Evaluation of the safety and effectiveness after switch from adalimumab originator to biosimilar SB5 in patients with inflammatory bowel disease in a real-life setting.

Background and study aims: Prospective data are lacking on evolution of trough levels, effectiveness, acceptance rate and patient satisfaction after switch from the adalimumab originator to a biosimilar in patients with inflammatory bowel disease. Patients and methods: Patients in clinical remission or stable response and treated with adalimumab originator in 2 Belgian centers were offered to participate in this phase IV, prospective trial in which patients were switched to adalimumab biosimilar SB5. The primary outcome was the description of adalimumab trough levels over time. Secondary outcomes were secondary loss of response, disease activity, patient satisfaction score and drug persistence over 12 months. Results: The study included 110 patients. Mean baseline adalimumab trough level was 9.21 µg/ml. Concentration remained within the therapeutic range over time. No changes were observed in disease activity scores nor in biochemical parameters over time. The acceptance rate of switch was 84.6%. By month 12, 74.5% was still treated with SB5. The most frequent reason for discontinuation was occurrence of adverse events. 50% of these adverse events were injection site pain. The local discomfort was only significant the first 30 minutes after injection. Satisfaction with the decision to switch to SB5 was high and remained stable over time. Conclusions: After being well informed the great majority of patients treated with the adalimumab originator is willing to switch to biosimilar SB5. In our study, there was a persistence rate of 75% over one year. The trough levels remained within the therapeutic range and no change in disease activity was seen over time.

Impact of antithrombotics on the fecal immunochemical test for colorectal cancer screening : a multi-center Belgian experience.

Background: Impact of antithrombotics on the fecal immunochemical test (FIT) for colorectal cancer (CRC) screening remains unclear. Methods: Patients undergoing colonoscopy for positive FIT in 2015 were assessed at 3 Belgian centers. Significant findings were advanced polyps (AP) (sessile serrated, tubular or villous adenomas >1cm or high-grade dysplasia) and CRC. False positive FIT and detection of AP/CRC with antithrombotics were calculated. Results: 510 patients (64% male, median (IQR) age 63.2 (60.2 - 66.4) years) were included. Colorectal pathology in 371/510 (73%) was associated with male gender (70% vs. 48% ; p= .0001) and family history (16% vs. 8% ; p= .02). Antithrombotics in 125/510 (25%) were associated with male gender (78% vs. 59% ; p= .0001), older age (65.2 (62.2-70.3) vs. 62.3 (58.7-66.3) years ; p= .0001) and GI-symptoms (18% vs. 11% ; p= .04). False positive FIT (25% vs. 28% ; p= .52) and detection of AP (42% vs. 36% ; p=.27) or CRC (6% vs. 5% ; p= .69) were similar in patients with vs. no antithrombotics. Use of antithrombotics did not predict a higher chance of colorectal pathology after adjusting for confounders. Conclusion: Although antithrombotics were prescribed more frequently in male and older patients, detection of AP/CRC was similar. Despite increased GI symptoms, false positive FIT was similar with antithrombotics.

Ulcerative colitis treatment : an insight into daily clinical practice.

BACKGROUND: The natural history of ulcerative colitis (UC) is unpredictable. Factors associated with the need for different types of step-up therapy in UC patients failing on 5-aminosalicylic acid (5-ASA) or corticosteroids are understudied. AIMS: Describe step-up therapy in patients with UC the first year after failing on 5-ASA or corticosteroids. METHODS: A Belgian, multi-center, prospective, non-interventional observational study comprising adult UC patients failing on 5-ASA or corticosteroids and naïve to immunomodulators/ biologicals. During a 12 months follow-up, patient characteristics, demography, medical therapy, biomarkers, therapy adherence and quality of life (QoL) were assessed. RESULTS: After 1 year, 35% of the patients were on biological therapy. Use of anti-TNF differed depending on baseline treatment: corticosteroid-refractory patients (55.8%), 5-ASA refractory (20.0%), and corticosteroid-dependent (16.0%) patients (p<0.001). The decision to start a line of therapy was based on the Mayo combined severity but not on biomarkers like faecal calprotectin, haemoglobin, CRP, albumin, platelets, and number of extraintestinal manifestations. At year 1, 84.2% of the patients had only mild UC or remission and a significant improvement of fatigue (p=0.004) and IBDQ scores (p<0.001) were observed implying an improved QoL. CONCLUSION: Treatment step-up, based on clinical scores in immunomodulatory and anti-TNF naïve patients with UC, provides good clinical outcomes and QoL.

Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline

This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). This Guideline was also reviewed and endorsed by the Governing Board of the American Society for Gastrointestinal Endoscopy (ASGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence. Main recommendations The following recommendations should only be applied after a thorough diagnostic evaluation including a contrast-enhanced computed tomography (CT) scan. 1 Prophylactic colonic stent placement is not recommended. Colonic stenting should be reserved for patients with clinical symptoms and imaging evidence of malignant large-bowel obstruction, without signs of perforation (strong recommendation, low quality evidence). 2 Colonic self-expandable metal stent (SEMS) placement as a bridge to elective surgery is not recommended as a standard treatment of symptomatic left-sided malignant colonic obstruction (strong recommendation, high quality evidence). 3 For patients with potentially curable but obstructing left-sided colonic cancer, stent placement may be considered as an alternative to emergency surgery in those who have an increased risk of postoperative mortality, I. e. American Society of Anesthesiologists (ASA) Physical Status ≥ III and/or age > 70 years (weak recommendation, low quality evidence). 4 SEMS placement is recommended as the preferred treatment for palliation of malignant colonic obstruction (strong recommendation, high quality evidence), except in patients treated or considered for treatment with antiangiogenic drugs (e. g. bevacizumab) (strong recommendation, low quality evidence).(AU)

Mixture designs in the optimisation of PLGA nanoparticles: influence of organic phase composition on ß-aescin encapsulation.

The objective of this study was to enhance the encapsulation of the antileishmanial saponin aescin in poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). We prepared the NPs by the O/W and W/O/W combined emulsification solvent evaporation/salting-out technique and investigated the influence of organic phase composition on the NPs' size, zeta potential and entrapment efficiency (EE%) using mixture designs. The obtained NPs were monodispersed with Z(ave)<300 nm and exhibited negative zeta potentials. For the single emulsion, the co-solvent concentration was shown to be the primary determinant of drug entrapment. The EE% increased from 14% to 22% by decreasing the amount of DMSO from 80% to 25% (v/v) in the organic polymer solution. For the double emulsion, EE% was 22% on average and independent of the organic phase composition. The double-emulsion technique did not enhance the aescin encapsulation as expected due to its amphiphilic nature. The optimised aescin-loaded NPs meet the requirements for further in vitro activity tests.

Colonic stenting as a bridge to surgery in malignant large-bowel obstruction: a report from two large multinational registries.

OBJECTIVES: To date, this is the largest prospective series in patients with malignant colorectal obstruction to evaluate the effectiveness and safety of colonic self-expanding metal stents (SEMSs) as an alternative to emergency surgery. SEMSs allow restoration of bowel transit and careful tumor staging in preparation for elective surgery, hence avoiding the high morbidity and mortality associated with emergency surgery and stoma creation. METHODS: This report is on the SEMS bridge-to-surgery subset enrolled in two multicenter international registries. Patients were treated per standard of practice, with documentation of clinical and procedural success, safety, and surgical outcomes. RESULTS: A total of 182 patients were enrolled with obstructive tumor in the left colon (85%), rectum (11%), or splenic flexure (4%). Of these patients, 86% had localized colorectal cancer without metastasis. Procedural success was 98% (177/181). Clinical success was 94% (141/150). Elective surgery was performed in 150 patients (9 stomas) and emergency surgery in 7 patients for treatment of a complication (3 stomas). The overall complication rate was 7.8% (13/167), including perforation in 3% (5/167), stent migration in 1.2% (2/167), bleeding in 0.6% (1/167), persistent colonic obstruction in 1.8% (3/167), and stent occlusion due to fecal impaction in 1.2% (2/167). One patient died from complications related to surgical management of a perforation. CONCLUSIONS: SEMSs provide an effective bridge to surgery treatment with an acceptable complication rate in patients with acute malignant colonic obstruction, restoring luminal patency and allowing elective surgery with primary anastomosis in most patients.

