Adverse drug reactions sensitivity

All drugs may cause adverse drug reactions (ADRs). These adverse effects are either unpredictable (hyper-sensitivity) or dose-depending. The risk of ADR is increased for several reasons in the elderly. The physiological alterations, the high number of medications and concomitant diseases increase the risk of ADR. This is further... 

Nolan L, O Malley K. Prescribing for the elderly. Part I Sensitivity of the elderly to adverse drug reactions. J Am Geriatr Soc 1988 36(2) 142-9. 

A search for an association between doxycycline and polyneuropathy failed to identify any documented cases. An inquiry to the Swedish Adverse Drug Reactions Advisory Committee elicited information about three cases of paresthesia, two cases of sensitivity disturbance, and one case of neuropathy. The last was a man who had had pain and paresthesia in the feet, arms, and face after taking doxycycline 100 mg/day for 2 weeks for prostatitis. The sjmptoms began to wane 1 week after treatment was stopped, and disappeared completely 1 week later. 

The value of computational tools arises from their applicability early in development. An excellent correlation with wet laboratory data, an easy to use and interpretable model, high sensitivity, as well as high specificity are key requirements for a useful in silico model. As a nonexpert tool it should be available to the medicinal chemist via computer networks. Ideally such potentially powerful tools can be used to predict liabilities to induce an adverse drug reaction but also to guide the chemists to structurally modify the molecules via discovering the features that prevent the binding to the ion channel and immediately verify any successful chemical optimization step. 

It is often possible to address function more specifically in in vitro assays, where functional parameters are usually very sensitive readouts of adverse effects. For example trans-epithelial electrical resistance (TEER) is a very sensitive marker of epithelial disturbances. TEER measures the barrier function of the entire mono-layer and is utilized to study functional disturbances of many epithelial/endothelial cell types including blood-brain barrier, pulmonary, renal, and gastrointestinal cells. Its sensitivity lies in the fact that only a small proportion of cell death has a very large impact on barrier function. Additionally, cell stress can interfere with the arrangement and population of tight junction proteins [16] thus, TEER can in certain conditions measure functional disturbances in the absence of cell death [13]. Also since TEER can be measured noninvasively, it is nondestructive and can be used to monitor the effects of treatment over days and weeks [13, 17]. For excitable cells, electrical activity has also been proven to be an extremely sensitive parameter of adverse drug reactions and microelectrode arrays have been employed successfully to monitor neurotoxicity in vitro [18]. Also, for contractile cells, such as cardiomyocytes, the use of impedance measurements to measure the effects of compounds on spontaneous contraction has been demonstrated to be a very sensitive functional monitoring parameter in vitro [19, 20], Admittedly, none of the aforementioned techniques are true biomarkers per se however, such measurements illustrate the fact that in vitro techniques allow certain possibilities that are not practically tenable in the whole body. 

Genetic variations that impact a patient s drug sensitivity can lead to adverse reactions, toxicity, or therapeutic failure [56]. Of 27 drugs frequently cited in adverse drug reaction studies, 59% are metabolized by at least one enzyme with a variant allele known to cause poor metabolism [57]. That compares with 7% to 22% of randomly selected drugs. Tailoring therapy based upon each individual s genotype should yield increased therapeutic effectiveness and minimize adverse effects. 

Schuhmann, D. et al., Adverse immune reactions to gold. I. Chronic treatment with an Au(I) drug sensitizes mouse T cells not to Au(I), but to Au(III) and induces autoantibody formation. J. Immunol., 145, 2132, 1990. 

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