Hexcel (United Kingdom)

Cancers can hijack neural properties to grow, disseminate, and to resist therapies, but effective drug development pipelines against these features are missing. Here, we establish a compound screening approach that allowed the identification of PKC modulators that target cancer cell-intrinsic neurodevelopmental mechanisms, suggesting a new class of neuroscience-instructed cancer therapeutics.

Propagation of ultrasonic wave in Carbon Fiber Reinforced Polymer (CFRP) is greatly influenced by the material’s matrix, resins and fiber volume ratio. Laser ultrasonic broadband spectral technique has been demonstrated for porosity and fiber volume ratio extraction on unidirection aligned CFRP laminates. Porosity in the matrix materials can be calculated by longitudinal wave attenuation and accurate fiber volume ratio can be derived by combined velocity through the high strength carbon fiber and the matrix material with further consideration of porosity effects. The results have been benchmarked by pulse-echo ultrasonic tests, gas pycnometer and thermal gravimetric analysis (TGA). The potentials and advantages of the laser ultrasonic technique as a non-destructive evaluation method for CFRP carbon fiber volume fraction evaluation were demonstrated.

The Global CRO Council for Bioanalysis (GCC) was formed in an effort to bring together many senior-level representatives of CROs to openly discuss bioanalysis and the regulatory challenges, many of them unique to the outsourcing industry. CROs are unique in that they work with many different pharmaceutical companies and agencies, which results in a distinctive and comprehensive perspective on scientific approaches in relation to regulatory requirements. More information on GCC unique structure can be found in the publication titled ‘Formation of a Global Contract Research Organization Council for Bioanalysis’ [1] and its scientific activities have been subsequently published in articles and White Papers [2–6].

Ixabepilone (BMS-247550, Ixempra is a semi-synthetic analog of the natural product epothilone B and marketed for its use in the treatment of cancer. A conventional human ADME study using decay counting methods for (14)C detection could not be conducted due to the radiolytic instability of [(14)C]ixabepilone at a typical specific activity (generally 1-10 microCi/mg). However, [(14)C]ixabepilone was sufficiently stable at low specific activity (1-2 nCi/mg). These low levels required the use of accelerator mass spectrometry (AMS) for radioactivity detection. The metabolic fate of this compound was investigated in eight patients following single intravenous doses of [(14)C]ixabepilone (70 mg, 80 nCi; specific activity: 1.14 nCi/mg). Metabolite profiles in pooled urine, feces and plasma samples were determined by HPLC-AMS analysis. The major radioactive component in urine and plasma was [(14)C]ixabepilone. Feces had a small amount of ixabepilone. There were numerous other drug-related components in both urine and fecal extracts (each <6% of the administered dose). LC/MS analysis of plasma, urine and feces samples showed the presence of three degradants of ixabepilone and several oxidative metabolites (M+16, M+14 and M-2 metabolites). This study demonstrates the utility of AMS in investigating the metabolite and excretion profiles of [(14)C]ixabepilone following administration to humans.

The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of (14)C-nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the 11-day study period. The moderate bioavailability of nelfinavir was due to significant first-pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden. Human absolute bioavailability studies with accelerator mass spectrometry microdosing, in which an intravenous microdose is given along with a conventional oral dose of the same drug, can differentiate between gastrointestinal absorption and the first-pass metabolism of new drug candidates. Accelerator mass spectrometry allowed a several thousand-fold dose reduction of (14)C-nelfinavir relative to that required for liquid scintillation counting. Accelerator mass spectrometry microdosing reduces potential safety issues around dosing radioactivity to humans and prevents the need to formulate high intravenous doses.