M. T. Davies, J. Forrest, F. Hartley
Sep 1, 1954
Citations
0
Influential Citations
15
Citations
Journal
Journal of Pharmacy and Pharmacology
Abstract
ALTHOUGH piperazine and its water-soluble salts have long been used medicinally in the treatment of gout and rheumatism because of their possible value in dissolving uric acid, the anthelmintic potentialities of piperazine and its derivatives have been realised only in recent years. Following the discovery of the value of diethylcarbamazine citratel in the treatment of filariasis, attention has been turned to the evaluation of other piperazine derivatives against helminth infections. In 195 1, Mouriquand, Roman and Coisnard2 reported the successful use of piperazine hydrate in the treatment of threadworm infestation in children. Wider use of this preparation was not immediately forthcoming as piperazine hydrate is a strongly basic substance of uncertain keeping qualities in solution. A more satisfactory derivative of piperazine was studied the following year by Turpin, Cavier and Sa~aton-Pillet~, who described the employment of the bisphenylacetate salt, which was administered orally with concomitant use of piperazine suppositories. Piperazine bisphenylacetate, though representing an advance on piperazine hydrate from the standpoint of pharmaceutical presentation, was not considered by us a satisfactory salt for the following reasons: (i) it contains only 25 per cent. of piperazine, so that the dose required is large, (ii) the material has a distinct urinary odour which renders it unpalatable to many patients and (iii) its solubility characteristics present difficulty in its alternative formulation as a liquid preparation stable to storage over a wide temperature range. We consequently turned our attention to other salts of piperazine. In particular, we sought a derivative of low solubility as we thought that such a compound might undergo slower absorption in the gut than the readily soluble hydrate, citrate, etc., thus avoiding the neurotoxic effects accompanying the use of the more soluble piperazine compounds which have subsequently been disc~ssed~,~. The search for such a compound proved difficult, in that with one exception, the sparingly soluble salts prepared had either too high a molecular weight to offer advantages over the bisphenyl acetate or else were too toxic for oral administration. Piperazine adipate6 alone of the many salts examined proved able to satisfy the pharmaceutical requirements we considered necessary. It was consequently submitted to pharmacological investigation (Part 11) which showed it to be a relatively non-toxic compound with a high margin of safety. Preliminary clinical trial^^?^ showed that piperazine adipate achieved complete eradication of threadworm infestation in man without the occurrence of any side effects and wider clinical usage has confirmed these qualitiesg. The salt was also examined, at our request, by The Cooper Technical Bureau for its