Cardiac glycosides development

K. Repke (1985). New developments in cardiac glycoside structure-activity relationships. Trends Pharmacol. Sci. 6 275-278. 

The net result of the action of therapeutic concentrations of a cardiac glycoside is a distinctive increase in cardiac contractility (Figure 13-5, bottom trace). In isolated myocardial preparations, the rate of development of tension and of relaxation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocardium, but in the intact patient the responses are modified by cardiovascular reflexes and the pathophysiology of heart failure. 

Natural products are generally classified by a number of criteria functional, structural and biosynthetic. Despite the reservations expressed above, certain functional subdivisions are useful in certain applications. Such terms as antibiotics, hormones or cardiac glycosides are commonly used. The grouping of natural products on the basis of common carbon skeletons is perhaps the most attractive for the chemist. The realization that many natural products fall into distinct structural groups which could be, at least formally, derived from much simpler molecules was an important development in that it led to the proposal of speculative biogenetic hypotheses which were largely responsible for stimulating the rapid development of the field of biosynthesis. However, such an approach is not entirely satisfactory since it is now clear that many compounds which are of similar structural types are derived by quite different routes in vivo. 

In recent years the chemistry of 2-desoxysugars generally, has been considerably broadened. In particular, new methods of synthesis have been developed for the preparation of many of the didesoxysugars known as the 2-desoxyhexomethyloses which occur naturally as components of the cardiac glycosides. The formation, structure, and stability of various 0- and iV-glycosides of sugars of this class have been examined in... 

Specialized aspects of the chemistry of 2-desoxyhexoses have been described in detail already. An excellent review of the chemistry of the carbohydrate components of the cardiac glycosides appeared in 1945 in Volume I of this series,12 and consequently only developments in this subject since that date will be included in the present account. 

The drug development process starts with the synthesis of novel chemical compounds. Substances with complex structures may be obtained from various sources, e.g., plants (cardiac glycosides), animal tissues (heparin), microbial cultures (penicillin G) or cultures of human cells (urokinase), or by means of gene technology (human insulin). As more insight is gained into structure-activity relationships, the search for new agents becomes more clearly focused. 

In a systematic review of 250 publications no controlled, randomized trials were found, and the authors concluded that there was little or no scientific evidence of efficacy, because there are no randomized, controlled trials (179). However, this is one case in which the cumulative anecdotal evidence is overwhelmingly convincing, and there can be no doubt that antidigoxin antibodies are highly effective in the treatment of digoxin intoxication and of intoxication with other cardiac glycosides. The important question is whether there are cases in which the antibodies need not be used, and guidelines have yet to be developed. 

The most important and often-used drugs in the treatment of CHF are the cardiac glycosides, which may exist and occur naturally in the body. Unfortunately, the margin of safety for these drugs is very narrow (therapeutic index, 3.0). Toxicity can develop readily, and careful attention to pharmacokinetic principles is absolutely crucial (see Table 12). 

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