We investigated some of the hormones that are often used clinically and found that the biological antagonism between male and female sex hormones is also apparent in their influence upon the s.d.c. pH, the male hormone having an alkalizing effect, the female hormone, an acidifying one. We must note here that the acidifying effect is also apparent for progesterol. This effect is opposite to that of the male hormone and similar to that of stilbestrol, contrary to what we expected. There is similar antagonism between desoxycorticosterol and suprarenin, the former being acidifying and the latter slightly alkalizing. The liver antianemic extract also has an alkalizing effect.

Several vitamins also were investigated. We were able to see that while vitamins B1, B2, E and K have an acidifying effect, vitamins A, D and B6 have an alkalizing action. Ascorbic acid seems to have no effect upon the s.d.c. pH.

A few alkaloids and glucosides, important for their pharmacodynamic activity, were studied. The two opium alkaloids and a similar synthetic agent are moderately acidifying. Atropine, caffeine, and quinine have a slight alkalizing effect. The different effects of digitaline and saponine were unexpected; both show slight but opposed action, the first acidifying and the second alkalizing.

Because of their effect upon the central nervous system, narcotics and hypnotics were studied. While ether and chloroform are slight alkalizing, the two barbiturates which we tested showed an acidifying effect. This is interesting, especially when related to the opium alkaloids and demerol which also induce acidification, although to a lesser extent than the barbiturates.

Various other agents were studied. Among pyretogenics and antipyretics, there is an obvious antagonism in influence upon the s.d.c. pH. While the pyretogenic, methylene blue, induces a frank acidification, the three antipyretics we examined produced alkalization. However, acetylsal icyclic acid does not follow this rule—it has an acidifying effect.

Among antimicrobial agents, a parallel action was apparent for the three antibiotics of fungal origin and the two sulfa drugs studied. All have an alkalizing effect, like the antipyretics. The acidifying effect noted for benzedrine does not accord with a similar effect observed for substances with hypnotic and sedative activity. This discordance between principal pharmacological activity and effect upon the s.d.c. pH indicates that the latter must, on many occasions, be considered to be due to a secondary influence exerted at the interstitial level.

The antagonistic biological activity of anti anemic liver extract and iron preparation, the former favorably influencing the hyperchromic anemias, the latter favorably influencing the hypochromic forms, is reflected in their opposite effect upon the s.d.c. pH. The anti anemic liver extract induces alkalization, while iron induces acidification. The same antagonism is seen with two agents having an opposite action on blood coagulation. While vitamin K induces acidification, dicumarol is alkalizing. Although rutin acts upon other factors when it intervenes in bleeding, it has the same effect as vitamin K on the s.d.c. pH.

Aminophyllin induces acidification in contrast to caffeine, which produces slight alkalization. On the other hand, procaine's effect is like that of the opium alkaloids and barbiturates, all inducing acidification. This can be related to the effect of higher alcohols which also have narcotic activity and, as seen above, also induce acidification.

Table XXVII shows the effects upon the s.d.c. pH of all of the substances examined.

Table XXVII. The Effect Of Various Substances Upon The S.D.C. Ph

Elevate

Reduce

No Effect

Vitamins......

A, D, B...........

B1, B2, K, E........

C

Hormones ....

Testosterone, Epinephrine

Stilbestrol

Progesterone,

Deoxycorticosterone

Alkaloids ....

Atropine, Quinine

Codeine, Morphine

Antibiotics ....

Penicillin,

Streptomycin,

Aureomycin

Sulfonamides ..

Sulfathiazole, Sulfamerazine

Antipyretics and analgesics

Acetophenetidin,

Aminopyrine

Antipyrine

Acetyl salicylic acid

Narcotics ....

Chloroform......

Phenobarbital, Pentobarbital

Anti anemics ..

Xanthines----

Miscellaneous ..

Liver extract......

Caffeine........

