The study of aliphatic alcohols has shown that only few members of this homologous series, beginning with butanol and ending with octanol, have an effect upon the s.d.c. pH. For octanol, only half of the test animals showed changes in second day wound crust pH. (Fig. 139) We thought it worthwhile to study the biological effects exerted by these members of the series, including those which demonstrated no effect on the second day wound crust pH. Comparative studies indicate definite differences between the two groups with odd or even number of carbons in their ability to act upon an existing offbalance and reduce the abnormal metabolism. Along with differences, many common properties were recognized through effects induced at various levels. In general, the effects are more profound for members with longer chains. This is true for butanol compared to hexanol in the even carbon series and for pentanol compared to heptanol in the odd carbon series. For octanol, most of the effects are diminished. In the group with odd carbon numbers, nonanol has very little or no influence.

Fig. 138. Influence exerted by different agents upon the mortality of mice scalded for 3 seconds in water at 90°C. While sodium lactate seems even to increase the mortality and NaCl and butanol in saline have little influence, a marked prolongation of the survival time is induced by the mixture of n butanol and Na lactate.

Influence exerted by different agents upon the mortality of mice

On viruses, a protective effect against external influences such as heat or fatty acids is evident. It is more striking for the even carbon group. In microbes, little except an antibacterial effect is produced by members in the even carbon group. The odd carbon group induces Gram positivity, irregularities in form with a tendency toward roundness, and vacuolization.

The influence exerted by heptanol, octanol and nonanol

Fig. 139. The influence exerted by heptanol, octanol and nonanol upon the s.d.c. pH. While heptanol induces constantly a lowering of the alkalinity of the second day wound crust, this effect is less constant for octanol and nil for nonanol.

No important changes occur at the cellular level. We have already mentioned the different effects upon wound crust pH for these alcohols. On pain, nonanol has no effect and hexanol and octanol relatively little. But pentanol and especially heptanol show a very marked influence, both immediate and prolonged. It is interesting to note another striking effect at the tissular level, observed only for heptanol. It corresponds to an abnormal accumulation of fluid in certain abnormal tissues. This was first seen in surgical scars even several months old. Edema of the entire scar occurred followed by blistering at the surface, or even by formation of fluid filled cavities in the scar itself. The same phenomenon appeared in other lesions such as tumors, especially when they were infected, although there had been no clinical indication of infection before the administration of heptanol. The effect sometimes was very intense, transforming an entire lesion, scar or tumor into a cavity with septic fluid exudate, but few leucocytes.

The influence of high doses of heptanol upon inflamatory processes could be judged experimentally in the gas pouch induced subcutaneously in rats or mice by injecting nitrogen and subsequently injected with a low pathogenic microbe. In controls, no unfavorable effects were noted. In animals injected with heptanol subcutaneously, fluid exudate accumulated in the pouch in a few days. (Note 11) Subcutaneous administration of heptanol also induced an exudate in the peritoneal cavity in mice and rats injected with the same microbial suspension. This did not occur in the controls. It must be emphasized that these effects were seen only with relatively high doses of heptanol.

At the organic level, while nonanol again showed no activity, the two higher alcohols, heptanol and octanol, had an influence upon the central nervous system. In humans, even in larger doses, such as 200 mgr. six times a day (2 cc. of a 10% solution in oil every four hours) repeated for ten days or more, the two higher alcohols produced no abnormal central nervous system manifestations. In some subjects who had previously had convulsive attacks, administration even in small doses, such as 25-50 milligrams once a day, did induce convulsive seizures. If these substances were given along with desoxycorticosterone, the latter even in doses of 1 mgr. a day, severe and even fatal convulsions were produced. Nonanol had no such effect. Somnolence followed by coma was observed with concomitant administration of cortisone and heptanol or octanol, but nonanol did not produce this effect either.

Of interest was the influence exerted by heptanol upon the different analyses. Fig. 140 shows how these values change toward the offbalance A under the influence of heptanol. It is to be noted that of all the analyses, the urinary pH and the blood serum potassium are the first to be changed. They are followed by specific gravity, while the urinary surface tension seems to be influenced last.