PLGA nanoparticles loaded with the antileishmanial saponin ß-aescin: factor influence study and in vitro efficacy evaluation.

Colloidal carriers are known to improve the therapeutic index of the conventional drugs in the treatment of visceral leishmaniasis (VL) by decreasing their toxicity whilst maintaining or increasing therapeutic efficacy. This paper describes the development of poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the antileishmanial saponin ß-aescin. NPs were prepared by the W/O/W emulsification solvent evaporation technique and the influence of five preparation parameters on the NPs' size (Z(ave)), zeta potential and entrapment efficiency (EE%) was investigated using a 2(5-2) fractional factorial design. Cytotoxicity of aescin, aescin-loaded and blank PLGA NPs was evaluated in J774 macrophages and non-phagocytic MRC-5 cells, whereas antileishmanial activity was determined in the Leishmania infantum ex vivo model. The developed PLGA NPs were monodispersed with Z(ave)<500 nm and exhibited negative zeta potentials. The process variables 'surfactant primary emulsion', 'concentration aescin' and 'solvent evaporation rate' had a positive effect on EE%. Addition of Tween 80 to the inner aqueous phase rendered the primary emulsion more stable, which in its turn led to better saponin entrapment. The selectivity index (SI) towards the supporting host macrophages increased from 4 to 18 by treating the cells with aescin-loaded NPs instead of free ß-aescin. In conclusion, the in vitro results confirmed our hypothesis.

Second primary malignancies in patients with a gastrointestinal neuroendocrine tumour: a case report and review of the literature.

A second primary malignancy (SPM) is frequently reported in patients with a gastrointestinal neuroendocrine tumour (NET). The majority of SPM are located in the gastrointestinal tract, but malignancies at other sites are described as well. This phenomenon might just be coincidental due to high incidence rates of asymptomatic NET lesions in patients who are operated or who undergo autopsy for another primary malignancy. However, other theories have been developed since the observed incidences rates seem to be double as high as expected. Some authors suggest a common genetic predisposition, while others report tumourigenic properties of various neuroendocrine peptides, including secretin, gastrin and cholecystokinin. This review is illustrated by a case report of a patient in whom the radiological diagnosis of a diffuse liver metastasized adenocarcinoma of the rectum changed dramatically after positron emission tomography and explorative laparoscopy to a curable adenocarcinoma of the rectum with a simultaneous well-differentiated neuroendocrine carcinoma.

Solid lipid nanoparticle (SLN) formulations as a potential tool for the reduction of cytotoxicity of saponins.

The present pilot study explored the potential of solid lipid nanoparticles (SLN) to entrap saponins and reduce the membrane toxicity of these compounds. SLN composed of different types of solid lipid were prepared by the cold homogenisation technique. Combinations of anionic, cationic and non-ionic stabilisers were selected in order to obtain negatively, positively and neutrally charged SLN. Mean particle size and zeta potential of blank and saponin-loaded formulations were measured by Dynamic Light Scattering (DLS), Electrophoretic Light Scattering (ELS) and in vitro cytotoxicity on MRC-5 SV2 and J774 cells was assessed using a resazurin-based assay. The type of solid lipid used for the formulation influenced the mean particle size, while the zeta potential mainly depended on the kind of surfactant utilised. Blank SLN composed of hard fat and anionic or non-ionic surfactants did not result in cytotoxicity. After loading with saponin, the anionic hard fat SLN was found to be the optimal formulation.

An investigation of misoprostol in the promotion of wound healing.

