Biological unwanted effects

A deeper understanding of the molecular mechanisms underlying tobacco addiction will lead to the identification of different types of smokers. Classifying smokers according to the underlying biological processes involved in their addiction will lead to new treatments for tobacco dependence. Patient-specific therapy with both choice of treatment and dose of drug informed by DNA analysis seems likely to be more effective than conventional therapy with fewer unwanted effects. 

Most of the proteins that are used clinically provide pharmaceutical properties that lead to safe and effective therapy for approved therapeutic indications. Some proteins, however, may influence multiple pharmacologic pathways and elicit unwanted effects. An understanding of the specific domains that mediate biologic response permits the engineering of macromolecules that are more specific and less likely to interact with receptors other than the target (see Boxes 4.4 and 4.5). 

The test samples should always be analyzed in random order to avoid the introduction of unwanted biases and time trends. A way to monitor such unwanted effects is to utilize quality control (QC) samples as a means to effectively examine system performance. QC samples are often made by pooling together subaliquots of biological test samples (29-31). This way a representative bulk sample is generated that should contain all metabolites present in the test samples. QC samples are typically analyzed through the analytical batch and data from the QC injections are scrutinized as a separate dataset by both multivariate analysis but also as typical LC-MS data. Data should pass certain criteria to ensure adequate quality of the dataset, that is, the number of zero values (which should be less than 40%), the CV% of the peak areas (should be less than 30% for a trustworthy peak), the number of peaks that pass the 30% CV filter (which should be higher than 70% in the dataset), the repeatability of retention times and peak areas, and so forth (29). 

In some cases the unwanted enantiomer can perturb other biological processes and cause catastrophic side effects. The use of enantiomerically pure compounds thus permits more specific drug action and the reduction in the amount of drug administered. Even in the cases where the other enantiomer is inactive, the work involved in its metabolism before secretion can be avoided. 

In the case of chiral molecules that are biologically active the desired activity almost always resides in only one of the enantiomers. The other enantiomer constitutes isomeric ballast that does not contribute towards the desired activity and may even exhibit unwanted side effects. Hence, there is a marked trend in pharmaceuticals, agrochemicals and flavours and fragrances towards the marketing of products as enantiomerically pure compounds. This, in turn, has generated a demand for economical methods for the synthesis of pure enantiomers (Sheldon, 1993a). 

Because of the complexity of biological systems, Eq. (1) as the differential form of Michaelis-Menten kinetics is often analyzed using the initial rate method. Due to the restriction of the initial range of conversion, unwanted influences such as reversible product formation, effects due to enzyme inhibition, or side reactions are reduced to a minimum. The major disadvantage of this procedure is that a relatively large number of experiments must be conducted in order to determine the desired rate constants. 

All of those substances have specific binding sites at the respective organs. The occupation of these receptors result in a transmitter-characteristic pattern of effects. These transmitters gain increasing interest as therapeutic targets as well as mechanisms for unwanted biological effects. 

In the present context, the term safe drug on the one hand includes the properties of a pharmaceutical related to its effectiveness, efficacy, and absence of unwanted side effects. On the other hand, the desired effects for its use, such as stability and biological activity, will be likely to have undesired consequences if the molecule enters the environment. This conflict can only be resolved if either the API compounds are not allowed to enter the environment, or they can quickly disintegrate... 

Prerequisites are (1) a biological test system that is capable of registering the observed effect in an environmental system and (2) an applied concentration technique that acts as an interface between the environment and the test system. If biomonitoring indicates an unwanted exposure to chemicals, it must be translated in chemical terms. This chemical information can be used for control purposes to eliminate the exposure, preferably to a real no-effect level, so that no risk evaluation has to be made. This method requires a bioassay that is specific for an effect in an environmental system and a concentration technique that is specific for the collection and transition of compounds causing the effect. 

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