Chapter 6, Note 39. Lipids And Convulsions

The administration of insaponifiable fractions of placenta or organs sometimes produces no observable manifestations in rats and mice, except an exophthalmia. However, more profound changes occur, since injections of thiamine in doses otherwise harmless are followed by lethal convulsions in these animals. 80 to 100 milligrams of thiamine/100 gr. of body weight produce lethal convulsions in rats or mice who received 1 cc. of 5% insaponifiable fractions of placenta per 100 gr. of body weight in daily injections for a week. In controls, 150 milligrams of thiamine per 100 gr. of body weight were necessary to induce fatal convulsions.

High doses of insaponifiable fraction of organs alone, also produced convulsions. The injection twice a day of a 5% oily solution of insaponifiable fraction of placenta in doses of 2 cc./100gr. of body weight was seen to induce lethal convulsions after less than a week of treatment.

Chapter 6, Note 40. Lipoids And Coma

The administration of heptanol even in larger doses was not seen to induce somnolence or coma. Intravenous injection of a saline solution of 1 milligram of heptanol per cc. induced death in mice in doses above 0.5 cc. With 0.3 cc, the mice remained in deep sleep, sometimes with respiratory arrest. Most of the animals, however, recovered, starting to breathe in less than half a minute and awakening in about ten minutes. A dose as high as 10 cc. of the same solution, containing 10 milligrams, injected intravenously in rabbits, produced no more than a very short period of inactivity, without inducing sleep. Intramuscular doses as high as 500 milligrams of heptanol in oil in humans did not produce somnolence. However, after several days of concomitant administration of heptanol and cortisone, even in reduced amounts such as SO milligrams of heptanol and of cortisone daily, deep somnolence was seen to appear in some patients, and coma in two cases. In one, a man of 85, we were unable to overcome the coma. In the other, administration of cod liver oil fatty acids, sodium thiosulfate, and especially 1/2 cc. of DOCA (desoxycorticosterol acetate), brought the patient back to normal state.

Chapter 6, Note 41. Cardiac Rhythm

The antagonistic influence exerted by the two groups of lipoids was seen to have an especially interesting effect upon the cardiac cells. The importance for the pharmacological study of the lipoids, as well as for the cardiac physiology and pathology of the changes induced, has urged us to study them in more detail.

The principal physiological property of the cardiac cell is its automatism, that is, its capacity to produce the proper energetic influx which when discharged, will induce the contraction of the myofibrils. Through the cytoplasmatic bond formations characteristic of the myocardial cells, the discharged influx passes also into the nearby cells where it acts as an external incitation which, in turn, induces the discharge of the influxes produced by these cells. It is through this progressive discharge of contiguous cardiac cells that the contraction progresses in a centrifugal manner through the heart.

Each cell needs a definite time to "mature" its own influx, a negative period following each discharge. During this refractory period, the cell does not respond to any influx, either from nearby cells or from any external excitation. On the other hand, due to the same progressive maturation of its proper energetic influx, if within a certain time this influx incitation produced in the cell has not been discharged by an influx coming from a nearby cell, the cell itself discharges it. This automatism is common to all cardiac cells. It differs however, from one cell to another in the time necessary for the influx to mature, that is, in the time necessary to bring the cell out of its negative refractory period or to discharge its own influx, if not discharged by an external incitation to the cell. A cell has a high automatism if it has a short refractory period, if it rapidly produces its influx, and if it discharges it early. A cell has a low automatism if its negative period is long and if it requires a long time to discharge its own influx if not discharged by an influx coming from the nearby cells. The rhythm of the contractions of the entire heart will be given by the discharge time of the cells with the highest automatism.

If groups of cells have an abnormally low automatism and their negative period is so long that these cells will still be in the refractive negative period when the influx from nearby cells arrives to them, they will not be dis charged by this flux. If the group of cells represents a part of the heart through which the influx has to pass in order to attain the entire heart, it will block its propagation.

