Conclusion and Future Perspective

Hepatic and intestinal induction of drug transporters is well documented however, data are sparse in other tissues. It is especially challenging to analyze the induction of drug transporters in kidney and blood-brain barrier, as these tissues play important roles in the elimination of chemicals and in controlling the CNS accessibility of drugs, respectively. 

Lothstein, L., and Horwitz, S. B. (1989) Differential overexpression of three mdr gene family members in multidrug-resistant J774. 2 mouse cells. Evidence that distinct P-glycoprotein precursors are encoded by unique mdr genes. J. Biol. Chem. 264, 12053-12062. 

Thiebaut, E, Tsuruo, T., Hamada, H., Gottesman, M. M., Pastan, I., and Willingham, M. C. (1987) Cellular localization of the multidrug-resistance gene product 

P-glycoprotein in normal human tissues. Proc. Natl Acad. Sci. USA 84, 7735-7738. 

Hisanga, E., Sai, Y., Tamai, I., and Tsuji, A. (1996) Active secretion of dmgs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier. J. Pharm. Pharmacol. 48, 1083-1089. 

To solve and at the same time to deeply understand the quite complicated and multi-disciphnary task of lield-effect-based DNA biosensors, many disciplines and research fields, scientists from bio- and electrochemistry, biophysics, device engineering, and analytics should work hand in hand. 

The authors thank A. Cherstvy for theoretical calculations, S. Ingebrandt for valuable discussions, and M. Abouzar for technical support. Part of the work was supported by the Miifisterium fiir Innovation, Wissenschaft, Forschung und Technologie des Landes NRW (Germany). 

Poghossian and M.J. Schoning, Silicon-based chemical and biological field-effect sensors, in Encyclopedia of Sensors (C.A. Grimes, E.C. Dickey, and M.V. Pishko, eds), Vol. 9, pp. 463-533. American Scientific Publisher, Stevenson Ranch, 2006. 

Schoning and A. Poghossian, Recent advances in biologically sensitive field-effect transistors. Analyst 127, 1137-1151 (2002). 

Blackburn, Chemically sensitive field-effect transistors, in Biosensors Fundamentals and Applications (A.P.F. Turner, 1. Karube, and G.S. Wilson, eds), pp. 481-530. Oxford University Press, Oxford (1987). 

1 Lima, L.M. and Barreiro, E.J. (2005) Bioisosterism a useful strategy for molecular modification and drug design. Current Medicinal Chemistry, 12, 23-49. 

2 Thornber, C.W. (1979) Isosterism and molecular modification in drug design. Chemical Society Reviews, 8, 563-580. 

3 Petersen, K.-U. (2002) From toxic precursors to safe dmgs mechanisms and relevance of idiosyncratic drug reactions. Arzneimittel-Forschung, 52, 423—429. 

Stanley, L, Gill, E.W., and Jones, A. (1988) Metabolites of procainamide and practolol inhibit complement components C3 and C4. The Biochemical Journal, 251, 323-336. 

Van Riper, G., Egger, LA., Mumford, R.A., Tong, X., MacCoss, M., Schmidt, (.A and Hagmatm, W.K. (2004) Bioisosteric replacement of anilide with benzoxazole potent and orally bioavailable antagonists 

Gulbake, S. Shilpi, A. Jain, and S.K. Jain, A new liorizon in modifcations of chitosan Syntheses and applications, Critical Reviews in Therapeutic Drug Carrier Systems, 30 (2), 91-181, 2013. 

Mourya, and N.N. Inamdar, Chitosan-modifications and applications Opportunities galore. Reactive and Functional Polymers, 68 (6), 1013-1051, 2008. 

Galaev, and B. Mattiasson, Smart Polymers Applications in Biotechnology and Biomedicine, CRC Press, 2012. 

E Mano, and N.M. Alves, pH-Responsive biomineralization onto chitosan grafted biodegradable substrates. Journal of Materials Chemistry, 18 (21), 2493-2499,2008. 

Chuang, T.M. Don, and W.Y. Chiu, Synthesis and properties of chitosan-based thermo-and pH-responsive nanoparticles and application in drug release. Journal of Polymer Science Part A Polymer Chemistry, 47 (11), 2798-2810, 2009. 

Zalkow LH, Harris RN, Van Derveer D, Bertrand JA (1977) J Chem Soc Chem Commun 456 

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Takahashi R, Chiang H-C, Aimi N, Tanaka O, Shibata S (1972) Phytochemistry 11 2039 

Molecularly imprinting technology seems to expand every year being more and more frequently applied in various fields of science. Only recently, MIPs started to be employed as chiral sensing interfaces in electrochemistry. 

