Evaluation of drugs in man

We must be daring and search after Truth even if we do not succeed in finding her. we shall at least come closer than wo are at present (Galen AD 130 -200) 

This chapter is about evidence-based drug therapy. 

The key to the ethics of such studies is informed consent from patients, efficient scientific design and review by an independent research ethics committee. The key interpretative factors in the analysis of trial results are calculations of confidence intervals and statistical significance.The potential clinical significance needs to be considered within the confines of controlled clinical crials.This is best expressed by stating not only the percentage differences, but also the absolute difference or its reciprocal, the number of patients who have to be treated to obtain one desired outcome.The outcome might include both efficacy and safety 

Surveillance studies and the reporting of spontaneous adverse reactions respectively determine the clinical profile of the drug and detect rare adverse events. Further trials to compare new medicines with existing medicines are also required.These form the basis of cost-effectiveness comparisons. 

As the number of potential medicines produced increases, the problem of whom to test them on grows. There are two main groups healthy volim-teers and volimteer patients (plus, rarely, nonvolrm-teer patients). Studies in healthy normal volrmteers can help to determine the safety, tolerability, pharmacokinetics and for some drugs, e.g. anticoagulants and anaesthetic agents, their dynamic 

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Chapter 4. Evaluation of drugs in man Chapter 5. Official regulation of medicines Chapter 6. Classification and naming of drugs... 

Sponer G, Mannesmann G, Bartsch W, Dietmann K (1981) A method for evaluating postural hypotension in conscious rabbits as a model to predict effects of drugs in man. J Pharmacol Methods 5 53-58... 

Estimation of the volume of distribution in man may be carried out in a number of ways. These methods have recently been reviewed by Obach et al. [60], who carried out a wide-ranging evaluation of a large number of different ways of predicting the human pharmacokinetics of 50 compounds that entered development at Pfizer. One of the simplest methods was reported to be the most reliable. It is based on the assumption that the free-fraction of drug in the plasma in dog and human and... 

There are many different examples of species differences in the toxicity of foreign compounds, some of which are commercially useful to man, as in the case of pesticides and antibiotic drugs where there is exploitation of selective toxicity. Species differences in toxicity are often related to differences in the metabolism and disposition of a compound, and an understanding of such differences is extremely important in the safety evaluation of compounds in relation to the extrapolation of toxicity from animals to man and hence risk assessment. 

While most drug systems evaluated have shown passive diffusional characteristics, Levy and Jusko have reported that the oral absorption of riboflavin in man possesses characteristics indicative of specialized transport mechanisms. The evidence in support of such a conclusion was based on the finding that as the dose of riboflavin was increased, the per cent absorbed (based on urinary recovery) decreased. This effect was observed only in fasted patients and was not observed when riboflavin was administered with a meal. The authors suggest that the presence of food in the alimentary tract delays the transit time of riboflavin, thus keeping it in the presence of absorptive sites for longer periods of time. 

In evaluating drugs in man, there also have been improvements in methodology, particularly in the design of better controlled experiments and the use of statistical techniques to interpret the data. This has been more significant in disease conditions in which subjective factors may obscure the interpretation of results. However, in some major diseases, as for example atherosclerosis, osteoporosis, and connective tissue degenerations, the absence of reliable qualitative measures for early identification of the disease state and quantitative measures for comparing improvements or deteriorations have become a much more serious limitation than they were 10 years ago. The requirement for proof of efficacy of a... 

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