Misoprostol is a synthetic analogue of prostaglandin E1 that is known to attenuate the inflammatory process and promote collagen formation by inhibiting IL-1 and TNF. The objective of this study was to determine if the application of misoprostol wound powder to open wounds in dogs would modulate inflammation and decrease wound healing time. This prospective randomized study included 20 dogs with 281 surgically created 8 mm open wounds over the dorsum. The wounds were assigned to one of three treatments: control (no treatment), treatment (misoprostol powder with 'avicel'), or vehicle ('avicel' alone). Open wounds were digitally photographed on days zero, one, three, seven, 10, and 15 to measure wound size. All wounds were harvested at day 15 and evaluated histologically for evidence of edema, inflammation, necrosis, and collagen characteristics. Amount of epithelialization of open wounds was not significantly different among the groups at days three, seven, 10, and 15. The vehicle treated wounds were found to have a significantly higher degree of necrosis in comparison to control and treatment wounds. The control wounds had significantly lower scores for deep inflammation. All of the other parameters evaluated including location of wound, oedema, and characteristics of collagen fibres in the wound showed no significance among groups. However, the total wound score for the misoprostol was statistically higher than that for the control wounds. Therefore the value of using misoprostol wound powder with 'avicel' as the vehicle to enhance wound healing cannot be substantiated by the results of this study.

The effect of freeze-drying with different cryoprotectants and gamma-irradiation sterilization on the characteristics of ciprofloxacin HCl-loaded poly(D,L-lactide-glycolide) nanoparticles.

In the present study, the influence of freeze-drying with several cryoprotective agents and gamma (gamma)-irradiation sterilization on the physicochemical characteristics of ciprofloxacin HCl-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles was evaluated. Nanoparticles were prepared by W/O/W emulsification solvent evaporation followed by high-pressure homogenization. They were freeze-dried in the presence of 5.0% (w/v) mannitol, trehalose or glucose, with 5.0% (w/v) or 15.0% (w/v) dextran as cryoprotectants. The nanoparticles were irradiated at a dose of 25 kGy using a 60Co source. The following physicochemical properties of the formulations were investigated: the ratio of particle size before (initial) and after freeze-drying, the ease of reconstitution of the nanoparticle suspensions and the drug-release profiles of irradiated and non-irradiated nanoparticles. The antibacterial activity against Pseudomonas aeruginosa was measured. The freeze-drying process induced a significant increase in particle size when no cryoprotectant was employed. Similar results were observed when cryoprotectants were added to the formulation. Only when mannitol was used was no significant size increase measured. Moreover, for formulations with dextran, reconstitution after freeze-drying was difficult by manual agitation and particle size could not be determined because of aggregation. After gamma-sterilization no significant difference in mean particle size was observed, but reconstitution was more difficult and drug release was influenced negatively. Ciprofloxacin HCl incorporated in the nanoparticles was still effective against the micro-organism selected after freeze-drying and gamma-sterilization.

Preparation and evaluation of drug-loaded gelatin nanoparticles for topical ophthalmic use.

Gelatin nanoparticles encapsulating pilocarpine HCl or hydrocortisone as model drugs were produced using a desolvation method. The influence of a number of preparation parameters on the particle properties was investigated. For the pilocarpine HCl-loaded spheres, an influence of the pH during particle preparation on the size was observed. Slightly negative zeta potential values were measured for all samples. In the case of pilocarpine HCl-loaded spheres, no influence of the gelatin type or the pH level was observed, which could be attributed to the shielding effect of ions present in the dispersion medium. When hydrocortisone was entrapped, a difference in zeta potential value between gelatin type A and gelatin type B particles was measured. A high pilocarpine HCl entrapment was established. Hydrocortisone was complexed with cyclodextrins in order to increase its aqueous solubility. The drug encapsulation was lower than in the case of pilocarpine HCl, but still amounted to approximately 30-40%. Compared to the aqueous drug solutions, a sustained release for both drugs was observed. The release kinetics of pilocarpine HCl are close to zero order, and no significant differences were measured between the various preparations. In the case of hydrocortisone, the release data suggests a difference in release rate depending on the type of cyclodextrin employed.

Lung function and nutritional status of semi-nomadic Fulani children and adolescents in northern Nigeria.

