Virtual early phase

Suggestive case histories raised at an early phase the notion of a possible correlation of oral contraceptives with endometrial cancer. Among cases of endometrial cancer there seemed to be an excess of users of oral contraceptives, particularly of the early high-dose estrogen type. With the virtual demise of these early products, the situation seems to have reversed a 1983 study from the Centers for Disease Control (CDC) in Atlanta showed that women who had used fixed combinations for oral contraception at some time in their lives had a relative risk of endometrial cancer of only 0.5 compared with never-users (112). The protective effect occurred only in women who had used oral contraception for at least 12 months, and lasted for at least 10 years after withdrawal. The WHO adopted the same view in 1988 in the light of multinational data (113). As in the case of hormonal replacement therapy, the protective effect seems to be due to the progestogen component. 

A better way to minimize the effects of this ion suppression is to have the luxury of a stable-label internal standard. The stable-label internal standard has the same structure as the analyte molecule, but certain atoms in the molecule will be replaced by nonradioactive isotopes, thus giving the stable-label compound a different molecular mass, but virtually identical properties in every other way. This stable-label internal standard will extract, chromato-graphically elute, and ionize in the same ways as the analyte. It will be distinguishable by mlz in parent and, possibly, daughter ions depending on the position(s) of the isotopic label. Unfortunately, stable-label internal standards are not available for most early-phase drug discovery work because of the rapid time scale and the large number of compounds involved. 

Research projects in pharmaceutical industry that are in an early phase need bioactive chemotypes as potential lead structures for optimization. Hits with a medium or even weak activity can serve as leads if the overall profile looks attractive. HTS of the in-house compound libraries is the most common source of these lead structures. If information about the 3D structure of the target and/or about bioactive ligand(s) is available, virtual screening can be used to add further active chemotypes either from the existing compounds, for example, from vendor catalogues, or from the virtual chemical space, for example, from virtual combinatorial libraries. Virtual screening can also be used to select a subset from the in-house screening collection if a full HTS is not possible due to cost or time limitations. 

New, powerful CAD technologies make it possible to check design varieties in real time employing virtual reality tools. The use of virtual prototypes, especitilly in the early phases of product development, enables time- and cost-efiBcient decision making. 

To sum up, creating physical or virtual prototypes of the entire system is of utmost importance, especially in the early phases of the product-development process. The extensive use of prototypes provides a structure, a discipline and an approach that increases the rate of learning and integration within the development process. 

The extension of the DMU to functional aspects (FDMU), is an attempt to create more powerful tools for product development. The virtual products stored in DMU shall be enriched by the information extracted from simulation and measurement tools which describes the functionality with respect to environment in an early phase of the product creation processes [26]. 

Considerable attention has also been given to the use of computer dose projections as the basis for initiating off-site protective actions. However, for very severe accidents, dose projections would be available too late and would not be adequate to initiate effective off-site protective response. To be useful, dose projections require an accurate estimate of the amount of material to be released and must project, with confidence, where the release will travel. The problem is that it is virtually impossible to predict the time or measure the magnitude of a severe release. Once the release does occur, its movement through the atmosphere will be very complex. In addition, a severe release may also last several days, ultimately impacting areas in every direction around the plant. The complexity of the resulting contamination (and dose) can be seen in Fig. 5.2, which shows the extent of contamination from the Chernobyl accident. Consequently, dose projections based on models will probably be of little value in the early phase of a severe accident. 

The previous seetion showed how the van der Waals equation was extended to binary mixtures. However, imieh of the early theoretieal treatment of binary mixtures ignored equation-of-state eflfeets (i.e. the eontributions of the expansion beyond the volume of a elose-paeked liquid) and implieitly avoided the distinetion between eonstant pressure and eonstant volume by putting the moleeules, assumed to be equal in size, into a kind of pseudo-lattiee. Figure A2.5.14 shows sohematieally an equimolar mixture of A and B, at a high temperature where the distribution is essentially random, and at a low temperature where the mixture has separated mto two virtually one-eomponent phases. 

In the United States all other processes have been completely phased out and virtually all benzoic acid is manufactured by the continuous hquid-phase air oxidation of toluene. In the late 1950s and the early 1960s both Dow Chemical and Snia Viscosa constmcted faciUties for Hquid-phase toluene oxidation because of large requirements for benzoic acid in the production of phenol and caprolactam. Benzoic acid, its salts, and esters are very useful and find appHcation in medicinals, food and industrial preservatives, cosmetics, resins, plasticizers, dyestuffs, and fibers. 

---