Enhancing Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Comparative Analysis of Rapid Point-of-Care Infliximab, Adalimumab and Anti-Drug Antibodies' Determination against ELISA.

The introduction of point-of-care (POC) assays into clinical practice in patients with inflammatory disease enables on-demand therapeutic decision making. The aim of this study was to compare the POC test Quantum blue (Bühlmann Laboratories) for infliximab (IFX), adalimumab (ADL), and its anti-drug antibodies with the traditional ELISA assay (Promonitor). A total of 200 serum samples were analyzed. Samples were classified into the following three different groups; sub-therapeutic range (IFX < 3 µg/mL and ADL < 5 µg/mL); therapeutic range (IFX: 3-7 µg/mL and ADL: 5-12 µg/mL) and supra-therapeutic range (IFX levels > 7 µg/mL and ADL levels > 12 µg/mL). Significant higher values were measured using the POC test (p < 0.001) for IFX results but no differences in ADL trough levels were observed (p = 0.3101). Spearman's correlation indicated a good correlation between the two assays (rs = 0.88 for ADL and rs = 0.93 for IFX), and McNemar's test revealed significant differences (p = 0.016) when classifying IFX samples between therapeutic and supra-therapeutic ranges but no significant differences were found among the other ranges for either IFX or ADL. These results show that we should be cautious when using these rapid measurement methods, and new targets should probably be defined for IFX when using this new analytical method.

Perspectives of Therapeutic Drug Monitoring of Biological Agents in Non-Infectious Uveitis Treatment: A Review.

Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians' treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed.

Endoscopic drainage with local infusion of antibiotics to avoid necrosectomy of infected walled-off necrosis.

BACKGROUND: Current treatment of infected pancreatic necrosis (IPN) follows a step-up approach. Our group designed a step-up protocol that associates endoscopic drainage with local infusion of antibiotics through transmural nasocystic catheter. Aim of our study was to evaluate our step-up protocol for IPN in terms of proportion of patients avoiding necrosectomy. METHODS: Retrospective analysis of patients admitted with acute pancreatitis (AP) between January 2015 and December 2018. The number of patients who responded to each therapeutic step were analysed: step 1, systemic antibiotics; step 2, endoscopic transmural drainage and local infusion of antibiotics; step 3, endoscopic necrosectomy. RESULTS: 1158 patients with AP were included. 110 patients (8.4%) suffered from necrotising pancreatitis; 48 of them had IPN (42.6% of necrotising pancreatitis) and were treated with systemic antibiotics. Nineteen patients (39.6% of IPN) responded and did not required any invasive therapy. Six patients with IPN on systemic antibiotics died within the first 4 weeks of disease before step 2 could be applied. Urgent surgical necrosectomy in the first 4 weeks was performed in three additional patients. Endoscopic drainage and local antibiotic therapy was performed in the remaining 20 patients; 9 (45% of them) did well and 9 patients underwent necrosectomy (18.7% of IPN). Two patients died on drainage. Overall mortality of the total cohort of AP was 2.53% CONCLUSIONS: Addition of local infusion of antibiotics to endoscopic drainage avoids the need of necrosectomy in half of patients with IPN not responding to systemic antibiotics.

Therapeutic drug monitoring of anti-tumour necrosis factor-α agents in inflammatory bowel disease: Limits and improvements.

AIMS: Since the publication of the American Gastroenterological Association's recommendations in 2017, there have been no significant changes in the biological monitoring recommendations in inflammatory bowel disease. Possible limitations are the lack of evidence to recommend proactive therapeutic drug monitoring (pTDM) over reactive TDM (rTDM), and the limited information about individualized dosing methods. This article aims to review the TDM strategy updates and the use of individualized dosing methods. METHODS: For the analysis of the TDM strategies and individualized dosing method, a search was carried out in PubMed and Cochrane Central. In the TDM case, since August 2017. RESULTS: A total of 263 publications were found, but only 7 related to proactive TDM. Five of these publications directly compared pTDM vs rTDM and 2 were randomized clinical trials. Six studies found benefits of pTDM and 1 found no differences. Regarding the individualized dosing method, 229 distinct results were found. Population pharmacokinetics was the most widely used method to develop individual dosage models and to analyse the influence of factors on drug concentrations (albumin concentration, weight, presence of anti-drug antibodies etc). CONCLUSION: We have found no major changes in TDM strategies. There is a growing trend towards the use of pTDM because it has shown a longer duration of treatment response, lower rates of discontinuation and relapses. However, the available evidence is limited and of low quality. Despite the common use of population pharmacokinetic methods to analyse pharmacokinetic factors, they are not commonly used for personalized dosing.

