Aerodynamical, Immunological and Pharmacological Properties of the Anticancer Antibody Cetuximab Following Nebulization

Purpose

Despite an increasing interest in the use of inhalation for local delivery of molecules for respiratory diseases and systemic disorders, methods to deliver therapy through airways has received little attention for lung cancer treatment. However, inhalation of anticancer drugs is an attractive alternative route to systemic administration which results in limited concentration of the medication in the lungs, and triggers whole-body toxicity. In this study, we investigated the feasibility of nebulization for therapeutic antibodies, a new class of fully-approved anticancer drugs in oncology medicine.

Materials and methods

Cetuximab, a chimeric IgG1 targeting the epidermal growth factor receptor (EGFR), was nebulized using three types of delivery devices: a jet nebulizer PARI LC+®, a mesh nebulizer AeronebPro® and an ultrasonic nebulizer SYST’AM® LS290. Aerosol size distribution was measured using a cascade impactor and aerosol droplets were observed under optical microscopy. The immunological and pharmacological properties of cetuximab were evaluated following nebulization using A431 cells.

Results

The aerosol particle clouds generated with the three nebulizers displayed similar aerodynamical characteristics, but the IgG formed aggregates in liquid phase following nebulization with both the jet and ultrasonic devices. Flow cytometry analyses and assays of EGFR-phosphorylation and cell growth inhibitions on A431 demonstrated that both the mesh and the jet nebulizers preserved the binding affinity to EGFR and the inhibitory activities of cetuximab.

Conclusions

Altogether, our results indicate that cetuximab resists the physical constraints of nebulization. Thus, airway delivery represents a promising alternative to systemic administration for local delivery of therapeutic antibodies in lung cancer treatment.     

Germination of seeds from an irradiated forest: implications for waste disposal.

Jack pine (Pinus banksiana Lamb.) retain their seeds from year to year, so that in an irradiated forest, each tree receives a specific dose rate but has seeds that have accumulated a range of total doses. The Field Irradiator-Gamma facility in Pinawa, Manitoba, contains jack pine that have been irradiated longer and at lower dose rates than previously reported. Seed germination and germination rate were examined on seeds irradiated on the parent tree for up to 5 years. Germination rate was most sensitive and showed deleterious effects at 1.1 mGy hr-1. This is not much lower than results reported by others in shorter-term studies. Effects were related to dose rate rather than total dose. Hormesis, indicated by statistically significant increased germination rate, was evident at 0.6 mGy hr-1. To put these results into context, the concentrations of selected radionuclides that, through internal contamination, would deliver 1.1 mGy hr-1 to plants were estimated. For 99Tc and 129I, these concentrations are far above the chemical toxicity thresholds for plants. Clearly, as assessments of waste repositories begin to consider effects on organisms other than humans, such as plants, chemical toxicity will be an important feature.     

Évaluation de l’état nutritionnel péri-opératoire

In surgical patients, malnutrition is associated with an increase in morbidity, mortality, length of stay and health care costs, and has an impact on quality of life. Before surgery, the risk of malnutrition is depending on patient-related factors (age, associated diseases, on-going symptoms, duration of pre-operative hospital stay), surgical procedure, and medical treatment (radiotherapy, chemotherapy, corticoid treatment). The early screening and management of malnutrition are mandatory during the peri-operative period, with the aim to improve post-operative prognosis and clinical outcome. The nutritional assessment is based on the research of weight loss, the calculation of body mass index and the research of an hypoalbuminemia, all of them having a negative impact on postoperative prognosis. The Nutritional Risk Index (NRI) is also of strong prognostic value. We propose a stratification of the nutritional risk indicating several levels of surgical risk. The organization, the planning and the traceability in the medical record of the nutritional assessment should allow optimizing the management and the clinical outcome of surgical patients. The pre-operative consultation of anaesthesia could be the privileged time to perform the screening of malnutrition and to plan its management, if they were not previously performed by the medico-surgical team.     

