Analysis of the natural anti fatty acid agents has revealed the importance of their positive polar groups. And this has guided us in attempts to obtain synthetic agents with anti fatty acid effects.

An important step was a study of alcohols with lipoidic properties, the lipoalcohols, starting with the primary mono alcohol homologous series. This study also has permitted us to recognize the importance of the lipoidic properties for their biological activity. We started with butanol which is the first member of the homologous series of aliphatic alcohols with lipoid characteristics.

Pharmacodynamic Activity Of Butanol

Butanol has a special place among the alcohols that have been utilized as anti fatty acid agents, not only by virtue of its physico chemical and biological properties but also because of interesting therapeutic results obtained in animals and humans.

Extensive studies with butanol have helped considerably in defining the physico chemical and biological differences between lipoids and nonlipoids. According to the concept advanced previously, lipoids and nonlipoids can be distinguished by solubility characteristics which are determined by the energetic relationship between their polar and nonpolar groups. The non polar group is predominant in a lipoid; the polar group is predominant in a hydroid. Lipoids have greater solubility in neutral solvents than in water, and this provides a simple criterion for their recognition.

Methyl, ethyl and propyl alcohols are all equally more soluble in water than in neutral solvents and therefore are recognized as nonlipoids. Butanol, however, differs from the lower members of the aliphatic alcohol series by being a lipoid, more soluble in neutral solvents than in water. This, however, is true only for three of the four isomers of butanol. n Butanol, sec butanol and iso butanol are all more soluble in neutral solvents than in water, whereas tert butanol is equally soluble in both. According to our criterion therefore, while the first three are lipoids, tert butanol is not. These considerations have enabled us to correlate lipoidal properties with one more precise intermolecular factor, the predominance of one of the van der Waals cohesion forces. Comparative analysis of the structural formula of the four isomers of butanol (Fig. 133), reveals the importance of forces related to the surface of the molecules in determining differences in their solubility. In contrast to the three lipoid isomers, the molecule of tertiary butanol is rounder and hence has a smaller surface. The difference between tert butanol and the other three isomers is apparently due to the cohesion forces related to the surface area of the molecule. Of the van der Waals forces, those described as related to the surface of the molecules, or as the constant b of the cohesion forces, thus appeared to be most important in determining lipoidic properties. (Fig. 134)

Schematic representation of the molecular surfaces of the 4 isomers of butanol

Fig. 133. Schematic representation of the molecular surfaces of the 4 isomers of butanol. The constant b of the van der Waals forces related to their surfaces are unequal. A minimum value is seen for almost spheric molecule of tertiary butanol, a fact which explains the nonpredominance of the polar group in this molecule, respectively its non lipoidic character.

The differences between the round shape of tertiary butanol and the longer form of the other isomers is evident with models of molecules

Fig. 134. The differences between the round shape of tertiary butanol and the longer form of the other isomers is evident with models of molecules.

While the 3 isomers of butanol which are lipoids influence the second day wound crust pH

Fig. 135. While the 3 isomers of butanol which are lipoids influence the second day wound crust pH, lowering its values, tertiary butanol which is not a lipoid, does not influence it.

Study of the four isomers of butanol has confirmed the importance of lipoidic properties for biological activity. Like the lower members of the homologous series of aliphatic alcohols which are not lipoids, tertiary butanol does not influence pH of the second day crust of a wound, while the three other isomers, all with lipoidic characters, lower the pH as the higher members of this series do. (Fig. 135)

Effect of 0.5% solution of n butanol

Fig. 136. Effect of 0.5% solution of n butanol administered instead of drinking water upon the increase in weight of young rats. The values represent the average for 20 females (....). No differences are seen from nontreated controls.

The fact that a saturated water solution at 20°C still contains 7.9% n butanol is of great practical importance. Because of its degree of solubility in water, n butanol could be utilized in aqueous solutions in sufficiently high concentration for pharmacological studies and could be used as a therapeutic agent in this form without need for an oily solvent vehicle.

The acute toxicity dose for butanol corresponds to the narcotic dose for the respiratory centers which is related to interference with the aerobi otic life of these cells.

The minimal lethal dose of n butanol administered subcutaneously was found to be 4.6-6.4 gm./Kgm. for mice, 3.7-5.9 gm./Kgm. for rats and 3.3-5.6 gm./Kgm. for rabbits, guinea pigs and hamsters. These values closely approximate the findings of other workers. The minimal lethal dose of n butanol injected intraperitoneally is very close to that for subcutaneous and intramuscular administration, indicating that absorption from the tissues is almost as rapid as from serous cavities.

We have administered butanol in large doses to human subjects, and these clinical studies have confirmed the laboratory findings that the toxic effect is especially manifest through the narcotic effect and is attained only with the use of very large doses. (Note 8)

The same daily change seen in male rats

Fig. 137. The same daily change seen in male rats.

Long term use of n butanol has virtually no influence upon normal physiology in animals. Administered continuously in the drinking water of young animals, it had no effect on growth. (Fig. 136) It also did not affect reproduction capabilities of mature animals or influence their offsprings.

n Butanol shows a definite influence on white blood cells in rats. The leucocyte count is increased in adult rats receiving daily injections of a saturated solution of n butanol. (Note 9)

The influence exerted by small doses of n butanol, as for other lipoids, appears to be almost entirely confined to abnormal tissues and cells. This is evident in the influence upon the pH of experimentally induced wounds in animals. Administered before wound inductions, n butanol showed no influence upon normal tissue, no differences were observed between pH of their normal tissues in treated and untreated animals. During the first day following wound inductions, pH of the lesion in treated animals was no different from pH in untreated control animals. However, by the second day. pH of the wound crust was lowered by butanol, as seen in Figure 135.

n Butanol accelerated the healing rate of wounds, although the differences between treated animals and controls was not striking. n Butanol enhanced healing of radiation burns to some extent but the effect was not constant in different groups of animals. In several animals treated with n butanol, radiation wounds healed within two or three weeks, while in controls healing took more than four weeks.

Butanol, when administered to patients with pain of alkaline pattern, has repeatedly provided relief within a very short time—in some cases within three to five minutes. In pain of an acid pattern, exacerbation occurs, also within a few minutes. Its quick effect has led to use of butanol as a diagnostic means for determining the pain pattern.

The anti fatty acid action of n butanol has led to the investigation of its effect upon shock since, as previously noted, shock appears to be related to intervention of abnormal fatty acids. Administration of butanol subcu taneously, even together with large amounts of saline, is only slightly beneficial for shock in mice with caloric burns. The addition of sodium lactate has markedly prolonged survival time in these animals. (Note 10) (Fig. 138) Still better effects upon traumatic conditions are obtained by associating butanol with glycerophosphoric acid in saline or in glucose saline solution. Especially effective and well tolerated is a solution containing 0.3-0.5 gm.% butanol with n/300 to n/200 glycerophosphoric acid and with 5% glucose in saline, used for intravenous infusions, as well as for subcutaneous clysis.

The administration of butanol in sufficient amounts to many patients having massive hemorrhages has clearly demonstrated that this substance has a hemostatic effect which will be discussed below.

After butanol studies, the effects of other aliphatic alcohols were investigated and revealed the importance of the nonpolar group in their biological activity.