Evaluación de la formación especializada en farmacia hospitalaria / Evaluation of specialized training in hospital pharmacy

OBJETIVO: Analizar el grado de satisfacción de los residentes de la especialidad de farmacia hospitalaria e identificar áreas de mejora en su formación. MÉTODO: Cuestionario on line con 51 preguntas dirigido a residentes de cuarto año en Farmacia Hospitalaria que finalizaban su formación en 2018. Se realizó un análisis bivariante y multivariante para identificar la asociación de cada una de las variables independientes con respecto a la satisfacción global y delimitar en qué medida las asociaciones pudieran explicarse por el efecto del resto de variables recogidas en el estudio. RESULTADOS: Un total de 91 (67,4%) residentes cumplimentaron el cuestionario. La media de satisfacción global fue aceptable-buena (3,52 ± 0,92). El 86,8% disponía de un Plan Individualizado de Formación y el 50% valoraron su adaptación al programa de la especialidad como buena o muy buena. El 63,7% valoró positivamente la labor del tutor principal y un 72,5% la del resto de adjuntos. El 15,4% contestó que su servicio disponía de un protocolo de supervisión y responsabilidad progresiva. El 81% consideró adecuado el nivel de responsabilidad en as guardias y el 69,2% su supervisión. El 96,7% disponía de menos de 10 horas semanales para actividades docentes o de investigación. Un 35,2% tenía cinco o menos publicaciones o comunicaciones a congresos como primer autor y un 45,1% participaba en algún proyecto de investigación. Un 89% valoró positivamente la formación recibida en su centro y un 75,8% de los residentes volvería a elegir el mismo hospital. El análisis estadístico mostró una asociación respecto a la satisfacción global con significación estadística de varias variables, siendo la labor del tutor principal la que se relacionó de forma independiente con la satisfacción global. CONCLUSIONES: La satisfacción global con la formación recibida es aceptable, siendo la tutorización del tutor principal y la del resto de farmacéuticos de los servicios de farmacia los factores que afectan a la satisfacción global, si bien sólo la del tutor de un modo estadísticamente significativo. Como áreas de mejora se han detectado la supervisión de la formación, la labor del colaborador docente farmacéutico en las rotaciones clínicas y la investigación

OBJECTIVE: To analyze the degree of satisfaction of hospital pharmacy residents and identify areas of improvement in their training. METHOD: A survey (5-point Likert scale) was administered among fourth-year hospital pharmacy residents due to complete their residency in 2018. Bivariate and multivariate logistic regression analyses was performed to identify the association of each independent variable with overall satisfaction. RESULTS: 67.4% (91/135) of residents filled out the questionnaire. The mean overall satisfaction rate was acceptable-good (3.52 ± 0.92); 86.8% of residents had received an individualized training program, with 50% of them considering their individualized training program to be very well attuned to their day-to-day professional practice. The work of the tutor and other staff members involved in resident education was rated as positive by 63.7% and 72.5% of residents, respectively. A total of 15.4% of residents said that their units had a supervision and progressive empowerment pr-tocol in place. With respect to the level of on-call responsibility bestowed on them, 81% of residents considered it to be adequate; 69.2% considered the supervision they received to be adequate. As many as 96.7% of residents dedicated less than 10 hours per week to teaching or research activities; 35.2% of residents had produced five or less articles or congress presentations as first authors. Residents that had defended or were in the process of writing their PhD dissertation were 30.8%; 45.1% were involved in an Research project. Finally, 89% of residents rated the training received as positive, with 75.8% of them stating that they would select the same hospital again. In the statistical analysis, an association was found between overall satisfaction and several variables, with the work done by the main tutor being independently related to overall satisfaction. CONCLUSIONS: Overall satisfaction with the training received by fourth-year residents was acceptable. The work of the tutor and other staff members involved in resident education were the variables with the greatest influence on overall satisfaction, albeit only the tutor ́s work achieved statistical significance. The supervision of residents' progress, the coaching provided by other staff members during clinical rotations, and research were identified as areas for improvement

Evaluation of specialized training in hospital pharmacy.

