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Basel, Switzerland

Quebatte G.,University of Basel | Kitas E.,F. Hoffmann LaRoche Ltd. | Seelig J.,University of Basel
Journal of Physical Chemistry B | Year: 2013

DNA condensation in the presence of polycationic molecules is a well-known phenomenon exploited in gene delivery. riDOM (retro-inverso dioleoylmelittin) is a cell-penetrating peptide with excellent transporter properties for DNA. It is a chimeric molecule where ri-melittin is fused to dioleoylphosphoethanolamine. The physical-chemical properties of riDOM in solution and in the presence of DNA and heparan sulfate were investigated with spectroscopic and thermodynamic methods. Dynamic light scattering shows that riDOM in solution aggregates to well-defined nanoparticles with a diameter of ∼13 nm and a ζ-potential of 22 mV, composed of about 220-270 molecules. Binding of riDOM to DNA was studied with dynamic light scattering, ζ-potential measurements, and isothermal titration calorimetry and was compared with authentic melittin-DNA interaction. riDOM binds tightly to DNA with a microscopic binding constant of 5 × 107 M-1 and a stoichiometry of 12 riDOM per 10 DNA base pairs. In the complex the DNA double strand is completely shielded by the more hydrophobic riDOM molecules. Authentic melittin binds to DNA with a much lower binding constant of 5 × 106 M-1 and lower stoichiometry of 5 melittin per 10 DNA base pairs. The binding enthalpies for riDOM and melittin are small and the binding reactions are entropy-driven. Sulfated glycosaminoglycans such as heparan sulfate are also linear molecules with a negative charge. riDOM binding to heparan sulfate on cell surfaces can therefore interfere with DNA-riDOM binding. riDOM-heparan sulfate complex formation was characterized by isothermal titration calorimetry and spectroscopic methods. The binding constant of riDOM for heparan sulfate is K ≈ 2 × 106 M-1. Authentic melittin has a similar binding constant but riDOM shows a 3-fold higher packing density on heparan sulfate than the distinctly smaller melittin. © 2013 American Chemical Society.

Paynter N.P.,Brigham and Womens Hospital | Mazer N.A.,F. Hoffmann LaRoche Ltd. | Pradhan A.D.,Brigham and Womens Hospital | Gaziano J.M.,Brigham and Womens Hospital | And 3 more authors.
Archives of Internal Medicine | Year: 2011

Background: It is unclear whether models that include hemoglobin A 1c (HbA 1c) levels only for diabetic patients improve the ability to predict cardiovascular disease (CVD) risk compared with the currently recommended classification of diabetes as a cardiovascular risk equivalent. Methods: A total of 24 674 women (including 685 diabetic participants at baseline) and 11 280 men (including 563 diabetic participants at baseline) were followed up prospectively for cardiovascular disease (CVD). One hundred twenty-five CVD events occurred in diabetic women (666 in nondiabetic women), and 170 events occurred in diabetic men (1382 in nondiabetic men). Models for CVD risk were generated separately for men and women using the traditional CVD risk factors with the addition of a term for HbA 1c levels only for diabetic individuals. In diabetic participants, the resulting predicted risks were compared with classification of diabetes as a cardiovascular risk equivalent (10-year CVD risk of at least 20%). Results: In women, the models including HbA 1c levels in diabetic participants improved the C statistic by 0.177 (P<.001) over the risk equivalence model and showed improved reclassification (net reclassification improvement [NRI] of 26.7% [P=.001]). In men, the improvements were more modest but still statistically significant (C statistic change of 0.039 [P=.02]; NRI of 9.2% [P=.04]). Including HbA 1c levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8% [P=.03]) but not in men. Conclusions: In both women and men with diabetes at baseline, we observed significant improvements in predictive ability of CVD risk using models incorporating HbA 1c levels compared with classification of diabetes as a cardiovascular risk equivalent. ©2011 American Medical Association. All rights reserved.

Muller D.,University of Cologne | Fischer K.,University of Cologne | Kaiser P.,University of Cologne | Eichhorst B.,University of Cologne | And 10 more authors.
Leukemia and Lymphoma | Year: 2015

The cost-effectiveness of rituximab in combination with fludarabine/cyclophosphamide (R-FC) for the first line treatment of chronic lymphocytic leukemia (CLL) was evaluated. Based on long-term clinical data (follow-up of 5.9 years) from the CLL8-trial, a Markov-model with three health states (Free from disease progression, Progressive disease, Death) was used to evaluate the cost per quality-adjusted life-year (QALY) and cost per life years gained (LYG) of R-FC from the perspective of the German statutory health insurance (SHI). The addition of rituximab to FC chemotherapy results in a gain of 1.1 quality-adjusted life-years. The incremental cost-effectiveness ratio (ICER) of R-FC compared with FC was €17 979 per QALY (€15 773 per LYG). Results were robust in deterministic and probabilistic sensitivity analyses. From the German SHI perspective, rituximab in combination with FC chemotherapy represents good value for first-line treatment of patients with CLL and compares favorably with chemotherapy alone. © 2015 Taylor & Francis

Venet D.,International Drug Development Institute IDDI | Venet D.,Free University of Brussels | Doffagne E.,International Drug Development Institute IDDI | Burzykowski T.,International Drug Development Institute IDDI | And 10 more authors.
Clinical Trials | Year: 2012

Background Classical monitoring approaches rely on extensive on-site visits and source data verification. These activities are associated with high cost and a limited contribution to data quality. Central statistical monitoring is of particular interest to address these shortcomings. Purpose This article outlines the principles of central statistical monitoring and the challenges of implementing it in actual trials. Methods A statistical approach to central monitoring is based on a large number of statistical tests performed on all variables collected in the database, in order to identify centers that differ from the others. The tests generate a high-dimensional matrix of p -values, which can be analyzed by statistical methods and bioinformatics tools to identify extreme centers. Results Results from actual trials are provided to illustrate typical findings that can be expected from a central statistical monitoring approach, which detects abnormal patterns that were not (or could not have been) detected by on-site monitoring. Limitations Central statistical monitoring can only address problems present in the data. Important aspects of trial conduct such as a lack of informed consent documentation, for instance, require other approaches. The results provided here are empirical examples from a limited number of studies. Conclusion Central statistical monitoring can both optimize on-site monitoring and improve data quality and as such provides a cost-effective way of meeting regulatory requirements for clinical trials. © The Author(s), 2012.

Wallace T.L.,Roche Holding AG | Callahan P.M.,Memory Pharmaceuticals | Tehim A.,Memory Pharmaceuticals | Bertrand D.,HiQ Screening Sarl | And 13 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

Neuronal nicotinic α7 acetylcholine receptors (α7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at α7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole- 3-carboxamide hydrochloride (RG3487) binds potently to the human α7nAChR (Ki = 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human α7nAChRs with an EC 50 of 0.8 μM (oocytes) and 7.7 μM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC50 = 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: ≤0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent α7nAChR partial agonist that improves cognitive performance and sensorimotor gating. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

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