The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles

The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity using ex vivo models. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin's neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug's myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy

The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles

The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity using ex vivo models. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin’s neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug’s myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy

No demonstrable association between the Leningrad–Zagreb mumps vaccine strain and aseptic meningitis in a large clinical trial in Egypt

AbstractTo address the claim that the Leningrad–Zagreb (L-Z) mumps vaccine strain is causally associated with aseptic meningitis, a prospective, post-marketing safety study was conducted with a measles-mumps-rubella vaccine (MMR) (TRESIVAC°; Serum Institute of India Ltd., Pune, India), which uses the L-Z strain as its mumps component in Egypt. In all, 453 119 children (65 423 children aged 16–24 months and 329 211 children aged 5–7 years) received MMR. The control groups which, as a result of local health regulations, were slightly younger than vaccinees, comprised 12 253 and 46 232 children, respectively. Using questionnaires, the parents recorded solicited local, systemic and neurological adverse events for up to 42 days post-vaccination. All data were analysed externally on an intention-to-treat basis by individuals not participating in the study. Local and/or systemic reactions were reported in a small percentage of participants, with pain, fever and parotitis being the most common signs among vaccinees in both age groups. No case of aseptic meningitis, encephalitis, anaphylaxis or convulsions was observed in any participant. Thus, in this series of more than 450 000 Egyptian children, the L-Z mumps vaccine strain in this vaccine did not cause aseptic meningitis. The vaccine is considerably cheaper than Western competitors and a valid alternative to other MMR vaccines

Tailoring the pressure-drop in multi-layered open-cell porous inconel structures

This study investigates the pressure-drop behaviour associated with airflow through bulk and structurally tailored multi-layered, open-cell porous Inconel structures over a wide airflow velocity range (0–50 m s-1). The effect of airflow velocity on the pressure-drop behaviour as a function of the sample thickness is presented and related to the flow behaviour corresponding to the relevant flow regimes (Darcy, Forchheimer, Turbulent and Postturbulent). Entrance effects are highlighted as a source of the pressure-drop increase for porous structures with air gaps, regardless of their sizes, as long as they are larger than those generated by loosely-stacked structures. The pressure-drops for gapped porous structures and the mathematical-summation of the pressure drop for the corresponding individual components, were in very good agreement, at lower airflow velocities. The potential for mass-efficient porous structures, providing a high pressure drop, was demonstrated using multiple thin porous laminates separated by air gaps

Experimental investigation of pressure-drop characteristics across multi-layer porous metal structures

This study investigates the effect of airflow (in the range of 0–70 m s-1) on the pressure-drop characteristics for a novel multi-layered, nickel-based porous metal, as a function of thickness (affected by sectioning) and density (affected by compression). In addition to generating unique data for these materials, the study highlights the need for precise pinpointing of the different flow regimes (Darcy, Forchheimer and Turbulent) in order to enable accurate determination of the permeability (K) and form drag coefficient (C) defined by the Forchheimer equation and to understand the complex dependence of length-normalised pressure drop on sample thickness

Pore-scale numerical investigation of pressure drop behaviour across open-cell metal foams

The development and validation of a grid-based pore-scale numerical modelling methodology applied to five different commercial metal foam samples is described. The 3-D digital representation of the foam geometry was obtained by the use of X-ray microcomputer tomography scans, and macroscopic properties such as porosity, specific surface and pore size distribution are directly calculated from tomographic data. Pressure drop measurements were performed on all the samples under a wide range of flow velocities, with focus on the turbulent flow regime. Airflow pore-scale simulations were carried out solving the continuity and Navier–Stokes equations using a commercial finite volume code. The feasibility of using Reynolds-averaged Navier–Stokes models to account for the turbulence within the pore space was evaluated. Macroscopic transport quantities are calculated from the pore-scale simulations by averaging. Permeability and Forchheimer coefficient values are obtained from the pressure gradient data for both experiments and simulations and used for validation. Results have shown that viscous losses are practically negligible under the conditions investigated and pressure losses are dominated by inertial effects. Simulations performed on samples with varying thickness in the flow direction showed the pressure gradient to be affected by the sample thickness. However, as the thickness increased, the pressure gradient tended towards an asymptotic value

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit