. CONCLUSIONS: In the current study, patients treated with FF/VIL as MART showed improvements in ACT scores, while those treated with BUD/FOR as MART exhibited a reduction in FeNO levels. However, the difference between the two treatment groups did not reach clinical significance. Thus, FF/VIL as MART showed similar effectiveness to BUD/FOR as MART.
Asunto(s)
Asma , Alcoholes Bencílicos , Clorobencenos , Combinación de Medicamentos , Humanos , Masculino , Femenino , Alcoholes Bencílicos/administración & dosificación , Alcoholes Bencílicos/uso terapéutico , Estudios Retrospectivos , Asma/tratamiento farmacológico , Persona de Mediana Edad , Clorobencenos/administración & dosificación , Clorobencenos/uso terapéutico , Adulto , Broncodilatadores/administración & dosificación , Broncodilatadores/uso terapéutico , Administración por Inhalación , Androstadienos/administración & dosificación , Androstadienos/uso terapéutico , Budesonida/administración & dosificación , Budesonida/uso terapéutico , Antiasmáticos/uso terapéutico , Antiasmáticos/administración & dosificación , Anciano , Fumarato de Formoterol/administración & dosificación , Resultado del Tratamiento , Óxido Nítrico/análisis , Óxido Nítrico/metabolismo , Combinación Budesonida y Fumarato de Formoterol/administración & dosificación , Combinación Budesonida y Fumarato de Formoterol/uso terapéutico , Pruebas de Función Respiratoria , Eosinófilos/efectos de los fármacosRESUMEN
Acute pancreatitis (AP) is a sudden inflammation of the pancreas which often manifests as a mild disease but can be associated with high morbidity and mortality. Drug-induced AP is rare and most likely underdiagnosed. Vedolizumab is a human monoclonal antibody with gut-selective integrin antagonist effect, and it is used for treatment of inflammatory bowel disease (IBD). Budesonid is a glucocorticoid which is released in the colon and it is also used in IBD treatment. This is a case report where vedolizumab or budesonide caused acute pancreatitis in a young man with ulcerative colitis.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Budesonida , Colitis Ulcerosa , Fármacos Gastrointestinales , Pancreatitis , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Pancreatitis/inducido químicamente , Budesonida/efectos adversos , Budesonida/uso terapéutico , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Adulto , Enfermedad Aguda , Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico , Glucocorticoides/uso terapéutico , Glucocorticoides/efectos adversosRESUMEN
BACKGROUND: Budesonide, capable of reducing vascular permeability, suppressing mucus secretion, and alleviating edema and spasms, is widely used in China for combined infectious disease treatment. This study assesses budesonide's efficacy and safety as an adjunct to azithromycin in pediatric Mycoplasma pneumonia management in China, aiming to establish a strong theoretical foundation for its clinical application. METHODS: We conducted a comprehensive search for qualifying studies across 5 English databases and 4 Chinese databases, covering publications until October 31, 2023. Endpoint analyses were performed using standard software (Stata Corporation, College Station, TX). This study was conducted in compliance with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: A total of 24 randomized controlled trials were involved in the current study, including 2034 patients. Our findings indicate that the combination of budesonide with azithromycin for the treatment of pediatric Mycoplasma pneumonia delivers superior therapeutic efficacy (Intravenous: odds ratio [OR], 0.156, Pâ <â .001; Sequential: OR, 0.163, Pâ =â .001; Oral: OR, 0.139, Pâ <â .001), improved pulmonary function (Forced expiratory volume in 1 second: weighted mean differences [WMD], -0.28, Pâ =â .001; Peak expiratory flow: WMD, -0.554, Pâ =â .002; Forced vital capacity: WMD, -0.321, Pâ <â .001), diminished lung inflammation (IL-6: WMD, 4.760, Pâ =â .002; c-reactive protein: WMD, 5.520, Pâ <â .001; TNF-α: WMD, 9.124, Pâ <â .001), reduced duration of fever, faster resolution of cough and rales, all without increasing the occurrence of adverse events. CONCLUSION: The combination of budesonide and azithromycin demonstrates enhanced therapeutic effectiveness, promotes improved pulmonary function, shortens the duration of symptoms, and effectively mitigates the overexpression of inflammatory factors like c-reactive protein, TNF-α, and IL-6, all without an associated increase in adverse reactions in pediatric mycoplasma pneumonia.
