Computational prediction of formulation strategies for beyond-rule-of-5 compounds

AbstractThe physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of ‘formulate-ability’ during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets

The polyoxyethylene/polyoxypropylene block co-polymer Poloxamer-407 selectively redirects intravenously injected microspheres to sinusoidal endothelial cells of rabbit bone marrow

AbstractSmall colloidal particulates (150 nm and below, in diameter) can be redirected specifically to the rabbit bone marrow following intravenous administration by coating their surface with the block co-polymer poloxamer-407, a non-ionic surfactant. The coated colloids are sequestered by the sinusoidal endothelial cells of the bone marrow and are accumulated in dense bodies within these cells. The uptake of poloxamer-4O7-coated colloids by marrow eondothelial cells suggests that the steric repulsive barrier, imposed by the polyoxyethylene segment of the polymer, to particle-cell interaction can apparently be overcome by a specific interaction mechanism(s) with the cell surface. Such a dramatic uptake cannot be achieved with other block co-polymers of similar structure to poloxamer-407. The application of the current model for the site-specific targeting or drug carriers to bone marrow and the prevention of the adherence of metastases of tumours which selectively colonize the bone marrow endothelium is discussed

Changing of flight phenology and ecotype expansion of the European corn borer (Ostrinia nubilalis Hbn.) in Hungary Part

The studies aimed to acquire the widest possible information on the annual flight in Hungary of the European corn borer (ECB), Ostrinia nubilalis Hübner (Lepidoptera: Pyralidae). The investigations used biomathematical (Part 1) and graphical (Part 2) evaluation to document changes in the individual population number.The study was conducted in Hungary using ECB moth capture records from the Plant Protection Information System black light trap system (1991–2004). We have drawn conclusions on the appearance of annual flights and the tendency of alterations in flight direction by means of light trap results in four different areas in Hungary. We calculated the flight peak quotients, the individual population numbers of the second flight peak, the distinctions of individual numbers of two flight peaks in this part.As previously published, alterations in flight direction of ECB flights began at different times in Hungary. In the current study, a gradual disappearance of the univoltine ecotype and gradual appearance of the bivoltine ecotype ECB in Hungary is confirmed by the data obtained between 1991–2004. Flight peak quotients and data concerning the second flight peak have confirmed change this process, too: the appearance of a second flight peak in Northwestern Hungary from 1995–1996 (FP = 1.27), the more significant appearance of flights in August in Western Hungary (FP = 1.05) and Northeastern Hungary (FP = 1.45), and a three and four times more individual number of the second flight peak in Southeastern Hungary (FP = 3.44). Flight peak quotients, individual population numbers of the second flight peak, the tendency towards a difference in population number of the two peaks, and size of increase of these values demonstrates the southeastern-northwestern presence of the bivoltine ecotype in Hungary

Astrophysical Uncertainties in the Cosmic Ray Electron and Positron Spectrum From Annihilating Dark Matter

In recent years, a number of experiments have been conducted with the goal of studying cosmic rays at GeV to TeV energies. This is a particularly interesting regime from the perspective of indirect dark matter detection. To draw reliable conclusions regarding dark matter from cosmic ray measurements, however, it is important to first understand the propagation of cosmic rays through the magnetic and radiation fields of the Milky Way. In this paper, we constrain the characteristics of the cosmic ray propagation model through comparison with observational inputs, including recent data from the CREAM experiment, and use these constraints to estimate the corresponding uncertainties in the spectrum of cosmic ray electrons and positrons from dark matter particles annihilating in the halo of the Milky Way.Comment: 21 pages, 9 figure

The Japanese model in retrospective : industrial strategies, corporate Japan and the 'hollowing out' of Japanese industry

This article provides a retrospective look at the Japanese model of industrial development. This model combined an institutional approach to production based around the Japanese Firm (Aoki's, J-mode) and strategic state intervention in industry by the Japanese Ministry of International Trade and Industry (MITI). For a long period, the alignment of state and corporate interests appeared to match the wider public interest as the Japanese economy prospered. However, since the early 1990s, the global ambitions of the corporate sector have contributed to a significant 'hollowing out' of Japan's industrial base. As the world today looks for a new direction in economic management, we suggest the Japanese model provides policy-makers with a salutary lesson in tying the wider public interest with those of the corporate sector

The Influence of the effect of solute on the thermodynamic driving force on grain refinement of Al alloys

Grain refinement is known to be strongly affected by the solute in cast alloys. Addition of some solute can reduce grain size considerably while others have a limited effect. This is usually attributed to the constitutional supercooling which is quantified by the growth restriction factor, Q. However, one factor that has not been considered is whether different solutes have differing effects on the thermodynamic driving force for solidification. This paper reveals that addition of solute reduces the driving force for solidification for a given undercooling, and that for a particular Q value, it is reduced more substantially when adding eutectic-forming solutes than peritectic-forming elements. Therefore, compared with the eutectic-forming solutes, addition of peritectic-forming solutes into Al alloys not only possesses a higher initial nucleation rate resulted from the larger thermodynamic driving force for solidification, but also promotes nucleation within the constitutionally supercooled zone during growth. As subsequent nucleation can occur at smaller constitutional supercoolings for peritectic-forming elements, a smaller grain size is thus produced. The very small constitutional supercooling required to trigger subsequent nucleation in alloys containing Ti is considered as a major contributor to its extraordinary grain refining efficiency in cast Al alloys even without the deliberate addition of inoculants.The Australian Research Council (ARC DP10955737)

NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT

Electromagnetic Probes

A review is presented of dilepton and real photon measurements in relativistic heavy ion collisions over a very broad energy range from the low energies of the BEVALAC up to the highest energies available at RHIC. The dileptons cover the invariant mass range \mll = 0 - 2.5 GeV/c$^2$, i.e. the continuum at low and intermediate masses and the light vector mesons, $\rho, \omega, \phi$. The review includes also measurements of the light vector mesons in elementary reactions.Comment: To be published in Landolt-Boernstein Volume 1-23A; 40 pages, 24 figures. Final version updated with small changes to the text, updated references and updated figure

Controlled release strategies for bone, cartilage, and osteochondral engineering: part I: recapitulation of native tissue healing and variables for the design of delivery systems

The potential of growth factors to stimulate tissue healing through the enhancement of cell proliferation, migration, and differentiation is undeniable. However, critical parameters on the design of adequate carriers, such as uncontrolled spatiotemporal presence of bioactive factors, inadequate release profiles, and supraphysiological dosages of growth factors, have impaired the translation of these systems onto clinical practice. This review describes the healing cascades for bone, cartilage, and osteochondral interface, highlighting the role of specific growth factors for triggering the reactions leading to tissue regeneration. Critical criteria on the design of carriersfor controlled release of bioactive factors are also reported, focusing on the need to provide a spatiotemporal control over the delivery and presentation of these molecules.The authors thank Fundacao para a Ciencia e Tecnologia for V.E.Santo's PhD grant (SFRH/BD/39486/2007). This work was carried out under the scope of the European FP7 Project Find and Bind (NMP4-SL-2009-229292) and Project MIT/ECE/0047/2009