As it has been shown, basically all chiral MIP-based electrochemical sensors were developed up till now for amino acids or monosaccharides. However, chiral pharmaceuticals present more complex structures compared to the already mentioned molecules thus, their efficient molecular imprint is considered to be more difficult. Moreover, in the case of amino acids, the asymmetric carbon is at the molecule s extremity carrying two functional groups (-NH2 and -COOH) strongly interacting with the used common functional monomers, thus easily leading to highly enantiospecific imprinted cavities. 

In order to really prove the versatility and real analytical potentials of MIP-based chiral electrochemical sensors, in the near future their performance also toward more complex chiral molecules ought to be demonstrated so they could overcome the laboratory scale barrier. 

Andersson, L., and Mosbach, K. (1990). Enantiomeric resolution on molecularly imprinted potymers prepared with only non-covalent and non-ionic interactions,516, 313-322. 

Schweitz, L., Andersson, L. I., and Nilsson, S. (1997). Capillary electrochromatography with predetermined selectivity obtained through molecular imprinting. Anal. Chem.. 69,1179-1183. 

Currently, it is clear that there is no in vitro model (and therefore no endpoint or marker) that can recapitulate in vitro, the role of the adaptive immune system in DILI (Uetrecht and Naisbitt, 2013). While there has been some progress at modeling the interactions of the innate immune system with hepatocytes through coculture with either monocytes or Kupffer cells, this is still a work in progress and needs to be refined based on further elucidation of immune mechanisms underlying human DILI. 

In summary, while the last 10 years has seen considerable developments and innovations in the use of in vitro toxicity models, particularly for predicting acute drug toxicity, there is still no single system that would predict acute hepatotox-icity induced by an agent such as APAP. Prediction of chronic hepatotoxicity is even less advanced, and until it is possible to incorporate components of both the innate and adaptive immune systems into the models, it is unlikely that these types of toxicity will be routinely detected preclinically. 

The lessons learned from the preclinical qualification of renal safety biomarkers have demonstrated that it is also clear that no single biomarker will be the answer and that a panel approach of novel biomarkers alongside a more intelligent use of currently used biomarkers represents the way forward to inform all stakeholders. Moreover, novel translational biomarkers that reflect the mechanistic basis of DILI are fundamental to efforts in translational research. Despite significant progress in preclinical renal injury biomarker qualification, to date, clinical biomaiker qualification studies are ongoing to achieve this objective. 

Defining the context of use for novel biomarkers in man represents an important area of collaborative research interest. Understanding reference ranges for novel DILI biomarkers in preclinical species and their evaluation in diverse healthy human populations and liver disease cohorts is an important area of investigation and question to address. Further areas of research focus should also be targeted toward the generation of robust cross species bioanalytical assays that are standardized or point-of-care tests in parallel with a comprehensive understanding of cross species differences in biomaiker expression, mechanisms of release, and clearance, distribution, and kinetics. 

TRANSLATIONAL MECHANISTIC BIOMARKERS AND MODELS FOR PREDICTING DRUG-INDUCED LIVER INJURY 

The studies presented above represent the most advanced pre-clinical and clinical therapy programmes for cancer management including drug targeting strategies. Patience is required 

Liposomal drugs have been suggested to be the magic bullet of cancer therapy due to their ability to accumulate selectively in the tumour. The problem remains that not all cancers and patients respond in the same way. The drug actually delivered to the required site of action plays an important role in the response achieved, while the potential toxicity of the surface modified liposomes in the macrophage system have to be taken into account on chronic administration. 

8 Strategies for Specific Drug Targeting to Tumour Cells 

Copyright 2001 Wiley-VCH Verlag GmbH ISBNs 3-527-29989-0 (Hardcover) 3-527-60006-X (Electronic) 

Nanocomposites in orthopedic tissue engineering mimic the complex nanoarchitecture of natural bone, muscle, cartilage, and tendon tissue, providing a novel and practical approach to tissue regeneration. All ceramic, polymer, and metallic matrix nanocomposites offer a wide range of properties with different chemical and mechanical features they also exhibit indispensable bioactivity. There is a great potential to improve current biomaterials and nanocomposite scaffolds for musculoskeletal tissue regeneration. However, the variety of different chemical elements and structures of nanocomposites make it difficult to predict unknown outcomes of exposure to musculoskeletal tissue. More research is clearly needed to fully understand favorable nanocomposite chemistries for musculoskeletal tissue. 

Alothman, O.Y., Ahnajhdi, F.N., Fouad, H., 2013. Effect of gamma radiation and accelerated aging on the mechanical and thermal behavior of HDPE/HA nano-composites for bone tissue regeneration. Biomedical Engineering Online 12, 95. 