Asunto(s)
Antibacterianos , Azitromicina , Budesonida , Quimioterapia Combinada , Neumonía por Mycoplasma , Humanos , Azitromicina/administración & dosificación , Azitromicina/uso terapéutico , Neumonía por Mycoplasma/tratamiento farmacológico , Budesonida/administración & dosificación , Budesonida/uso terapéutico , Niño , China , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Administración por Inhalación , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Preescolar , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer with an aggressive metastatic phenotype and very poor clinical prognosis. Interestingly, a lower occurrence of PDAC has been described in individuals with severe and long-standing asthma. Here we explored the potential link between PDAC and the glucocorticoid (GC) budesonide, a first-line therapy to treat asthma. METHODS: We tested the effect of budesonide and the classical GCs on the morphology, proliferation, migration and invasiveness of patient-derived PDAC cells and pancreatic cancer cell lines, using 2D and 3D cultures in vitro. Furthermore, a xenograft model was used to investigate the effect of budesonide on PDAC tumor growth in vivo. Finally, we combined genome-wide transcriptome analysis with genetic and pharmacological approaches to explore the mechanisms underlying budesonide activities in the different environmental conditions. RESULTS: We found that in 2D culture settings, high micromolar concentrations of budesonide reduced the mesenchymal invasive/migrating features of PDAC cells, without affecting proliferation or survival. This activity was specific and independent of the Glucocorticoid Receptor (GR). Conversely, in a more physiological 3D environment, low nanomolar concentrations of budesonide strongly reduced PDAC cell proliferation in a GR-dependent manner. Accordingly, we found that budesonide reduced PDAC tumor growth in vivo. Mechanistically, we demonstrated that the 3D environment drives the cells towards a general metabolic reprogramming involving protein, lipid, and energy metabolism (e.g., increased glycolysis dependency). This metabolic change sensitizes PDAC cells to the anti-proliferative effect of budesonide, which instead induces opposite changes (e.g., increased mitochondrial oxidative phosphorylation). Finally, we provide evidence that budesonide inhibits PDAC growth, at least in part, through the tumor suppressor CDKN1C/p57Kip2. CONCLUSIONS: Collectively, our study reveals that the microenvironment influences the susceptibility of PDAC cells to GCs and provides unprecedented evidence for the anti-proliferative activity of budesonide on PDAC cells in 3D conditions, in vitro and in vivo. Our findings may explain, at least in part, the reason for the lower occurrence of pancreatic cancer in asthmatic patients and suggest a potential suitability of budesonide for clinical trials as a therapeutic approach to fight pancreatic cancer.
Asunto(s)
Budesonida , Proliferación Celular , Metabolismo Energético , Neoplasias Pancreáticas , Humanos , Budesonida/farmacología , Budesonida/uso terapéutico , Ratones , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Metabolismo Energético/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Animales , Línea Celular Tumoral , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacosAsunto(s)
Budesonida , Esofagitis Eosinofílica , Suspensiones , Humanos , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/diagnóstico , Budesonida/administración & dosificación , Budesonida/uso terapéutico , Budesonida/efectos adversos , Administración Oral , Resultado del Tratamiento , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: Microscopic colitis has been increasingly recognized as a cause of chronic diarrhoea. We aimed to characterize the role of disease-related factors and treatments on the clinical outcomes of microscopic colitis. METHODS: We retrospectively reviewed the medical records of patients with microscopic colitis who were treated at the University of Chicago and Oregon Health & Science University between August 2010 and May 2016. Patient characteristics and treatments were evaluated as predictors of clinical outcomes using univariate and multivariate analyses. Clinical remission was defined as no symptoms associated with microscopic colitis based on physician assessment and histologic remission was defined as no evidence of histological inflammation of microscopic colitis. RESULTS: Seventy-two patients with microscopic colitis were included in the study (28 with lymphocytic colitis and 44 with collagenous colitis). Non-steroidal anti-inflammatory drugs, proton pump inhibitors and selective serotonin reuptake inhibitors were used in 23 (31.9%), 14 (19.4%) and 15 (20.8%), respectively, at the time of diagnosis. Among 46 patients with adequate follow-up data, 25 (54.3%) patients achieved clinical remission. Response to budesonide (p = .0002) and achieving histologic remission (p = .0008) were associated with clinical remission on univariate analysis. On multivariate analysis, budesonide response (p = .0052) was associated with clinical remission (odds ratio 25.00, 95% confidence interval 2.63-238.10). Among 22 patients who underwent a follow-up colonoscopy, five patients (22.7%) achieved histologic remission. All patients with histologic remission maintained clinical remission without medication, whereas only two patients (11.8%) were able to discontinue medical therapy when histologic inflammation was present (p = .0002). CONCLUSIONS: In the present cohort of patients with microscopic colitis, a favourable response to budesonide was significantly associated with long-term clinical remission, and all patients achieving histological remission were able to maintain clinical remission without further medical therapy. Larger studies are required to confirm these findings.