Dicoumerol, Benzene, Toluol, Saponin, Pteryl glutamic acid Teropterin)

Iron (reduced)

Aminophylline

Procaine,

Benadryl,

Coramine,

Glucose,

Glycerine,

Sodium gluconate,

Rutin,

Methylene blue, Mercuhydrin, Benzedrine, Demerol

Based upon the findings for such different groups of agents, the s.d.c. pH method appears to be an interesting tool for the study of pharmacological activity. We must emphasize that not one of these substances, at least in the dosage given, has had any influence in changing the pH of normal tissues from normal range, as indicated by pH values obtained immediately after wound production. As our research concerns only abnormal tissues, the s.d.c. pH is of use. However, in integrating the pH values into the general picture of the offbalances, it must not be forgotten that they represent changes in the interstitial fluids, which correspond to the secondary part of the tissue level.

Fig. 238. The effect of a growing transplanted Walker tumor on the s.d.c. pH determinations in surgical wounds produced serially on the day of transplant and every three days thereafter. A marked reduction in the s.d.c. pH was observed in all animals.

The effect of a growing transplanted Walker tumor on the s.d.c.

Physical Agents

Animals kept in an incubator at 38° C. showed a definite tendency toward a lowering of the s.d.c. pH. The effect of cold upon animals maintained in a refrigerator for forty eight hours before operation was less apparent.

Fig. 239. Serial s.d.c. pH changes in animals with transplanted tumors that regressed rapidly or failed to grow. A slight fall is seen to occur in the fourth and seventh post transplant day determinations, with a return to the control range in all the animals by the tenth day.

Serial s.d.c. pH changes in animals

Biological Factors

Transplanted Tumors. Preliminary studies regarding the effect of a transplanted Walker tumor upon the s.d.c. pH of an experimental wound have been carried out. Prior to transplantation, the control s.d.c. pH was determined for each animal. Tumors were then transplanted subcutaneously to the left flank region by the trocar method. After the tumor had been transplanted to the animals, experimental operative wounds were produced at intervals of three days and the serial s.d.c pH values on the fourth, seventh, tenth and thirteenth post transplant days determined. The pH values determined each time immediately after the wound was produced, did not differ from the values found in untreated controls. As in all other animals, the s.d.c. pH only showed significant changes.

The s.d.c. pH changes in two rats with growing Walker tumors

Fig. 240. The s.d.c. pH changes in two rats with growing Walker tumors (—-), from which the tumor was removed on the seventh post transplant day. Following the removal, the s.d.c. pH began to return towards the control range. A similar large incision was made in two animals without tumors and no effect was observed upon the s.d.c. pH in these animals (....).

Serial s.d.c. pH determinations in rats

Fig. 241. Serial s.d.c. pH determinations in rats without transplanted tumors. The serial small surgical procedures did not alter the s.d.c. pH from the control range.

Figure 238 illustrates graphically the changes in the s.d.c. pH in a group of twelve animals with successful tumor transplants. A steady and maintained lowering of the s.d.c. pH was observed in each animal, with a tendency for it to rise slightly in those animals surviving thirteen days.

In some of our animals the tumor has shown a tendency to regress spontaneously or fail to take. In six animals in which the tumor failed to take or underwent early regression and disappeared, the s.d.c. pH in the fourth and seventh post transplant day tests fell slightly, but thereafter returned to control levels. (Fig. 239)

When transplanted tumors that were growing well, were surgically removed following the second post transplant determination on the 7th day, the s.d.c. pH was seen to increase at the next test. (Fig. 240)

Surgical wounds. The same incision as for the removal of the tumors was produced in control animals, but the incision alone did not affect the s.d.c. pH. (Fig. 240)

In order to further control these experiments, repeated s.d.c. pH determinations were carried out upon wounds produced serially as in the tumor bearing animals. When no tumor was present the serial s.d.c. pH values did not vary from one examination to the next. (Fig. 241)

The serial small surgical procedures did not alter the s.d.c. pH from the control range.