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Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011.

Introduction: Community pharmacy increasingly features in global strategies to modernise the delivery of primary healthcare. Medicine Use Reviews (MURs) form part of the English Government’s medicines management strategy to improve adherence and reduce medicine waste. MURs provide space for patient– pharmacist dialogue to discuss the well-known problems patients experience with medicine taking. However, ‘underserved’ communities (eg, black and minority ethnic communities, people with mental illness), who may benefit the most, may not receive this support. This study aims to develop, implement and evaluate an e-learning education intervention which is coproduced between patients from underserved communities and pharmacy teams to improve MUR provision. Methods and analysis: This mixed-methods evaluative study will involve a 2-stage design. Stage 1 involves coproduction of an e-learning resource through mixed patient–professional development (n=2) and review (n=2) workshops, alongside informative semistructured interviews with patients (n=10) and pharmacy staff (n=10). Stage 2 involves the implementation and evaluation of the intervention with community pharmacy staff within all community pharmacies within the Nottinghamshire geographical area (n=237). Online questionnaires will be completed at baseline and postintervention (3 months) to assess changes in engagement with underserved communities and changes in self-reported attitudes and behaviour. To triangulate findings, 10 pharmacies will record at baseline and postintervention, details of actual numbers of MURs performed and the proportion that are from underserved communities. Descriptive and inferential statistics will be used to analyse the data. The evaluation will also include a thematic analysis of one-to-one interviews with pharmacy teams to explore the impact on clinical practice (n=20). Interviews with patients belonging to underserved communities, and who received an MUR, will also be conducted (n=20). Eth

GA Walker,1 M Xenophontos,2 LC Chen,3 KL Cheung2 1Clinical Oncology, East Midlands Deanery, 2Breast Surgery, School of Graduate Entry Medicine and Health; 3Medicine Use, School of Pharmacy, University of Nottingham, Nottingham, UK Abstract: Exemestane, a steroidal aromatase inhibitor, is licensed for postmenopausal patients with estrogen receptor (ER)-positive breast cancer as second-line therapy in metastatic disease following antiestrogen failure and as part of sequential adjuvant therapy following initial tamoxifen. This study is a systematic literature review, evaluating exemestane in different clinical settings. The Ovid Medline (1948–2012), Embase (1980–2012), and Web of Science (1899–2012) databases were searched. Forty-two relevant articles covering randomized controlled trials were reviewed for efficacy and safety, and three for adherence. With regard to efficacy in metastatic disease, exemestane is superior to megestrol acetate after progression on tamoxifen. There is evidence for noninferiority to fulvestrant (following a prior aromatase inhibitor) and to nonsteroidal aromatase inhibitors in the first-line setting. Combined use with everolimus is shown to be more efficacious than exemestane alone following previous aromatase inhibitor use. In the adjuvant setting, a switch to exemestane after 2–3 years of tamoxifen is superior to 5 years of tamoxifen. Exemestane is noninferior to 5 years of tamoxifen as upfront therapy, and may have a role as an extended adjuvant therapy. Used as neoadjuvant therapy, increased breast conservation is achievable. As chemoprevention, exemestane significantly reduces the incidence of breast cancer in “at-risk” postmenopausal women. Exemestane is associated with myalgias and arthralgias, as well as reduced bone mineral density and increased risk of fracture, which do not appear to persist at follow-up, with subsequent return to pretreatment values. Compared with tamox

The realization of polymer solar cells is the driving force behind this research. In an idea inspired by photosynthesis, the authors have constructed efficient bilayer photodiodes by a well-chosen combination of conjugated polymers (see Figure) in the donor layer. Forster energy transfer within the donor layer allows the absorbed light to be channeled to the C-60 acceptor layer, improving the total photoconversion of the blend device.

We report the use of self organised blends of conjugated polymers for improving the spectral coverage of the solar spectrum, and in this way to enhance solar energy conversion efficiency in photodiodes and solar cells. (C) 2000 Elsevier Science S.A. All rights reserved.

Vile use a combinatorial approach to develop molecular plastic solar cells based on soluble fullerene derivatives blended with conjugated polymers. A combinatorial way of sample preparation is well suited to deal with the multitude of possible combinations of the components of such blends. We use high mobility poly(thiophene) and poly(phenylenevinylene) derivatives to be combined with accepters, Gradients of methanofullerene/polymer concentration were formed by diusion of the low molecular weight component in the spin-cast polymer matrix, Likewise the gradients of zinc phthalocyanine/C-60 were prepared by co-evaporation of the two materials from two sources to make a linear array of photodiode devices, Photo- and electrophysical properties, such as absorption, luminescence, short circuit photocurrent and open circuit photovoltage, were measured using a specially designed installation with a resolution of 70-100 mu. Clear evidence was obtained that the photoconversion efficiency increased with the amount of methanofullerene up to very high levels, in the case of methanofullerene/polymer blends, verifying the important role of the acceptor in the photoconversion. By choosing the optimal ratio between C-60 and ZnPc in the evaporated layer it Is possible to obtain high photocurrent in the 600-700 nm range, due to the added contribution from photoinduced electron transfer between the two molecules, Copyright (C) 2000 John Wiley & Sons, Ltd.