A RECENT report by Andersonet al.1on the antithyroid activity of a series of alkyl derivatives of thiouracil shows that peak activity is reached at then-propyl compound. A similar series of compounds is under investigation in this Laboratory, and some preliminary results may be of interest as confirming those of Andersonet al.in regard to the high activity of then-propyl derivative. The substances under examination comprise methyl, ethyl,n-propyl, isopropyl andn-amyl thiouracil, and preliminary screening experiments indicated that then-propyl compound was probably the most active of the series. Our experiments are not yet sufficiently complete to allot comparative values to the whole series, but they confirm the preliminary findings of the high activity of then-propyl compound.The work was carried out on inbred Wistar rats, weighing 100-200 gm., and the compounds were administered by stomach tube daily for 28 days. The rats were then killed and the thyroid gland cleanly dissected, rapidly weighed on a torsion balance and fixed in Bouin's fluid. Typical results were as follows: ThiouraciMethyl thiouradl AverageAverage wt. wt. of No. of Daily dose of thyroid No. of Daily dose thyroidRats (mgm./gm.) (mgm./lOO rats (mgm./gm.) (mgm./lOO gm. body wt.) gm. body11(6 J5$) 0-10 12-68 10(5 J5$) 0-05 wt.) 15-70 9(4^5?) 0-025 8-67 8(5cJ3£) 0-0125 8-3710(5 ?5$) 0-00625 6-77 9(4?5$) 0-003125 6-37 Nil 4-45 Nil 4-45n-Propyl thiouracil o Average wt.No. of Daily dose j of thyroid rats (mgm./gm.) (mgm./lOO gm.body wt.) 73J4$) 0-10 28-577(3?4$) 0-025 17-65 7(3c?4?) 0-00625 18-927(3J4$) 0-00156 12-22 7(3?4?) Nil 6-30Histological examination of the thyroids of rats treated with n-propyl thiouracil revealed the usual marked hyperplasia with absence of ‘colloid’ material and increased height of epithelial cells. In some instances., with the lower doses, the degree of hyperplasia was not so marked as would have been expected in view of the large increase in the weight of the thyroid. The acute oral toxicity of the series of compounds is also being determined. The L.D. 50 by oral administration to rats of n-propyl thiouracil is approximately 1-25 mgm./gm. compared with 1-5 mgm./gm. for methyl thiouracil. The interpretation of these figures is rendered difficult by the relative insolubility of the substances and the consequent uncertainty regarding the proportion of the drug absorbed from the gastro-intestinal tract. This uncertainty probably does not apply to the doses used to test the therapeutic action of the drugs, since these amounts were sufficiently small to be given in aqueous solution.Chronic toxicity tests on w-propyl thiouracil, during which oral doses were given daily for four months, showed that, under these conditions, a daily dose of 0-1 mgm./gm. produced a 50 per cent mortality in a group of 10 rats and a dose of 0-05 mgm./gm, a mortality of 10 per cent, the latter rate being identical with that in the control group animals. A comparison of the rate of growth of the animals in these last two groups shows that, whereas the control rats grew steadily throughout the period of the experiment, the rats receiving 0-05 mgm./gm. per day of n-propyl thiouracil ceased to grow after the twentieth day and thereafter suffered a slight but steady loss of weight. We are indebted to Dr. J. F. Martin for supplies of the thiouracil derivatives, and to the Directors of Genatosan Ltd. for permission to publish this