Bechert, T., Steinrucke, R, Wagener, M., Seidel, R, Dingeldein, E., Domann, E., Schnetder, R., 2004. An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement. Biomaterials 25, 4383-4391. 

Alves Da SUva, M.L., Martins, A., Costa-Pinto, A.R., Costa, R, Eaiia, S., Gomes, M., Reis, R.L., Neves, N.M., 2010. Cartilage tissue engineering using electrospun PCL nanofiber meshes and MSCs. Biomacromolecules 11, 3228-3236. 

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Polymeric excipients are showing amazing growth in the field of pharmaceutical technology. In this chapter, the behavior and characteristics of the main polymers employed for the preparation of matrix systems that constitute the most popular type of prolonged drug delivery systems have been studied, from both the point of view of classical theories, as well as from the new perspective offered by a theory coming from Statistical Physics and named the percolation theory. 

On the other hand, in 2004 the U.S. Food and Drug Administration published a directive introducing the concepts of Quality by Design (QbD). This initiative encourages a science-based knowledge of the pharmaceutical formulations in order to be able 

One of the main concepts introduced by QbD is the Design Space, defined as the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. 

The concepts of QbD and Design Space are already included in the ICH directives, concretely in the ICH Q8 Pharmaceutical development. Therefore, the regulatory agencies are already asking for the pharmaceutical industry to fulfill these directives. 

As explained before, the percolation threshold corresponds to a critical phase transition that supposes an important change in the properties of the system. Therefore, the critical points associated with the percolation thresholds are natural limits of the Design Space. This is an important reason why much more research is expected in this area in the near future. 

While dramatic progress has been made using stimuli-tri ered formulations, this has been accomplished with increased complexity and a higher number of subunits whose pharmacodynamics could be difficult to evaluate [18]. For the same reasons, scaling up of these formulations may face the same unfavorable cost versus benefit faced by ligand-targeted nanomedicine [18,30]. 

Although promising results have been observed, some approaches for preclinical optimization of nanomedicine design have not been extensively explored and represent further possible routes of optimization. 

most therapies rely on administering the maximal tolerated dose. Use of nanomedidne to estimate the tumor load and drug dosage proportional to the tumor size—a strategy reported by Maeda and coworkers with SMANCS ((poly-styrene-co-maleic acid-half-butyrate) neocarzinostatin)—as larger tumors require more drug, is a not frequently exploited strategy [188]. 

Ultimately, these strategies could be combined with EPR potentiation strategies [17,18,22]. 

This work was supported by grant U54CA151881 to V.P.T. We are grateful to W.C. Hartner for critical review of the manuscript. 

Part I (Chap. 1) identifies these challenges through an state-of-the-art review. Although SC planning has become the subject of intensive and extensive research, an attentive review reveals those areas where new contributions are expected for a major impact in real applications. In this part, the fundamental concepts underlying the methods used throughout the book are presented as well. 

Part II presents mathematical models to approach the problem of integrating enterprise functionalities. Chapter2 addresses the design and retrofit of SCs taking into account financial concerns. The proposed framework applies MILP modeling 

Lalnez-Aguirre and L. Puigjaner, Advances in Integrated and Sustainable Supply Chain Planning, DOI 10.1007/978-3-319-10220-7 10 

The authors would like to thank the National Science Council of the Repubhe of China (contract numbers NSC 96-2120-M-002-019, NSC 96-2120-M-001-009 and NSC 96-2120-M-002-017) and the Industrial Technology Research Institute for financially supporting this research. 

El-Sayed, M.A. (2001) Some interesting properties of metals confined in time and nanometer space of different shapes. Accounts of Chemical Research, 34, 257-64. 

2 Burda, C, Chen, X., Narayanan, R. and El-Sayed, M A. (2005) Chemistry and properties of nanocrystals of different shapes. Chemical Reviews, 105, 1025-102. 

3 Jain, P.K., Huang, X., El-Sayed, I. and El-Sayed, M.A. (2007) Review of some interesting surface plasmon resonance-enhanced properties of noble metal nanopartides and their applications to biosystems. Plasmonics, 2,107-18. 

Sdiatz, G.C. and Hupp, J.T. (2004) Synthesis and optical properties of anisotropic metal nanopartides. Journal of Fluorescence, 

The work presented here represents the first few steps towards the production of tailored oligosaccharides in E. coli. Obviously, there are several critical points that can be improved, as well as the production of other oligosaccharides and other applications that can be envisaged. 

1 Production of Labeled Chitin Oligosaccharides to Study Their Interactions with Proteins 

Product Plasmid used Estimated production yield (g L ) 

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Conclusions and Future Perspectives for Free Energy Calculations... 

Designs of Hybrid Hydrogels Conclusions and Future Perspectives References... 

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