It has been previously noted that hydroperoxides resulting from the oxidation of mono- and polyunsaturated fatty acids are found normally in the organism, but peroxides appear only under abnormal conditions and particularly when abnormal fatty acids intervene. The manifestations of the type D offbalance in its oxygen phase thus can be attributed to the presence of peroxides. Biologically, the intervention of peroxides would be counteracted by peroxidases and catalases. It was interesting to study a clinical curiosity which could be connected with a probable intervention of peroxidases.

In several patients with frequent headaches, whose analyses showed a typical acid pain pattern, pain was repeatedly intensified or even induced by eating pears. No other fruit had such effect; some had the opposite effect. This led us to consider that the pain intensifying action was not due to an acid base change. The large amount of peroxidases in pears led us to isolate this enzyme in order to study its direct influence upon pain. Peroxidase could be obtained from pears in relatively small amounts, and showed reduced activity upon peroxides even in vitro. We were able to prepare much larger quantities of a highly active peroxidase from horse radish.

After being purified and tested for antiperoxide activity, preparations were administered orally to patients with acid or alkaline pain pattern. While the former was definitely intensified, there was no relief of the latter. It seemed that the effects obtained through the administration of isolated pexoridases were the same as those obtained when pears were eaten.

Antioxidants

The relationship between fixation of oxygen and chlorides has led to the study of antioxidants capable of acting in situations of abnormal oxidation. It was hoped that these substances also would be able to influence the fixation of chloride ions.

We have utilized several groups of known antioxidants, starting with manganese compounds, such as inorganic salts, and later binding these to lipids. It is too early yet to draw any definite conclusions from animal experiments, and we have not used the compounds clinically. However, our studies up to now do not show any influence that could be interpreted as sufficient to warrant hope that these compounds can control the fixation of chlorides on fatty acids.

In the same series of researches, other antioxidants—some of them used for the preservation of edible fats and others for the control of oxidation in other substances such as rubber—were tried. We investigated the influence of tocopherols, the natural antioxidants for vegetable oils. Alpha tocopherol in doses of 100 mg. was administered several times a day to patients having symptoms and signs corresponding to an intervention of abnormal fatty acids. A decrease in the intensity of pain of an alkaline pattern was observed.

Along the same lines, we investigated the influence exerted by maleic acid, used to prevent the rancidity of edible fats. In proportion of 1 /10,000 this acid conserves these fats for months. Curiously enough, maleic and citraconic acid have shown an influence upon the abnormal manifestation of the type D.

For these reasons we utilized these two acids—maleic and citraconic— as anti D agents. In one study, the acids were injected intravenously in proportion of from 0.1 to 1 mgr./100 cc. of saline. In others, the sodium salts of the acid were used, while in still others the butyl esters were prepared and administered intramuscularly in oily solutions. For the present it is difficult to judge the effects obtained.

All the above mentioned attempts were made on the basis of a direct action upon fatty acids and other lipoidic constituents with negative polar groups which intervene in inducing offbalances. For the present, it seems that no single agent can resolve the problems that result from the plural intervention of various abnormal fatty acids at the different levels. The use of various agents acting selectively at the different levels involved seems to be the only available path by which therapeutic intervention against the multiple manifestations at different levels can be accomplished.

Before going further, we thought it useful to have a synoptic view of this special part of the pharmacological activity as obtained through the study of the influence upon pain and the systemic level analyses as seen in humans. To this we added the effect seen upon tumors in humans. Tables XX and XXI which give this information in a very condensed form, were limited to the most important agents tested for each group studied. The effects are indicated as clinical results also for the facility of the presentation.

Table XX. Clinical Results With Agents That Act Upon The Offbalance Type "A"

Group

Agent

Systemic Level

Pain

Influences Exerted Upon Tumor

Fatty Acids

Saturated

None

None

None

Polyunsaturated

Slight

Fair

Some, not consistent,

not persistent

Mixtures from organs

"

Good

" " "

" from cod liver

"

Fair

Fair, not consistent,

oil

not persistent

Irradiated

"

"

Conjugated

"

"

i"

a—OH

None

None

None

Polyhydroxy

Slight

Slight

None

Chloro derivatives

Fair

Fair

Some, not consistent,

not persistent

Oleic

Slight

None

None

A Idehydes

Crotonic

Slight

Slight

Slight, not consistent,

not persistent

Propionic

Good

Good

Fair

Heptylic

Good

Slight

Fair

Sulfur

Thiosulfates

Good

Good

Fair

Compounds

S. Colloidal

None

None

None

Mercaptans

Slight

Slight

Good, consistent,

persistent

Hydropersulfides

Fair

Fair

Fair, not consistent,

not persistent

Methyl thioglycolate

Slight

Fair

" " "

Tetrahydronaphtha-

Fair

Fair

Good, consistent

lene persulfides

and persistent

Selenium

Alkyldiselenide

Fair

Slight

Good, consistent,

Compounds

persistent

Perselenide

Fair

Good

" " "

Peracids

Perborate

Fair

Fair

Some, not consistent,

Perchlorate

not persistent

Hormones

Testosterone

Slight

None

Seldom, not consist-

ent, not persistent

Mustards

Sulfur mustard

Fair

Fair

Fair, "

Hydrines

Epichlorohydrin

Fair to good

Slight

Fair, consistent, persistent

Table XXI

Clinical Results With Agents That Act Upon The Offbalance Type "D"

Systemic

Influences Exerted

Group

Agent

Level

Pain

Upon Tumor

Sterols

Cholesterol

Fair

Fair

Seldom, not consist-

ent, not persistent

Insapon. fraction

of organs

"

"

of eggs

"

"

"

of milk

"

"

"

Alcohols

A liphatic saturated

"

Butanol

Good

Good

"

Pentanol

Fair

Fair

Fair, " "

Heptanol

"

Slight

Good, consistent, per-

sistent

Octanol

Slight

44

Fair, not consistent,

not persistent

Octanediol

"

"

Slight

Nonanol

None

None

None

Polyalcohol

Glycerol

Slight

Good

Good, consistent, per-

sistent

Inositol

None

None

None

Unsaturated

Oleic

Slight

Slight

None

Linoleic

"

None

Polyunsaturated

"

Fair

Slight, not consistent.

not persistent

Polyconjugated

"

"

Fair, " "

Crotonic

"

Slight

"

Ricinoleic

"

Fair

Slight, " "

Salicylic

Slight

Fair, " "

Hormones

Estrogens

"

I"

Slight, " "

Amines

Aminobutanol

"

Fair

"

Hexylamine

"

"

Heptylamine

Good

"

Fair, " "

Glucosamine

Good

Slight

None

Nicotinic

acid deriv.

Niketamide

"

Good

None

Metals

Iron

Fair

Slight

None

Mercury

None

Bismuth

"

"

Halogen

Iodine

Slight

Fair

"

Oxygen

None

Good

None