Low-dose rate stereotactic iodine-125 brachytherapy for the treatment of inoperable primary and recurrent glioblastoma: single-center experience with 201 cases

Treatment options for inoperable glioblastoma are limited. Low-dose-rate stereotactic iodine-125 brachytherapy (SBT) has been reported as an effective and low-risk treatment option for circumscribed low-grade gliomas and brain metastases. The present study evaluates this treatment approach for patients with inoperable glioblastoma. Between 1990 and 2012, 201 patients with histologically proven glioblastoma were treated with SBT (iodine-125 seeds; median cumulative surface dose, 60 Gy; median dose-rate, 6 cGy/h; median gross-tumor-volume, 17 ml) either as primary treatment (n = 103) or at recurrence (n = 98). In addition to SBT, 90.3 % of patients in the primary treatment group received external boost radiotherapy (median dose, 25.2 Gy). Adjuvant chemotherapy was added for 30.8 % of patients following SBT and consisted of temozolomide for the majority of cases (88.7 %). Procedure-related complications, clinical outcome, progression-free and overall survival (PFS, OS) were evaluated. Median follow-up was 9.8 months. The procedure-related mortality was zero. During follow-up, transient and permanent procedure-related morbidity was observed in 7.5 and 2.0 %, respectively. Calculated from the time of SBT, median OS and PFS rates were 10.5 and 6.2 months, with no significant differences among primary and recurrent tumors (11.1 vs.10.4 months for OS and 6.2 vs. 5.9 months for PFS). For OS, multivariate analysis revealed Karnofsky performance score, age, and adjuvant chemotherapy as independent prognostic factors (all p < 0.01). Low-dose-rate SBT is a relatively safe and potentially effective local treatment option for patients with circumscribed inoperable glioblastoma initially or at recurrence. It deserves prospective validation since it may improve the outcome for a subset of patients with inoperable GBM.     

Identifying the needs of elderly, hearing-impaired persons: the importance and utility of hearing aid attributes

Older patients represent the majority of hearing-aid users. The needs of elderly, hearing-impaired subjects are not entirely identified. The present study aims to determine the importance of fundamental hearing-aid attributes and to elicit the utility of associated hypothetical hearing aids for older patients. This was achieved using a questionnaire-based conjoint analysis--a decompositional approach to preference measurement offering a realistic study design. A random sample of 200 experienced hearing-aid users participated in the study. Though three out of the six examined attributes revealed age-related dependencies, the only significant effect was found for the attribute "handling", which was considerably more important for older than younger hearing-aid users. A trend of decreasing importance of speech intelligibility in noise and increasing significance of speech in quiet was observed for subjects older than 70 years. In general, the utility of various hypothetical hearing aids was similar for older and younger subjects. Apart from the attribute "handling", older and younger subjects have comparable needs regarding hearing-aid features. On the basis of the examined attributes, there is no requirement for hearing aids designed specifically for elderly hearing-aid users, provided that ergonomic features are considered and the benefits of modern technology are made fully available for older patients.     

The thrombin inhibitors hirudin and Refludan(®) activate the soluble guanylyl cyclase and the cGMP pathway in washed human platelets

A number of direct thrombin inhibitors are successfully used clinically and experimentally as novel antithrombotics and specific anticoagulants. They are also used as anticoagulants in certain blood collection tubes for the analysis of platelet function. A series of platelet function tests have emerged to measure adequate responses to antiplatelet therapy. For comparative and practical reasons, it would be of advantage to use the same anticoagulant in blood collection tubes for different methods, e.g. thrombin inhibitors. However, there are little data on the effects of thrombin inhibitors on platelet signalling pathways that could influence results. We examined the applicability of thrombin inhibitor containing blood for platelet reactivity index (PRI) measurements of the VASP assay and investigated the effects of two thrombin inhibitors (hirudin and lepirudin) on cAMP- and cGMP-mediated signalling pathways in washed human platelets. We show that induction of VASP phosphorylation by PGE1 is markedly reduced in lepirudin containing blood samples. In consequence, PRI levels were highly variable compared to routinely used citrated blood. Surprisingly, in vitro incubation of platelets with thrombin inhibitors increases platelet cGMP levels and induces NOS independent sGC/PKG-mediated VASP phosphorylation. We conclude that thrombin inhibitors activate sGC/PKG-dependent pathways resulting in an increase of VASP phosphorylation which contributes to deviations in PRI measurements. These effects of thrombin inhibitors on sGC- and cGMP-mediated pathways including increased VASP phosphorylation may indicate the presence of an important additional platelet-based mechanism for the reduction of thrombus formation and thromboembolism by thrombin inhibitors.     

