Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole

AbstractThis study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance

Customizing systemic therapy in patients with advanced non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths worldwide. Standard chemotherapy has been shown to improve quality of life and has a modest influence on overall survival. This modest improvement in survival is partly due to the choice of chemotherapy regimens that have been based on prognostic factors such as age, performance status and comorbidities of the patient. This underlines the importance of developing a more personalized therapy for patients with non-small cell lung cancer. Such an approach may reduce the variation in how individual patients respond to medications by tailoring therapies to their genetic profile. In this review we focus on several aspects of customized therapy, looking not only at patient characteristics but also to tumor histology and specific tumor biomarkers

Endoscopic management of enteral tubes in adult patients-Part 2: Peri-and post-procedural managementEuropean Society of Gastrointestinal Endoscopy (ESGE) Guideline

Main recommendations ESGE recommends the pull technique as the standard method for percutaneous endoscopic gastrostomy (PEG) placement. Strong recommendation, low quality evidence. ESGE recommends the direct percutaneous introducer (push) technique for PEG placement in cases where the pull method is contraindicated, for example in severe esophageal stenosis or in patients with head and neck cancer (HNC) or esophageal cancer. Strong recommendation, low quality evidence. ESGE recommends the intravenous administration of a prophylactic single dose of a beta-lactam antibiotic (or appropriate alternative antibiotic, in the case of allergy) to decrease the risk of post-procedural wound infection. Strong recommendation, moderate quality evidence. ESGE recommends that inadvertent insertion of a nasogastric tube (NGT) into the respiratory tract should be considered a serious but avoidable adverse event (AE). Strong recommendation, low quality evidence. ESGE recommends that each institution should have a dedicated protocol to confirm correct positioning of NGTs placed blindly at the patient's bedside; this should include: radiography, pH testing of the aspirate, and end-tidal carbon dioxide monitoring, but not auscultation alone. Strong recommendation, low quality evidence. ESGE recommends confirmation of correct NGT placement by radiography in high-risk patients (intensive care unit [ICU] patients or those with altered consciousness or absent gag/cough reflex). Strong recommendation, low quality evidence. ESGE recommends that EN may be started within 3-4 hours after uncomplicated placement of a PEG or PEG-J. Strong recommendation, high quality evidence. ESGE recommends that daily tube mobilization (pushing inward) along with a loose position of the external PEG bumper (1-2cm from the abdominal wall) could mitigate the risk of development of buried bumper syndrome. Strong recommendation, low quality evidence

Endoscopic management of enteral tubes in adult patients - Part 1: Definitions and indicationsEuropean Society of Gastrointestinal Endoscopy (ESGE) Guideline

Main recommendations ESGE recommends considering the following indications for enteral tube insertion: (i) clinical conditions that make oral intake impossible (neurological conditions, obstructive causes); (ii) acute and/or chronic diseases that result in a catabolic state where oral intake becomes insufficient; and (iii) chronic small-bowel obstruction requiring a decompression gastrostomy. Strong recommendation, low quality evidence. ESGE recommends the use of temporary feeding tubes placed through a natural orifice (either nostril) in patients expected to require enteral nutrition (EN) for less than 4 weeks. If it is anticipated that EN will be required for more than 4 weeks, percutaneous access should be considered, depending on the clinical setting. Strong recommendation, low quality evidence. ESGE recommends the gastric route as the primary option in patients in need of EN support. Only in patients with altered/unfavorable gastric anatomy (e. g. after previous surgery), impaired gastric emptying, intolerance to gastric feeding, or with a high risk of aspiration, should the jejunal route be chosen. Strong recommendation, moderate quality evidence. ESGE suggests that recent gastrointestinal (GI) bleeding due to peptic ulcer disease with risk of rebleeding should be considered to be a relative contraindication to percutaneous enteral access procedures, as should hemodynamic or respiratory instability. Weak recommendation, low quality evidence. ESGE suggests that the presence of ascites and ventriculoperitoneal shunts should be considered to be additional risk factors for infection and, therefore, further preventive precautions must be taken in these cases. Weak recommendation, low quality evidence. ESGE recommends that percutaneous tube placement (percutaneous endoscopic gastrostomy [PEG], percutaneous endoscopic gastrostomy with jejunal extension [PEG-J], or direct percutaneous endoscopic jejunostomy [D-PEJ]) should be considered to be a procedure with high hemorrhagic risk, and that in order to reduce this risk, specific guidelines for antiplatelet or anticoagulant use should be followed strictly. Strong recommendation, low quality evidence. ESGE recommends refraining from PEG placement in patients with advanced dementia. Strong recommendation, low quality evidence. ESGE recommends refraining from PEG placement in patients with a life expectancy shorter than 30 days. Strong recommendation, low quality evidence*

Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis

Objectives: This study sought to develop an integrative positron emission tomography (PET) with magnetic resonance imaging (MRI) procedure for accurate atherosclerotic plaque phenotyping, facilitated by clinically approved and nanobody radiotracers. Background: Noninvasive characterization of atherosclerosis remains a challenge in clinical practice. The limitations of current diagnostic methods demonstrate that, in addition to atherosclerotic plaque morphology and composition, disease activity needs to be evaluated. Methods: We screened 3 nanobody radiotracers targeted to different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor (LOX)-1, and macrophage mannose receptor (MMR). The nanobodies, initially radiolabeled with copper-64 (64Cu), were extensively evaluated in Apoe–/– mice and atherosclerotic rabbits using a combination of in vivo PET/MRI readouts and ex vivo radioactivity counting, autoradiography, and histological analyses. Results: The 3 nanobody radiotracers accumulated in atherosclerotic plaques and displayed short circulation times due to fast renal clearance. The MMR nanobody was selected for labeling with gallium-68 (68Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by 68Ga-MMR–PET, plaque burden by T2-weighted MRI, and neovascularization by dynamic contrast-enhanced (DCE) MRI. Additionally, inflammation and microcalcifications were evaluated by fluorine-18 (18F)-labeled fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) PET, respectively. We observed an increase in all the aforementioned measures as disease progressed, and the imaging signatures correlated with histopathological features. Conclusions: We have evaluated nanobody-based radiotracers in rabbits and developed an integrative PET/MRI protocol that allows noninvasive assessment of different processes relevant to atherosclerosis progression. This approach allows the multiparametric study of atherosclerosis and can aid in early stage anti-atherosclerosis drug trials