Altered lipid profile, lipoprotein composition, and oxidant and antioxidant status in pediatric Crohn disease

BACKGROUND: Growing evidence supports a role for peroxidation in the pathogenesis of Crohn disease (CD). The activation of inflammatory cells, the release of their mediators, and the excessive production of free radicals may affect circulating lipids. OBJECTIVE: We examined the lipid profile, lipoprotein composition, and oxidant-antioxidant status of children with CD. DESIGN: We studied 22 pediatric CD patients and 10 healthy control subjects. RESULTS: The proportion of saturated and monounsaturated fatty acids in plasma of CD patients was higher but that of polyunsaturated fatty acids was lower than in control subjects. This resulted in higher ratios in CD patients of palmitoleic acid to linoleic acid (P < 0. 05) and of eicosatrienoic acid to arachidonic acid (P < 0.04), 2 established indexes of essential fatty acid deficiency. Hypocholesterolemia was noted in CD patients as a result of lower LDL-cholesterol concentrations than in control subjects (P < 0.02). Plasma apolipoproteins B (P < 0.02) and A-I (P < 0.02) were also lower in CD patients, whereas plasma triacylglycerols were higher (P < 0.005). Lipoprotein composition was altered in CD patients, with relative triacylglycerol depletion and protein enrichment in VLDL. In contrast, intermediate-density lipoprotein of CD patients was characterized by an increased percentage of triacylglycerol and protein (P < 0.005) and a reduced proportion of phospholipids (P < 0. 01). Additional abnormalities were observed in the chemical distribution of HDL(2) and HDL(3) moieties. Lipid peroxidation was documented by higher plasma malondialdehyde concentrations in CD patients (P < 0.05), accompanied by lower retinol concentrations (P < 0.02). CONCLUSION: Disturbances in the lipid profile, in lipoprotein concentrations and composition, and in oxidant-antioxidant status occur in CD patients.     

Effect of quipazine, a selective 5-HT3 agonist, on dietary self-selection of different macronutrient diets in male and female rats

Macronutrient intakes, 2h and 12h, following administration of a selective 5-HT3 agonist, quipazine, N methyl, dimaleate (QUIPAZINE; 2.5, 5.0 and 7.5 mg/kg, i.p.) at dark onset were examined in three groups of adult male and female Wistar rats fed different sources of the three macronutrients: Group 1 (casein, corn starch, safflower oil), Group 2 (egg protein, corn starch/sucrose, lard) and Group S (casein hydrolysate, maltose dextrin, butter). QUIPAZINE decreased total food intake only in female rats from Group 1 (2 h) at a dose of 7.5 mg/kg and Group 2 (2h and 12h) with doses of 2.5 and 7.5 mg/kg. Intakes from corn starch and corn starch/sucrose diet (12h) were reduced in male and female rats, respectively, with doses of 2.5 and 7.5 mg/kg of QUIPAZINE. In conclusion, when provided with different sources of the three macronutrients, quipazine injection reduces specifically carbohydrate ingestion from corn starch-containing diets in male and female rats. Thus, the nature of the macronutrient source is of major importance to assess the effect of a drug on nutrient-specific selection.     

Comparison of the isotope dilution method for determination of the ileal endogenous amino acid losses with labelled diet and labelled pigs

The aims of the present study were first to compare the amino acid dilution method performed using labelled animals with that using labelled diets, and second to determine real digestibilities and total ileal endogenous losses of N and amino acids. Two diets containing pea cultivars (Solara and Amino) and a protein-free diet were compared in a 3 x 3 Latin-square experiment. The three pigs were each prepared with an ileo-rectal anastomosis and were continuously infused with [1-13C]leucine. For each cultivar, 15N-labelled and unlabelled diets were formulated. The real digestibility and endogenous losses of leucine were higher when obtained by labelling the pig than by labelling the foodstuff. This was due either to the inadequate estimation of the endogenous protein enrichment in the first case or to the importance of dietary N recycling in the second case. However, in both cases the ileal endogenous losses of N and amino acids were higher than the basal losses determined with the protein-free diet. There were significant differences between the two pea cultivars in terms of phenylalanine and leucine when measured with labelled diets. It is suggested that, although ileal endogenous losses may be underestimated, using labelled feedstuffs is of great interest due to the direct estimation of the individual amounts of amino acids.     