OBJECTIVE: To analyze the degree of satisfaction of hospital pharmacy residents and identify areas of improvement in their training. METHOD: A survey (5-point Likert scale) was administered among  fourthyear hospital pharmacy residents due to complete their residency  in 2018. Bivariate and multivariate logistic regression analyses was  performed to identify the association of each independent variable with  overall satisfaction. RESULTS: 67.4% (91/135) of residents filled out the questionnaire. The  mean overall satisfaction rate was acceptable-good (3.52 ± 0.92);  86.8% of residents had received an individualized training program, with  50% of them considering their individualized training program to be very  well attuned to their day-to-day professional practice. The work of the  tutor and other staff members involved in resident education was rated  as positive by 63.7% and 72.5% of residents, respectively. A total of  15.4% of residents said that their units had a supervision and  progressive empowerment protocol in place. With respect to the level of  on-call responsibility bestowed on them, 81% of residents considered it  to be adequate; 69.2% considered the supervision they received to be  adequate. As many as 96.7% of residents dedicated less than 10 hours  per week to teaching or research activities; 35.2% of residents had  produced five or less articles or congress presentations as first authors.  Residents that had defended or were in the process of writing their PhD  dissertation were 30.8%; 45.1% were involved in an Research project.  Finally, 89% of residents rated the training received as positive, with  75.8% of them stating that they would select the same hospital again. In the statistical analysis, an association was found between overall  satisfaction and several variables, with the work done by the main tutor  being independently related to overall satisfaction. CONCLUSIONS: Overall satisfaction with the training received by  fourthyear residents was acceptable. The work of the tutor and other  staff members involved in resident education were the variables with the  greatest influence on overall satisfaction, albeit only the tutor´s work  achieved statistical significance. The supervision of residents' progress,  the coaching provided by other staff members during clinical rotations,  and research were identified as areas for improvement.

Objetivo: Analizar el grado de satisfacción de los residentes de la especialidad de farmacia hospitalaria e identificar áreas de mejora en su formación.Método: Cuestionario on line con 51 preguntas dirigido a residentes de  cuarto año en Farmacia Hospitalaria que finalizaban su formación en  2018. Se realizó un análisis bivariante y multivariante para identificar la  asociación de cada una de las variables independientes con respecto a la  satisfacción global y delimitar en qué medida las asociaciones pudieran  explicarse por el efecto del resto de variables recogidas en el estudio.Resultados: Un total de 91 (67,4%) residentes cumplimentaron el cuestionario. La media de satisfacción global fue aceptable-buena (3,52 ± 0,92). El 86,8% disponía de un Plan Individualizado de  Formación y el 50% valoraron su adaptación al programa de la  especialidad como buena o muy buena. El 63,7% valoró positivamente la labor del tutor principal y un 72,5% la del resto de adjuntos. El 15,4%  contestó que su servicio disponía de un protocolo de supervisión y  responsabilidad progresiva. El 81% consideró adecuado el nivel de  responsabilidad en las guardias y el 69,2% su supervisión. El 96,7%  disponía de menos de 10 horas semanales para actividades docentes o  de investigación. Un 35,2% tenía cinco o menos publicaciones o  comunicaciones a congresos como primer autor y un 45,1% participaba  en algún proyecto de investigación. Un 89% valoró positivamente la  formación recibida en su centro y un 75,8% de los residentes volvería a  elegir el mismo hospital. El análisis estadístico mostró una asociación  respecto a la satisfacción global con significación estadística de varias  variables, siendo la labor del tutor principal la que se relacionó de forma  independiente con la satisfacción global.Conclusiones: La satisfacción global con la formación recibida es aceptable, siendo la tutorización del tutor principal y la del resto de farmacéuticos de los servicios de farmacia los factores que afectan a  la satisfacción global, si bien sólo la del tutor de un modo  estadísticamente significativo. Como áreas de mejora se han detectado la supervisión de la formación, la labor del colaborador docente  farmacéutico en las rotaciones clínicas y la investigación.

Estimulación preoperatoria del asa eferente de la ileostomía con ácidos grasos de cadena corta / Stimulation the efferent limb before loop ileostomy closure with short chain fatty acids

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Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis.

OBJECTIVE: The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and meta-analysis of randomised controlled trials of PERT to determine the efficacy of PERT in exocrine pancreatic insufficiency (EPI) from CP. DESIGN: Major databases were searched from 1966 to 2015 inclusive. The primary outcome was coefficient of fat absorption (CFA). Effects of PERT versus baseline and versus placebo, and of different doses, formulations and schedules were determined. RESULTS: A total of 17 studies (511 patients with CP) were included and assessed qualitatively (Jadad score). Quantitative data were synthesised from 14 studies. PERT improved CFA compared with baseline (83.7±6.0 vs 63.1±15.0, p<0.00001; I2=89%) and placebo (83.2±5.5 vs 67.4±7.0, p=0.0001; I2=86%). PERT improved coefficient of nitrogen absorption, reduced faecal fat excretion, faecal nitrogen excretion, faecal weight and abdominal pain, without significant adverse events. Follow-up studies demonstrated that PERT increased serum nutritional parameters, improved GI symptoms and quality of life without significant adverse events. High-dose or enteric-coated enzymes showed a trend to greater effectiveness than low-dose or non-coated comparisons, respectively. Subgroup, sensitive and meta-regression analyses revealed that sample size, CP diagnostic criteria, study design and enzyme dose contributed to heterogeneity; data on health inequalities were lacking. CONCLUSIONS: PERT is indicated to correct EPI and malnutrition in CP and may be improved by higher doses, enteric coating, administration during food and acid suppression. Further studies are required to determine optimal regimens, the impact of health inequalities and long-term effects on nutrition.