Decision tree models for data mining in hit discovery

INTRODUCTION: Decision tree induction (DTI) is a powerful means of modeling data without much prior preparation. Models are readable by humans, robust and easily applied in real-world applications, features that are mutually exclusive in other commonly used machine learning paradigms. While DTI is widely used in disciplines ranging from economics to medicine, they are an intriguing option in pharmaceutical research, especially when dealing with large data stores. AREAS COVERED: This review covers the automated technologies available for creating decision trees and other rules efficiently, even from large datasets such as chemical libraries. The authors discuss the need for properly documented and validated models. Lastly, the authors cover several case studies in hit discovery, drug metabolism and toxicology, and drug surveillance, and compare them with other established techniques. EXPERT OPINION: DTI is a competitive and easy-to-use tool in basic research as well as in hit and drug discovery. Its strengths lie in its ability to handle all sorts of different data formats, the visual nature of the models, and the small computational effort needed for implementation in real-world systems. Limitations include lack of robustness and over-fitted models for certain types of data. As with any modeling technique, proper validation and quality measures are of utmost importance.     

Development and evaluation of sustained-release clonidine-loaded PLGA microparticles

This work describes the encapsulation of a small, hydrophilic molecule (clonidine) into a PLGA matrix to provide sustained release over more than one month after intra-articular administration. The microparticles were prepared using a double emulsion (w(1)/o/w(2)) method followed by evaporation of the organic solvent. To optimize the efficiency of encapsulation and the mean size of the microparticles, which was targeted around 30μm, the following parameters were modulated: the viscosity and the volume of the organic phase, the molecular weight of the polymer, the volume of the internal and external aqueous phases, the drug loading, the concentration of surfactant, and the stirring parameters. Blends of polymers characterized by different molecular weights (34000-96000Da) as well as copolymers of PLGA-PEG were used to enhance the entrapment of the drug. The pH of the aqueous phases was adjusted to obtain suitable encapsulation efficiency. Characterization was made of the physico-chemical properties of the microparticles, such as their crystallinity (DSC and PXRD) and microstructure (SEM). When performing in vitro dissolution studies, controlled release for up to approximately 30days was achieved with several of the formulations developed. Diffusion was found to be the dominant drug release mechanism at early time points.     

Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs

The purpose of this study was to validate human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for predicting the oral drug absorption in humans with the main focus on moderately and poorly permeable compounds. The obtained apparent permeability coefficient (P(app)) of eleven test compounds was compared to their fraction absorbed (Fa) in humans taken from the literature. Beside the conventional P(app) a new parameter, the apparent permeability coefficient total (P(app,total)), involving both the apical-to-basolateral permeability and the time-dependent compound accumulation in the tissue was established. The permeability of lucifer yellow (LY), a fluorescent marker of the paracellular pathway and the test compounds showed no obvious differences between small intestine and colon. Furthermore, small intestinal and colonic tissue from a single donor showed similar permeability of both LY and a transcellularly transported compound metoprolol. All test compounds including low molecular weight hydrophilic compounds such as metformin, atenolol, sulpiride and famotidine showed adequate permeability reflecting human Fa values (R(2)=0.87). The P(app) values of digoxin, a P-glycoprotein (P-gp) substrate, were not significantly affected by the addition of verapamil, a P-gp inhibitor. In contrast, the P(app,total) values of digoxin increased approximately threefold in the presence of verapamil. In conclusion, both small intestinal and colonic tissue mounted in the Ussing chamber provide a good opportunity to predict the oral drug absorption rate in humans even for moderately and poorly absorbed compounds. The novel calculation of P(app,total) allows the study of the carrier-mediated drug-drug interactions in human intestine.