Chronic use of benzodiazepines and latent cognitive decline in the elderly: Results from the Three-city study

We aimed to examine whether long-term use of benzodiazepines is associated with an accelerated decline of cognitive performances by using a statistical model specifically adapted to multivariate longitudinal bounded quantitative outcomes. The data came from the “Three-city” study, a French population based study. All the subjects were 65 years old or older at inclusion and had been followed-up for 7 years. The use of benzodiazepines and cognitive functioning were assessed at each examination phase (baseline, 2, 4 and 7 years). Cognitive decline was analyzed using a nonlinear multivariate mixed model with a latent process. This model makes it possible to assess change over time of the latent cognitive process underlying several neuropsychological tests: Mini Mental Status Examination, Isaacs Set test, Benton Visual Retention Test, and Trail Making Test (A and B), and to describe and account for their metrological properties. Analyses were adjusted for age, center, gender, education, socio-professional status, depression, insomnia, high blood pressure, hypercholesterolemia, alcohol, tobacco consumption and physical activity. Nine hundred and sixty nine subjects who reported taking benzodiazepines for 2, 4 or 7 consecutive years were compared to 4226 subjects who were non-benzodiazepine users. Chronic use of benzodiazepine was significantly associated with a lower latent cognitive level (β=?1.79 SE=0.25 p=<0.001), but no association was found between chronic use and an acceleration of cognitive decline, neither on the latent cognitive process (β×time=0.010 SE=0.04 p=0.81), nor on specific neuropsychological tests. Our results suggest that chronic benzodiazepine use is associated with poorer cognitive performance but not with accelerated cognitive decline with age.     

Investigational drugs for the treatment of Zika virus infection: a preclinical and clinical update

ABSTRACT

Introduction: The Zika virus (ZIKV) infection results in severe neurological complications and has emerged as a threat to public health worldwide. No drugs or vaccines are available for use in the clinic and the need for novel and effective therapeutic agents is urgent.

Areas covered: This review describes the latest progress of antiviral development for the treatment of ZIKV infection; it primarily focuses on the literature describing 20 potential anti-ZIKV drugs/agents currently being tested in vivo or in clinical trials. The paper also discusses the need for novel ZIKV inhibitors and the critical issues for successful antiviral drug development.

Expert opinion: So far, 20 compounds have been tested in vivo and three in the clinical trials; progressing these compounds to the clinic is a challenge. Novel ZIKV inhibitors that target virus or host factors are urgently needed. Knowledge-driven drug repurposing, structure-based discovery, RNA interference, long noncoding RNAs, miRNAs, and peptide inhibitors may pave the way for the discovery of such novel agents.     

Chitosan-based therapeutic nanoparticles for combination gene therapy and gene silencing of in vitro cell lines relevant to type 2 diabetes

Glucagon like peptide 1 (GLP-1), a blood glucose homeostasis modulating incretin, has been proposed for the treatment of type 2 diabetes mellitus (T2DM). However, native GLP-1 pharmacokinetics reveals low bioavailability due to degradation by the ubiquitous dipeptydil peptidase IV (DPP-IV) endoprotease. In this study, the glucosamine-based polymer chitosan was used as a cationic polymer-based in vitro delivery system for GLP-1, DPP-IV resistant GLP-1 analogues and siRNA targeting DPP-IV mRNA. We found chitosans to form spherical nanocomplexes with these nucleic acids, generating two distinct non-overlapping size ranges of 141-283 nm and 68-129 nm for plasmid and siRNA, respectively. The low molecular weight high DDA chitosan 92-10-5 (degree of deacetylation, molecular weight and N:P ratio (DDA-Mn-N:P)) showed the highest plasmid DNA transfection efficiency in HepG2 and Caco-2 cell lines when compared to 80-10-10 and 80-80-5 chitosans. Recombinant native GLP-1 protein levels in media of transfected cells reached 23 ng/L while our DPP-IV resistant analogues resulted in a fivefold increase of GLP-1 protein levels (115 ng/L) relative to native GLP-1, and equivalent to the Lipofectamine positive control. We also found that all chitosan-DPP-IV siRNA nanocomplexes were capable of DPP-IV silencing, with 92-10-5 being significantly more effective in abrogating enzymatic activity of DPP-IV in media of silenced cells, and with no apparent cytotoxicity. These results indicate that specific chitosan formulations may be effectively used for the delivery of plasmid DNA and siRNA in a combination therapy of type 2 diabetes.