The fact that in the first phases of the defense mechanism the organism uses fatty acids acting largely through their products of oxidation, has directed us—as we have seen above—to search in the therapeutic approach for agents having as pharmacodynamic activity an intervention of peroxides. In a further step, parallel to lipidic peroxides, we investigated similar products in which, instead of peroxides, persulfides were present, sulfur being the element immediately above oxygen in the Vlth series of elements. We studied thus the persulfides, among which the tetrahydronaphthalene per sulfide has been an interesting compound. Its activity was explained, according to the biological systematization of the elements in which oxygen corresponds to the organism level, while sulfur represents a metazoic element. Following the same line, we searched similar compounds for selenium —an element still higher in the Vlth series, which corresponds to the cellular level. We thus prepared and studied perselenides by bounding selenium to tetraline in the same way as was done for oxygen and sulfur.

The effects of the perselenides on microbes or animals were similar to those of the other selenium preparation discussed above. Tetraline perselenide showed low toxicity in animals,1/4 cc. of the 10% solution of the product obtained having 25 mg. selenium %, was not toxic in intraperitoneal injections in mice. Administered orally in humans, in doses from 1/50-2 cc. of the solution containing 25 mg. of selenium per 1 cc., repeated even several times a day, did not show toxic effects. The influence exerted on pain and systemic changes took some time to appear as with the other selenium preparations. The influence exerted upon the growth of experimental tumors in animals was more manifest than for the other selenium preparation. Similar results were obtained with the perselenides of naphthalene and other aromatic hydrocarbons.

An investigation of the influence exerted by the immediately heavier member of this Vlth series, tellurium, is in progress.

The foregoing data on lipoids with negative character indicate that then activity generally is related to changes in processes in which ultimately an intervention of oxygen takes place. This brings us to the first member of the sixth series, oxygen, a nonmetal with D inducing biological activity.

We studied the effects of ionic oxygen, using compounds which liberate oxygen readily. These included hydrogen peroxide as well as peracids and their salts, such as perchloric, perboric, persulfuric and periodic.

The changes induced by these substances upon microbes, viruses and cells are similar to those obtained with polyunsaturated fatty acids and all are catalogued as radiomimetic. This fact tends to confirm the importance of oxidation changes in the pharmacodynamy of fatty acids. The effects upon pain and at organic and systemic levels also were similar to those of polyunsaturated fatty acids. It is interesting to note in the same frame of activity the appearance of oxidizing substances in the urine following the oral administration of these agents in higher doses.

We investigated the effects of turpentine oil which is known to induce the appearance of peroxide in vitro. Highly oxidized through treatment with oxygen or especially bound to sulfur, turpentine oil has shown interesting pharmacological activity. An old therapeutic device was parenteral administration of turpentine oil to stimulate the defense mechanism in cases of septicemia. However, we saw no such stimulating effect in the fight against cancerous cells. The influence exerted upon the cellular level of the organization was quite reduced. The action of atomic oxygen appears to be different from that of the molecular, as we will see later.

Alkylating Agents

We investigated, as compounds with negative character, certain alkylating agents, choosing from the large number available those which also showed lipidic properties. We were especially interested in two members, sulfur mustard and epichlorohydrine. Sulfur mustard contains, along with one active polar chloroethyl group, a second represented by the bivalent sulfur polar group. It has the effect at different levels of organization of producing an offbalance with predominance of the acid lipids. We will discuss briefly here some of the experiments in which this influence upon the body lipids has been observed.