We investigated thiosulfates with the intention of studying agents which, in addition to a manifest reduction effect, would act through bivalent sulfur liberated in the body. The elimination of part of the sulfur of thiosulfates as mercapturic acid has led to the supposition that the bivalent sulfur ion, separated from the thiosulfate ion, would act through combinations similar to those found in the metabolism of thiolipoids. It is for this indirect action that although hydrosoluble, without any direct connection to lipoids, we investigated the biological activity of thiosulfate together with and under the same specific aspect as the lipoidic sulfur compounds considered above.

There was a very limited effect upon microbes and viruses, no effect upon phages, and no change in the receptivity of rabbits to smallpox virus. With either oral or parenteral administration, the immediate effect upon pain was manifest. Oral administration of 1/2 cc. of a 10% solution of sodium thiosulfate in water, or intramuscular injection of 1/2 cc. of the 4% solution, was usually followed by a definite effect upon pain in less than 10 minutes. As this was found to be opposite for the two patterns of pain, sodium thiosulfate was used even for diagnosis of pain pattern. Pain of an alkaline pattern increased while a decrease occurred in pain of an acid pattern. The second day wound crust pH increased manifestly with the use of this substance.

Cellular and nuclear changes following administration of thiosulfate preparations were similar to those produced by mercaptans. The effects upon the lymphatic system and on liver regeneration, however, were minimal. Convulsions induced by thiamine were controlled well by thiosulfate in doses of 120 mgr. per 100 gram of body weight. Injected simultaneously with administration of thiamine, thiosulfate prevented convulsions in a high proportion of animals (17/20).

The effect upon radiation lesions was less manifest. An increase in wound size and prolonged ulceration occurred only with use of relatively large amounts of sodium thiosulfate daily. Doses above 40 mg./100 gm. of body weight were needed to obtain these effects. The healing of a simple wound was retarded only with large doses, around 50 mg./100 gm. of body weight. On the other hand, when very small doses were administered, such as 5 mg./100 gm., the healing effect was enhanced. Effects upon tumors were less manifest in animals. Slight and inconsistent changes were seen in grafted tumors. Very often in the same experimental group, tumors disappeared in some animals while in others the growth rate was only slowed or remained unchanged. The erratic results on tumors in animals produced by thiosulfates were similar to those seen for many of the sulfur preparations, and appeared as characteristic for this group. Repeated injections of thiosulfates in tumors were seen to induce the disappearance of the tumor if growth was slow enough to permit such injections for several weeks. At the systemic level, the most marked effect, other than that on sulfhydryl index, was on surface tension which usually dropped with the administration of a sufficiently large amount.

Most of the research on thiosulfate was done with sodium salts. In a few cases, very high dosage, such as 6-10 grams daily, produced moon face and slight leg edema, apparently related to sodium retention. This disappeared with cessation of the medication.

Changing the cation of the thiosulfate from sodium to magnesium appeared to increase, sometimes markedly, the results obtained in our experiments. Potassium thiosulfate seemed to be more effective, especially against pain. Its use however, has been limited by disadvantages. When administered parenterally, it causes considerable local pain at the site of injection as most potassium salts do. If administered to patients having pain or other symptoms of an alkaline pattern or systemic manifestations corresponding to type D, a more marked increase in intensity of symptoms occurs than for the sodium or magnesium salts.

We also investigated sodium tetrathionate. Except for lower dosage requirements, no other advantages were found in its use. Its relative instability is a handicap.