The Fulani are semi-nomadic pastoralists of the western Sahel whose culture and economy are centered on cattle. We have shown previously that Fulani children and adolescents (5-18 years old) are stunted and underweight. Nutritional status and lung function were studied in Fulani children and adolescents (n = 70), aged 6-18, and compared with a non-Fulani, rural Nigerian control group (n = 153) of the same age. Participants were restricted to healthy individuals with no prior history of respiratory disease and no symptoms of an upper respiratory tract infection within the past 6 weeks. Significant deficits in forced vital capacity (FVC; Fulani males, 1.51 l; non-Fulani males, 1.86 l, p = 0.009; Fulani females, 1.36 l; non-Fulani females, 1.79 l, p < 0.001), forced expiratory volume in one second (FEV1; Fulani males, 1.44 l; non-Fulani males, 1.76 l, p = 0.02; Fulani females, 1.24 l; non-Fulani females, 1.69 l, p < 0.001), and peak expiratory flow rate (PEFR; Fulani males, 2.69 l/s; non-Fulani males, 3.48 l/s, p = 0.002; Fulani females, 2.29 l/s; non-Fulani females, 3.35 l/s, p < 0.001) were found in both the Fulani boys and girls compared with the non-Fulani controls. The diminished lung function in the Fulani group could be attributed to respiratory muscle weakness or an overall deficit in energy.

Influence of process parameters of high-pressure emulsification method on the properties of pilocarpine-loaded nanoparticles.

Poly(lactide-co-glycolide) nanoparticles loaded with pilocarpine hydrochloride were prepared by the high-pressure emulsification-solvent evaporation method. The nanoparticles were produced using polyvinylalcohol (PVA), carbomer (Carbopol 980) or poloxamer (Lutrol F-68) as stabilizers during emulsification. The influence of pressure and number of cycles on the nanoparticle properties was investigated. For comparison, nanoparicles without high-pressure treatment of the emulsion were made. The nanoparticle size, drug loading and release properties depended strongly on the homogenization pressure and number of cycles applied. Nanoparticles obtained without high pressure homogenization showed larger size and high values of polydispersity index, especially when carbopol and poloxamer were used as emulsifiers. Drug loading and encapsulation efficiency of all samples also decreased with pressure. The low drug loading could be due to two reasons. First, the high pressure promoted drug diffusion out of protoparticles during emulsification either by size reduction or shear forces. Secondly, the characteristics of the outer water phase of the emulsion also influenced the nanoparticle drug loading. This was proven by the different drug loadings measured when nanoparticles were made with PVA, carbopol or poloxamer at equal pressures applied. The main factor influencing the release properties of nanoparticles was the pressure used during emulsification. Faster drug release was observed from nanoparticles obtained after high-pressure emulsification compared to those prepared without homogenization of the emulsion.

Safety of ERCP during pregnancy.

OBJECTIVES: There are few data in the literature regarding the indications, therapy, and safety of endoscopic management of pancreatico-biliary disorders during pregnancy. We report the largest single center experience with ERCP in pregnancy. METHODS: We reviewed 15 patients that underwent ERCP during pregnancy. In all patients, the pelvis was lead-shielded and the fetus was monitored by an obstetrician. Fluoroscopy was minimized and hard copy radiographs taken only when essential. RESULTS: The mean patient age was 28.9 yr (15-36 yr). The mean duration of gestation was 25 wk (12-33 wk); one patient was in the first, five in the second, and nine in the third trimester. The indications were gallstone pancreatitis (n = 6), choledocholithiasis on ultrasound (n = 5), elevated liver enzymes and a dilated bile duct on ultrasound (n = 2), abdominal pain and gallstones (n = 1), and chronic pancreatitis (n = 1). ERCP findings were bile duct stones (n = 6), patulous papilla (n = 1), bile duct debris (n = 1), normal bile duct and gallstones or gallbladder sludge (n = 3), dilated bile duct and gallstones (n = 1), normal bile duct and no gallstones (n = 2), and chronic pancreatitis (n = 1). Six patients underwent sphincterotomies and one a biliary stent insertion. One sphincterotomy was complicated by mild pancreatitis. All infants delivered to date have had Apgar-scores >8, and continuing pregnancies are uneventful. Mean fluorosocopy time was 3.2 min (SD +/- 1.8). An estimated fetal radiation exposure was 310 mrad (SD +/- 164) which is substantially below the accepted teratogenic dose. CONCLUSIONS: ERCP in pregnancy seems to be safe for both mother and fetus; however, it should be restricted to therapeutic indications with additional intraprocedure safety measures.

