COMPARATIVE EVALUATION OF THE EMETIC EFFECTS OF SOME NATURAL AND SEMI-SYNTHETIC ESTERS OF PROTOVERINE
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Ever since the introduction of protoveratrine for the treatment of hypertension, attempts have been made to augment its inadequate therapeutic margin. Considerable efforts to synthesize veratrum alkaloids with a greater ratio between hypotensive and emetic effects were made, notably by Kupchan and co-workers (1-6). While efforts to secure a hypotensive veratrum alkaloid devoid of emetic activity failed, it was soon discovered that some semisynthetic acetic acid esters of germine (7, 8) and protoverine (9-12) showed no hypotensive activity but retained a marked tension increasing effect on skeletal muscle. This effect designated, the ‘<I>veratrine response</I>’, by von Bezold (13) consists in the conversion of a single action potential after a stimulus, into a series of “repetitive” action potentials resulting in an augmented response of the muscle.<BR> Recently, Flacke and co-workers (14, 15) using germine diacetate, were able to demonstrate improvement in muscle power in a small group of myasthenic patients who derived little or no benefit from treatment with anticholinesterase. In these patients the ptosis, ocular mobility and facial and lingual muscles responded better to germine diacetate than a standard dose of pyridostigmine (16-18).<BR> The present investigation compares the emetic activity in pigeons, of a series of semisynthetic acetic acid esters of protoverine with the naturally occurring protoveratrine A and B. The skeletal muscle and cardiovascular system effects of some of these alkaloids which are similar to those of germine diacetate, have been described in detail by us elsewhere (11, 12). The series comprised of the following compounds : protoverine acetonide diacetate (PADA); protoverine triacetate (PTA); protoverine acetonide triacetate (PATA); protoverine pentaacetate (PPA); protoverine isopentaacetate (PIPA) and protoverine hexaacetate (PHA). The study also confirms and extends Winers observation of a quantitative difference between protoveratrine A and B with respect to emetic potency in man (19, 20).
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