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Liposomes containing antimonial compounds trapped in the aqueous phase were tested in the treatment of experimental leishmaniasis. The rationale of this approach was based on the hypothesis that the liposomes and the parasite are taken up by the same cell, the reticuloendothelial cell, and we present electron microscopic evidence that supports this hypothesis. Suppression of leishmaniasis was quantified by determining the total number of parasites per liver from impression smears. When two antimonials, meglumine antimoniate and sodium stibogluconate, were encapsulated within lipo somes, each was more than 700 times more active compared to either of the free (unencapsulated) drugs. After infection, if untreated, all of the hamsters eventually would die from the disease. Liposome-encapsulated meglumine antimoniate was about 330-640 times more effective in causing a drop in the death rate than was the free antimonial. The efficacy of treatment was influenced by the lipid composition and charge of the liposomes. For example, positively charged liposomes containing egg phosphatidylcholine were much less effective than negatively charged ones. In contrast, positively and negatively charged sphingomyelin liposomes were equally effective. Liposomes containing phosphatidylserine (which were negatively charged, but also had a much higher charge density) were among the less-effective preparations. Among those tested, the most consistently efficacious liposomes contained highly saturated long-chain phospholipids (eg., dipalmitoyl phosphatidylcholine), cholesterol, and a negative charge.We conclude that liposomes may be useful as carriers of drugs to treat infectious diseases involving the reticuloendothelial system. The toxicities of antimony are very similar to those of arsenic. Encapsulation of antimonial drugs and reduction of the dose required for effective therapy should minimize such systemic toxicities as acute cardiomyopathy and toxic nephritis.

Of 49 compounds known to have antitumor properties, 6 were found to have significant activity against Trypanosoma rhodesiense infections in mice. Activity against the African trypanosomes has not been reported previously for any of these six compounds. In order of decreasing activity these compounds were: (i) imidazole-4-carboxamide, 5-(3,3-dimethyl-1,1-triazene), (ii) inosine diglycolaldehyde, (iii) cis-diamminedichloro-platinum, (iv) streptozotocin, (v) coralyne sulfate, and (vi) 5-fluoro-2'-deoxyuridine. The percentage of "hits" (12.2%) from these known antitumor agents was approximately twice as great as when other means are employed for the selection of compounds for this test system.

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A series of lepidines (6-methoxy-4-methyl-8-aminoquinoline derivatives) was studied in a hamster-Leishmania donovani model. Members of this class were found to have activity many-fold that of the standard, meglumine antimoniate (Glucantime). One of them, 8-(6-diethylamino-hexylamino)-6-methoxy-4-methylquinoline, designated WR 6026, when given orally was over 700 times as effective as the standard antimonial drug.

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Absorption Spectra of Quinolinols and Isoquinolinols 2181 colored vanillic acid, whereas sulfur dioxide gave a white product in all cases.Reaction of Vanillin with Fused Potassium Hydroxide above 240°.-The same apparatus was used. A mixture of 165 g, of potassium hydroxide and 20 g. of water was heated to 225 °and with vigorous stirring was treated with 60 g. of vanillin in small portions at such a rate as to keep the resulting vigorous reaction from effervescing out of the crucible and to maintain the temperature at 225 °. Vanillin addition required approximately twenty minutes. The temperature was maintained at 225°for another five minutes, at which time all effervescence had ceased. A sample dissolved in water and acidified with hydrochloric acid gave only crystals of vanillic acid melting sharply at 207-208°. The mixture was heated to 240°for five minutes, which caused the fused mass to become more fluid. A sample at this point indicated only vanillic acid. No test for protocatechuic acid could be obtained by the very sensitive ferric chloride reaction. The temperature was then raised to 245-250 °, at which temperature effervescence again took place. After five minutes at 250°, a sample no longer gave a precipitate of vanillic acid when dissolved in water and acidified with hydrochloric acid. The fusion mixture was allowed to cool somewhat and was dissolved in 600 ml. of water. The alkaline solution was acidified with 6 N hydrochloric acid, giving an effervescent yellow solution which, upon standing, deposited colorless crystals. The crystals were filtered, washed with water, and dried at 105°to yield 36 g. (59%) of protocatechuic acid melting at 199-200°and not depressing the melting point of a mixture with authentic protocatechuic acid. Saturation of the acid filtrate with sodium chloride and extraction with ether yielded an additional 24 g. (40%) of protocatechuic acid melting at 195-200°. This experiment was repeated, the temperature being maintained just below 245°for thirty minutes. At that point no protocatechuic acid could be found. Raising the temperature to 245°caused reaction to set in and the temperature to rise to 255°. The mixture was worked up as above to yield 99% protocatechuic acid.Summary Caustic fusion of vanillin below 240-245°results in very high yields of vanillic acid free from protocatechuic acid. Fusion of vanillin above 240-245°y ields protocatechuic acid free from vanillic acid. The critical demethylation temperature varies somewhat with the alkali-vanillin ratio. Reaction of vanillin with strong alkali solution at elevated temperatures does not yield either of the acids.

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