The normal cardiac physiology results from the inequality of the automatism of the different cardiac cells. Those with the highest automatism will represent the pacemaker for the entire heart contraction. Under normal conditions the cells of the sino auricular node show this highest automatism. Other cells with an automatism lower than that of the pacemaker, but still sufficiently high to be out of their refractive period, will respond when the influx started by the sino auricular node arrives to them. The automatism of the other centers present in the heart—Aschoff Tawara's node, Hiss's band, its branches, Purkinge's cells—progressively lower than that of the sino auricular node, will supply an influx if that of the sino auricular fails to reach them in due time.

Under abnormal conditions, this automatism is influenced. It can be either increased or decreased. In general, if the automatism of cells other than those of the sino auricular node, is increased above that corresponding to the rhythm of this node, their influx will be prematurely discharged. If the cells around it are out of their refractive period, this influx will propagate and induce a contraction. They appear as abnormal pacemaker centers due to their premature discharge and also to their ectopic position. The resulting contractions will be manifested as extrasystoles, if the abnormal discharge appears as an isolated event, or as paroxysmal tachycardia if the abnormality persists. In auricular fibrillation, this abnormality takes place in a larger group of cells. Oppositely, a lowered automatism affecting an entire group of cells will result in a blockage of the passage of the normal influx due to this lengthened negative period.

The factor which appears to govern the differences seen in automatism of the various centers in the heart, is the degree of differentiation of the respective cells. As a general rule, a less differentiated cell has a higher automatism, while a more differentiated cell has a lower automatism.

We have seen that up to a certain point, the properties related to the degree of the differentiation of these cells can be connected with youth characters. The changes seen in heart cellular physiology, and especially those which appear under abnormal conditions, can be conceived as taking place through changes in the degree of the differentiation of the cells. We have seen above, in the study of the influence exerted by lipids, that while the unsaponifiable fraction induces a "prolonged youth" with a degree of the dedifferentiation of the cells, the acid lipid fractions induce a process similar to a more rapid aging, respectively a more advanced differentiation. This effect was seen also to be general for the respective positive and negative lipoids. While for other cells such a change may be uneventful, for the cardiac cell it will be marked by a change in automatism.

From this specific point of view, we have studied the influence exerted by different agents upon the heart, seeking in the changes induced, modification corresponding to an increased or decreased automatism. Clinical observations have shown such correlation. Extrasystoles were seen to appear in subjects who had previous extrasystoles, when lipoids with positive polar groups were administered in high doses. They disappeared when the medication was stopped and reappeared when medication was resumed. In cases with previous auricular fibrillation we have seen it reappear with high doses of positive lipoids, disappear with cessation of the medication and reappear when medication was resumed for even a short time. This was fully controlled by the administration of lipoids with negative polar groups.

In hundreds of electrocardiograms taken of experimental animals, such a correlation between the administration of lipoids and induced arrhythmias was investigated in collaboration with I. Eroglu. We studied thus various substances, lipoids with positive or negative characters administered intraperitoneally or intraveneously in rabbits. An extremely high amount of the agent was necessary to influence the cardiac rhythm in normal animals. It was usually near a lethal dose and in general, proportionately many hundred times that used therapeutically in humans. In repeated injections however, changes could be induced with relatively smaller doses. In sufficient doses, the positive lipoids were seen to induce extrasystoles. Figures 292 and 293 show such changes obtained with huge doses of butanol and glycerol administered intravenously. (Page 714)

In animals, the negative lipoids induce a dromotropic negative effect, leading to auricular contractions not passing to the ventricles. Huge doses were seen to induce a bigeminated pulse.

The study of the intervention of lipoids has led to a new therapeutic approach. Extrasystoles, paroxysmal tachycardia and auricular fibrillation were seen to respond well to the administration of lipoacids and lipoids with negative polar groups, while partial blocks were influenced by lipoids with positive polar groups.