Bedside scoring system to predict the risk of developing pancreatitis following ERCP.

BACKGROUND AND STUDY AIMS: Pancreatitis is the most common significant complication of endoscopic retrograde cholangiopancreatography (ERCP). The aim of the present study was to develop a simple scoring system that clinicians can use to predict the risk of post-ERCP pancreatitis. PATIENTS AND METHODS: We analyzed a prospectively assembled database of 1835 ERCP procedures at a single referral hospital. Multivariate logistic regression analysis was performed to identify risk factors for pancreatitis and determine their relative contributions. From these results, a scoring system was constructed. The performance of the scoring system was assessed on the entire procedure database and in selected subgroups. RESULTS: Multivariate analysis yielded four risk factors: pain during the procedure, cannulation of the pancreatic duct (PD), previous post-ERCP pancreatitis, and number of cannulation attempts. Based on the regression model, the scoring system was: 4 points for pain, 3 points for PD cannulation, 2 points for a history of post-ERCP pancreatitis, and 1 - 4 points depending on the number of cannulation attempts. A total score of 1 - 4 points was associated with a low risk of pancreatitis (< 2 %), while a score of 5 - 8 points had an intermediate risk (7 %), and a score of 9 or above had a high risk (28 %). CONCLUSIONS: This simple scoring system may enable clinicians to stratify patients into low-risk, medium-risk, and high-risk groups for the development of post-ERCP pancreatitis. In addition, when patients with suspected sphincter of Oddi dysfunction and patients who underwent minor papilla cannulation were analyzed separately, the scoring system was able to predict accurately the pancreatitis risk of these patients as well.

Biocompatible stabilizers in the preparation of PLGA nanoparticles: a factorial design study.

Poly(lactic-co-glycolic-acid) nanoparticles are often produced using the w/o/w emulsification solvent evaporation method. In most cases poly(vinyl alcohol) (PVA) is used as stabilizer of the emulsion. The goal of this study was to compare a series of polymers to PVA in a 2(2) full factorial design study. The influence of the concentration of PVA and the polymers tested on particle size and zeta potential value was evaluated before and after freeze-drying of the prepared particles. Nanoparticles were obtained with most polymers when they were used in combination with PVA. Leaving PVA out of the formulation, however, increased the size of the particles over 1 microm. Two exceptions are poloxamer and carbopol, which can be considered as valuable alternatives to PVA. Zeta potential values were usually slightly negative, the most extreme zeta potential values were measured when poloxamer and carbopol were employed. The use of gelatin type A made it possible to achieve positive values. The original 2(2) full factorial design study was further expanded to a central composite design for poloxamer and carbopol, in order to fit the measured data to a quadratic model and to calculate response surfaces.

Use of a polymerase chain reaction assay to detect infection with Eperythrozoon wenyoni in cattle.

OBJECTIVE: To determine whether a polymerase chain reaction (PCR) assay could be used to detect Eperythrozoon wenyoni in the blood of cattle. DESIGN: Prospective study. ANIMALS: 95 cattle from various herds in Alabama and Georgia and 96 bulls enrolled in Auburn University's Alabama Beef Cattle Improvement Association Bull Test program. PROCEDURE: Blood samples were collected by means of venipuncture of the median caudal vein and submitted for a CBC and PCR assay. Blood smears were made immediately after blood collection and examined by means of light microscopy. RESULTS: Three of 95 cattle from herds in Alabama and Georgia and 5 of 96 bulls enrolled in the Bull Test program had positive PCR assay results. Organisms were seen in blood smears from only 5 of these 8 animals. Organisms were not seen in blood smears from any animals for which results of the PCR assay were negative. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that a PCR assay may be an effective method for detecting E wenyoni infection in cattle and that the PCR assay may be a more sensitive test than evaluation of blood smears.