In this group of agents we studied procaine. We became especially interested in procaine after we had seen some cases of ulcerations due to varicose veins healed in a few days with only two intra arterial injections of procaine according to Leriche's method. With the idea in mind that an action through its lipoidic properties intervenes, we studied procaine base. Solutions of procaine base in sesame oil, or suspension in Tween or gum cellulose were prepared. Parallel with these procaine base preparations, we studied also the hydrochloride as well as several salts of procaine, such as lactate, glycerophosphate, where a further effect was sought through the acids at which procaine was bound. We studied all these agents but only under the aspect of their activity in relationship to the dualistic offbalances.

No special effects were seen upon viruses and microbes from this point of view. Injected subcutaneously to rabbits, it was seen to increase in the skin corresponding to the place of injection, the manifestations of a subsequent smallpox inoculation. Added to the medium for cultures of tetra hymena pyriformis in higher doses, it led to the appearance of almost round forms. We studied the survival time through the capillary tubes method mentioned above. For progressive amounts of procaine hydrochloride added to a culture of tetrahymena, no immediate effect of the life span of the culture could be seen. In another group of experiments, the procaine was added to the culture before its inoculation and the life span of the tetrahymena grown on this medium was studied. Under these circumstances a prolongation of the life of the culture itself could be seen, but only in the cultures which were showing also a slow growth.

Procaine in general, and much more evident in the base preparations, was seen to reduce the pH values of the second day wound crust. In mice and rats, the lethal doses were seen to be manifested through the appearance of convulsions. Sublethal doses were seen to lead to convulsions after a few successive days of administration. In humans, an intramuscular injection with procaine base was seen to influence pain but this effect was apparently limited only to the cases with an alkaline pattern present. This and the fact that the effects were no more manifest with procaine base than with other lipoidic preparations with positive polar group, even when administered in relatively high doses such as of 2 cc. of the 5% solution of procaine in oil, indicates that its action other than at the place of the injection, has to be related largely to the intervention of procaine as lipoid. A special mention, however, has to be made for the angina pain which seems to be more evidently influenced by the injection with procaine base than other pains.

The immediate influence exerted upon systemic analyses, if any. was in general reduced even after the administration of 10 cc. of 2% procaine hydrochloride. It was manifested particularly upon the urinary pH, inducing a change toward more alkaline values. This effect was transitory and especially seen for the first injections. With repeated doses, this effect decreased even to the point of disappearing.

The study of the pharmacology of procaine has emphasized the character of its activity as a lipoid with a positive polar group rather than a direct one through its chemical constituents. This view is confirmed by the fact that the same effects are not obtained with any one of the two constituents of procaine, para aminobenzoic acid and diethylaminoethanol, administered separated or even together. The only difference in this case between procaine and its constituents resides in the properties of procaine as such, which we related largely to its lipoidic properties.

Furthermore, the study of the different effects induced by procaine can be seen to result from a nonspecific effect in which these agents intervene indirectly upon the metabolic processes which occur at the cells for instance, rather than to a direct influence exerted by procaine constituents upon specific metabolic processes. In this group would enter the effects seen upon different enzymatic processes indirectly influenced by procaine through the nonspecific changes induced.

We have investigated under this special aspect the use of procaine hydrochloride in solutions with a pH between 3 and 4, as indicated by A. Asian, against the manifestations of old age. The low pH seems to intervene by preventing, as long as possible, the enzymatic hydrolysis of procaine and thus permitting its absorption and action as a nondissociated lipoid. We found that the protection exerted by the low pH would result from the chemotactic negative influence exercised by hydrosoluble acids upon the leucocytes, which thus will reduce the intervention of the leucocytic enzymes in the process of hydrolysis.

Furthermore, the fact that the bond of procaine, as such, takes place through the amino radical of the P A B A explains why a high acidity would prevent this local bond of procaine to occur at the place of the injection and thus would favor its action at other sites in the organism. This action is confirmed by the fact that the analgesic properties of procaine decrease through the low pH, while at the same time, its other metabolic effects increase.

The fact that good effects were observed with procaine in old age and arthritis, schizophrenia and many other conditions, indicates that a nonspecific action would take place. The fact that the effects obtained are similar to those observed in the same conditions with other lipoidic agents with a positive polar group, permits us to see as principal factor in the pharmacological action of procaine, its nonspecific intervention as positive lipoid. Besides this nonspecific lipoidic effect, some others related to its chemical constituents and which would represent specific added factors have to be considered. The relation to the folic acid would be an example.

All these considerations led us to study various preparations in which procaine was bound to different agents, with the aim to enhance its nonspecific intervention. Through procaine lactate, malate and citrate, the chemotactic negative effect was highly increased and procaine activity enhanced. Bound to maleic or citraconic acids, the anti fatty acid activity of procaine was further directed toward influencing more specifically, the abnormal changes occurring leading to the appearance of abnormal fatty acids.