Theoretical approach to local infusion of antibiotics for infected pancreatic necrosis.

BACKGROUND/OBJECTIVES: Infected pancreatic necrosis is a major complications of acute pancreatitis. If drainage is required, local administration of antibiotics through transmural nasocystic or percutaneous catheter may allow increasing local antibiotic concentrations. Drug diffusion becomes the main factor influencing local drug tissue penetration. The present study aims at providing the rationale for the design of new research protocols evaluating the efficacy of local antibiotics for infected pancreatic necrosis. METHODS: A review of microbiological data was performed for the most common organisms causing the infection, antibiotics spectrum and minimum inhibitory concentrations (MIC). A search of the physico-chemical properties of antibiotics was performed to calculate the diffusion coefficients. An estimation of the antibiotic concentrations in pancreatic tissue was obtained using a mathematical model. Efficacy factors (EF) were calculated and the stability of the antibiotic solutions were evaluated to optimize the dosing regimen. RESULTS: Piperacillin, vancomycin and metronidazole achieve high concentrations in the surrounding tissue very fast. Imipenem, ceftriaxone, ciprofloxacin, gentamicin, linezolid and cloxacillin achieve intermediate concentration values. Tigecycline, showed the lowest concentration values (<2 mg/L). Calculated EF is highest for piperacillin and imipenem short after administration and near to surface diffusion area (0.5 cm), but EF of imipenem is higher at deeper areas and longer time after administration. CONCLUSIONS: Considering obtained results, some solutions are proposed using saline as diluent and 25 °C of temperature during administration. Imipenem has the best theoretical results in empiric local treatment. Linezolid and tigecycline solutions are not recommended.

Self-associative behavior and drug-solubilizing ability of poloxamine (tetronic) block copolymers.

The incidence of the structural features on the self-assembly of different poloxamines (the conventional sequential Tetronic 304, 901, 904, 908, 1107, 1301, and 1307; a reverse-sequential counterpart Tetronic 150R1; and a chemically modified derivative, N-methylated Tetronic 1107) was thoroughly studied in 10 mM HCl by means of pi-A isotherm, surface tension, and pyrene fluorescence measurements. The size and size distribution of the aggregates were investigated by dynamic and static light scattering, and the morphology was probed by transmission electron microscopy. The abilities of the different derivatives to solubilize the drug simvastatin were also evaluated. Poloxamines with both higher PO/EO ratio and molecular weight (T1301 and T150R1) led to micelles with larger and more hydrophobic cores, particularly adequate for hosting hydrophobic molecules and protecting the labile lactone form of simvastatin from hydrolysis. On the other hand, the hydroxy acid form of simvastatin interacted with the central ethylenediamine group under alkaline pH (T304) or when a permanent positive charge due to methylation was present. Micelles of long poloxamine molecules containing large PPO blocks (with 23-29 units, namely, T1301, T1307, and T150R1), particularly the one that also has long PEO blocks, were the most physically stable toward dilution.

Tetronic micellization, gelation and drug solubilization: Influence of pH and ionic strength.

The aim of this work was to gain an insight into the self-associative processes and drug solubilization ability of a Tetronic variety, T904 (4 x 15 EO units; 4 x 17 PO units; HLB 15), in aqueous media covering the physiological range of pH and ionic strength, applying isoperibol microcalorimetry, transmission electronic microscopy (TEM), dynamic light scattering (DLS), oscillatory rheometry, and drug diffusion experiments. T904 shows two pK(a) (pK(a1)=4.0 and pK(a2)=7.9) and, at pH<5.8, the diprotonated form predominates over the non-protonated one. Deprotonization of the central diamine group is a required condition for micellization, which is an endothermic entropy-driven process owing to hydrophobic interactions between the PPO chains. As the pH of the solutions decreases, the coulombic repulsions among the positively charged amine groups make the aggregation more difficult, raising the critical micellar concentration (CMC) and decreasing the size of the micelles. The changes in the conformation and hydrophilicity of the Tetronic were reflected in its gelation temperature (around 30 degrees C at neutral-alkaline pH; no gelation at pH<2) and solubilization capacity for griseofulvin (2-fold greater at neutral-alkaline pH than at pH<2) and rate of diffusion (slower at pH 7.4). Such alterations in self-assembly are relevant when using Tetronic in the design of drug delivery systems.