M. Bier, in our laboratories, has shown that alcohols, when added in vitro to freshly obtained blood, reduced blood clot retractibility. It is interesting to note here the relationship Bier has shown between this effect in retractibility and other properties of the alcohol series members. Thus, he could demonstrate that there is a critical value for the concentration of each alcohol, when mixed with fresh blood: blood clot retraction is prevented only when this value is exceeded. The critical value varies with the length of the chain, decreasing for the higher members. (Fig. 143) Bier also has shown that, since the toxicity of these alcohols seems to be related to the same factor, a correlation can be established between critical concentration values and lethal toxic doses.

In a patient with bone metastatic lesions the administration of heptanol

Fig. 140. In a patient with bone metastatic lesions the administration of heptanol and butanol shows a progressive decrease in the values of serum potassium and increase in the urinary pH, toward offbalance type A.

This relationship, as shown in Fig. 142, applies to the members of this series of saturated alcohols, but not to alcohols of another series also studied. For the latter, the toxic dose is higher than the critical dilution at which the clot retraction is influenced, and this can be explained by the intervention of the double bond in the molecules.

Systemic effects were seen for these alcohols if administered in sufficient doses. Some special effects also were seen. Heptanol decreased the sulfhydryl index in urine analyses, especially if it had been high previously. Octanol's action was mainly to increase surface tension if it had been low. Nonanol did not show any such activity at all.

Clot retraction

Fig. 141. Clot retraction, measured as percent weight of clot/total weight of blood, plotted against molar concentration of butanol in blood. Different symbols used for blood samples of each animal.

Clot retraction

Fig. 142. Clot retraction, measured as percent weight of clot/total weight of blood, plotted against similar concentration of butanol in blood. Averages of different age group animals were studied.

Clot retraction

Fig. 143. Clot retraction, measured as percent weight of clot/total weight of blood, plotted against similar concentration of various alcohols in blood.

Polyols

In another study, we considered the polyalcohols, bearing in mind the important role played by glycerol in the biological activity of lipids. In animals, ethylene glycol and diethylene glycol proved to be too toxic for parenteral administration. However, near toxic doses produced interesting results especially in tumors. Even in relatively small subcutaneous Walker rat tumors, 2.5 cm. in diameter, for instance, necrosis was constantly induced and followed by skin ulceration. The characteristic influence of these alcohols was to induce a necrotic process not limited to the tumor alone but affecting surrounding tissues.

1.2 Diols

By following the influence exerted by more than one hydroxyl in the molecule, we tried to relate properties of glycerol to those of aliphatic lipoids. We prepared lipoids having a polar formation of 2 or 3 hydroxyls bound to the first carbons of an aliphatic chain. The lipoidic character was induced by the length of the chain. To prepare these substances, we started with corresponding alph hydroxy fatty acids in which the carboxyl was reduced to a primary alcohol by treatment with lithium aluminum hydride. As a prototype, we studied 1.2 octanediol. The lipoidic character was recognized by its high solubility in neutral solvents and a limited solubility in water.

There were no marked differences between the effects of octanol and 1.2 octanediol in systemic analyses. Both raised surface tension values in particular. However, the new component had an effect upon the central nervous system different from most other higher alcohols. As mentioned above, these aliphatic mono alcohols do not induce convulsions without the concomitant intervention of another factor. The second factor can be a local condition in the nervous system itself, as in subjects with cerebral tumors, or others who have had previous convulsions. It can also be another substance; desoxycorticosterol, coramine, glycerol or glucose, when administered with octanol, for example, induced convulsions in some subjects. However, 1.2 octanediol, in repeated doses of around 200 mgr. daily, induced convulsions by itself. This could be explained by the fact that 1.2 octanediol contains in its molecule a group which energetically resembles glycerol. Beyond this effect, there were no manifest differences between this substance and corresponding mono alcohols in influence upon pain, tumor growth or systemic manifestations.