Current Drug Discovery Technologies - Volume 3, Issue 4, 2006

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a poor prognosis where incidence mirrors mortality. Gemcitabine and gemcitabine plus erlotinib (epidermal growth factor receptor tyrosine kinase inhibitor) are the only FDA approved therapies for unresectable or metastatic PDA and are at best palliative. Hence, considerable efforts have been initiated to identify novel targets for monoclonal antibody (Mab) therapies that may safely and effectively be combined with gemcitabine. Mabs to cell surface receptors and/or their ligands have shown efficacy in pre-clinical and clinical studies in both solid and hematological malignancies and can safely be given with chemotherapy. A number of clinical trials have evaluated the safety and efficacy of Mabs targeting the tumor and/or tumor micro-environment and in combination with chemotherapy for PDA with very little success. Here we review the rationale for Mab therapies, targeted clinical trials, rational basis for target selection, pre-clinical models and promising novel cell surface targets and/or growth factor ligands that are amenable to ongoing and future Mab therapies that hold promise and hope for patients and their families with this devastating disease.

Cells, tissues and organs function in a three-dimensional (3D) environment. Ideally, cell-based models that capture both the 3D organization and multi-cellular complexity of the native system provide the most powerful tools for screening the effects of therapeutic candidates. This approach to drug discovery bridges tissue engineers, who are constructing 3D tissues, with biologists, who are studying healthy versus diseased states and to pharmacologists, who are developing screening assays. Within this context, an innovative biophysical perspective of tissue morphogenesis, malignancy and treatment responsiveness has been established recently. Numerous experimental studies have shown that mechanical loading regulates the anabolic and catabolic metabolism of cells. Anabolic mechanisms, in particular, are of vital importance in the process of tissue engineering, which is of increasing scientific and clinical interest. Cells seeded and cultured in appropriate constructs should be mechanically stimulated to produce and to structure the required constituents of the extracellular matrix. However, the determination of the most effective type of loading, the appropriate load history and the mechanical field variables responsible for the stimulation of the cell activity, as well as the pathways of communication among cells, are still subject of contrary discussions and motivation of recent investigation. In this review we discuss the tissue-level response to mechanical signalling, we provide an overview of prominent techniques currently used for exerting mechanical stresses on engineered tissue and an overview of numerical mechanics studies providing information on mechanical field variables potentially triggering the biological activity.

The decrease in the drug approval rate by the FDA and the recent failure of some blockbuster drugs has prompted a re-examination of the focus of the pharmaceutical industry on increasing drug selectivity. As a result, it has been proposed that the most efficient cure is in developing promiscuous drugs and selective drug mixtures. Rational design of drug mixtures has been nearly impossible due to the lack of information about in vivo cell regulation, mechanisms of pathway activation, and interactions between different pathways in vivo. We review the current state of the art for rational design of combination therapy and argue that the current industry-wide development of the infrastructure for pathway analysis provides unprecedented opportunity for the rational design of multicomponent and multifunctional drugs. We propose several ways how to use pathway analysis to rationally combine known drugs for either synergizing their efficacy or suppressing individual side effects.

Goatskin is used instead of rat-skin to study the permeation and the results are compared. The percentage of permeation is double in goatskin. We have five different oils to study, how they influence permeation and all of them have improved permeation when used on goatskin. To analyze further two parameters-percentage and rate of permeation are used. When these five oils are used with salicyclic acid on goatskin the following results are obtained. The percentage of permeation is as follows [Caraway oil (48%) > Lemon oil (36%) > Peppermint oil (29%) > Lemon Grass oil (22%) > Citronella oil (19%)]. The caraway oil has the highest percentage of permeation whereas citronella oil has the lowest percentage of permeation. Caraway oil has three times more permeation than that of citronella oil. The selection of polymer for the formulation of TDDS was done basing on a comparative study of five polymers and their various combinations using such parameters as uniformity of weight, thickness and content and percentage and rate of diffusion counted. Results show that methylcellulose and hydroxy propyl methyl cellulose record more control release of salicyclic acid than the other polymers. Except HPMC all other polymers follow zero order kinematics. Basing on this experimental evidence transdermal patch of salicyclic acid was formed with HPMC, MC polymer incombination with caraway oil has permeating enhancer and evaluated using goatskin. Comparative study shows that there is two fold increases in the percentage of permeation.