Further biological assessment

The isolation of the bioactive constituent(s) from a given biomass can be a challenging task, particularly if the active constituent of interest is present in very low amounts. The actual procedure will depend to a large extent on the nature of the sample extract a marine sample, for example, may well require a somewhat different extraction and purification process from that derived from a plant sample. Nevertheless, the essential feature in all of these methods is the use of an appropriate and reproducible bioassay to guide the isolation of the active compound. It is also extremely important that compounds that are known to inhibit a particular assay, or those that are nuisance compounds be dereplicated (identified and eliminated) as early in the process as possible. Procedures for doing this have been discussed, and various new approaches to isolation and stracture elucidation have been reviewed.  

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DEVELOPMENT G. Further biological assessment V. FUTURE DIRECTIONS IN... 

This overlaps with the answer to Question 1, but it goes much further into assessment of the scientific rationale underlying the product, the availability of appropriate background biological, chemical, and pharmaceutical information, consideration of the nature and state of the human or animal patients who will eventually be treated with it, and a definite decision whether the results are needed for product registration or other regulatory purposes. The latter defines the need for and consequences of the application of GLP and GMP requirements. 

In the case that a protein exerts more than one biological activity, the assay that most closely reflects the clinical situation should be chosen. Assays for measuring further biological function(s) of the drug should also be established to assess possible side effects in vivo. 

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

Only a few in vivo dermal toxicity studies have been reported so far. Huczko and Lange [50] evaluated the potential of raw CNTs to induce skin irritation by conducting two routine dermatological tests (patch test on 40 volunteers with allergy susceptibilities and Draize rabbit eye test on four albino rabbits). Koyama etal. [51] showed the biological responses to four different types of carbon nanotubes (SWNTs, two types of MWNTs with different diameters, and cup-stacked carbon nanotubes) after their subcutaneous implantation in mice. Both tests [50, 51] showed no or poor irritation effects. However, the in vitro studies in epidermal cell lines exposed to CNTs, and also a more recent report on the toxic outcomes of topical exposure of mice to SWNTs [46], have raised concerns over these assessments. Clearly, this is an area requiring further scientific evaluation. 

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