Glycerol is the most ubiquitous fatty acid binding substance in nature. We attempt to explain this fact on the basis of glycerol's structure and the special biological role it confers. We have seen that fatty acid molecules take reciprocal parallel positions when they form monomolecular layers. In their bond to glycerol, these fatty acid molecules conserve this reciprocal relationship. (Fig. 129) This could explain why, in the body, the bond of fatty acid and glycerol always is a triglyceride, mono and diglycerides being only intermediate steps. The same fatty acid has different biological activities if administered as free acid or as triglyceride. The combination seems to serve as an energy furnishing metabolite. Bound to glycerol, fatty acids with long or short chains, saturated, monounsaturated, polyunsaturated, and even conjugated, seem to represent energetic reserves which are utilized as caloric metabolites, especially in those species which are able to store them.

The fatty acid radicals take in the triglyceride molecules

Fig. 129. The fatty acid radicals take in the triglyceride molecules a similar parallel position as when they form a monomolecular layer at the surface of water.

With this relationship in mind, we administered glycerol with two objectives: 1) to obtain, as an immediate effect, the inactivation of the free fatty acids present in abnormal conditions through the neutralization of their polar groups, and 2) to eliminate these fatty acids by turning them into caloric metabolites.

Studying the activity of glycerol at different levels, we could see no influence upon phages. However, an indirect effect was observed upon viruses. Glycerol is widely used as a special medium for the preservation of viruses in tissues. Its preservative value can be correlated, at least in part, with its influence upon fatty acids. We have seen that fatty acids have a noxious effect upon viruses, leading to their disappearance in various organs. The treatment with pure glycerol reduces autolysis of organs through a dehydration effect. Curtailing the lytic activity of the enzymes active in autolysis, glycerol reduces the amount of fatty acids liberated through such autolysis, and thus prevents the destruction of the virus. Glycerol may also preserve viruses by acting antagonistically to any fatty acids which still manage to appear.

Glycerol has a bacteriostatic effect upon only a few species of microbes and only when applied in high concentrations.

A minimal influence upon cells was seen for glycerol in Tetrahymena pyriformis and ascites tumor cells. To study its action at higher levels, glycerol was administered orally or parenterally to animals or humans. Solutions of 20% glycerol were well tolerated when injected subcutane ously or intramuscularly. It should be noted that when glycerol was administered to complex organisms, it was largely absorbed and circulated without alteration, a fact which would explain the effectiveness of relatively small amounts. At the tissue level, glycerol induced a change of the local pH of a lesion toward the acid side, as seen in the second day wound crust. Figure 130 illustrates this. The change explains glycerol's action in increasing intensity of acid pattern pain and decreasing intensity of the alkaline. This influence upon pain was obtained constantly with very small amounts, permitting the use of glycerol even as a test for diagnosis of pain pattern. Intramuscular injection of 1/2 cc. of a 20% solution or oral administration of 1/2 cc. of a 50% solution in water has been used for this purpose. However, later, when other agents were found to produce even more overt responses, we stopped using glycerol as a routine test.

Glycerol has almost no beneficial influence upon the healing of wounds or radiation lesions. Healing was even retarded in some experiments. Various changes in the evolution of tumors occur when host or transplant are treated with glycerol. In some, these changes are minimal; in others an obvious reduction in growth occurs. In a high proportion (12/20), a marked involution has been noted for Walker tumors in rats. Ascites Sa 180 in mice, after repeated intraperitoneal injections of a solution of 2% glycerol, disappeared in 70% of the cases. A lesser effect was seen in Ehrlich and Krebs ascites tumors and still less in the solid tumors obtained with these ascites cells. (Fig. 131) One of the most interesting effects of glycerol was that seen upon the tumors in humans where a manifest involution was obtained in cases in which an offbalance of type D was present. This important effect will be discussed below with the therapeutic use of glycerol. Glycerol administration had an interesting effect upon the amount of cholesterol in the blood in a few subjects. When ten drops of glycerol were given orally three times a day for a month or more, cholesterol values decreased. In some patients, with no change in diet and no medication other than glycerol, values originally above 300 mgr./100 cc. serum fell to below 170 mgr. If these patients also were hypertensive, long term administration of glycerol produced a reduction of blood pressure.

Glycerol induces a lowering of the second day wound crust pH

Fig. 130. Glycerol induces a lowering of the second day wound crust pH.

Changes induced in Walker tumors in rats by the treatments of the animals with glycerol

Fig. 131. Changes induced in Walker tumors in rats by the treatments of the animals with glycerol (daily subcutaneous injections with 1/2 cc of 5% glycerol solution in saline isotonic solution).

An impressive hemorrhagipar effect was noted, frequently ulcerated lesions starting to bleed shortly after administration of even a few drops of glycerol. The relationship of hemorrhaging to glycerol was clear when in the same subjects, repeated administration of this agent invariably was followed by bleeding. The bleeding usually was arterial; only occasionally was an oozing hemorrhage seen.

Many years ago we became interested in studying, in a group of severely burned subjects, the role of fatty acids in the pathogenesis of burn complications. Glycerol was administered to these patients with good effects upon pain. Before the use of antibiotics, one of the principal manifestations in burn patients with widely infected wounds was repeated chills. These chills also were influenced by glycerol. (Note 1) A direct action upon the parasympathetic system could be attributed to glycerol and could explain the effect upon chills. This view has been confirmed by studying the effects upon cardiac rhythm produced by intravenous administration of glycerol in rabbits. (Note 2)

Convulsions could be induced by glycerol in animals and also were seen to occur in humans. (Note 3) They could be induced, with much smaller doses in animals when, along with glycerol, an otherwise harmless dose of deoxycorticosterone acetate was administered. Injection of 0.1 mg. of this hormone in mice weighing 25 to 30 grams, followed by an injection of 1/4 cc. of a 5% solution of glycerol, induced convulsions which were usually lethal. In terminal cancer patients, too, concomitant administration of the cortical hormone and glycerol for a few days has produced convulsive seizures, which proved to be lethal in one subject in whom no previous abnormal cerebral manifestations had been observed, and who had received these two medications for only a few days.

The administration of 1 cc glycerol daily induces a change of the urinary pH toward the type A

Fig. 132. The administration of 1 cc glycerol daily induces a change of the urinary pH toward the type A, before changes in the other analyses take place.

Of the different systemic manifestations influenced by glycerol, the effect upon acid base balance is most striking. Even before any other effect upon systemic analyses becomes apparent, an immediate change of urinary pH from acid to alkaline values is induced by glycerol administered in sufficient quantity. (Fig. 132)