FOOTNOTES:
[76] Recherch. expériment. sur les mouvements des liquides dans les tubes de petits diamètres, Paris, 1828. Quoted from Hay.
[77] Über die Saftbewegung, 1848.
[78] L’Union médicale, 1871, 50, 51. Gaz méd. de Paris, 1879.
[79] Substances toxiques et médicamenteuses, 1857.
[80] Action of Medicines, 1867.
[81] Archiv. général d. médicine, VI Série f. XVI, 1870. Centralbl. f. d. medicin. Wiss., 1868, p. 209.
[82] Arch. f. exp. Path. u. Pharm., Bd. VIII, 1878, S. 355.
[83] Reichert’s u. DuBois-Reymond’s Archiv, 1870, S. 37.
[84] Pflüger’s Archiv, 1872, S. 266.
[85] Loc. cit.
[86] Arzneimittellehre, Leipzig, 1883.
[87] Amer. Journ. Physiol., 1898, Vol. I, p. 411.
[88] Loeb: Decennial Publications, University of Chicago, Vol. X, 1902, p. 10.
[89] MacCallum, J. B.: University of California Publications, Physiology, Vol. II, 1905, p. 65.
[90] MacCallum, J. B.: University of California Publications, Physiology, Vol. I, 1904, p. 115.
[91] MacCallum, J. B.: University of California Publications, Physiology, Vol. II, 1905, p. 93.
CHAPTER X.
Possible Therapeutic Value of These Experiments.
It at once suggests itself to the physician that some clinical use might be made of the facts outlined above. If such striking results can be obtained in a rabbit it is possible that some modifications of the use of these saline purgatives might be made in the human being.
If in the first place it is found that subcutaneous or intravenous injections of saline purgatives are effective in man, there arise in both medical and surgical practice occasions in which these methods of administration would be of the greatest advantage. It is to be remembered in this connection that the administration by these methods of MgSO4 is especially dangerous. This salt when rapidly absorbed seems to be very poisonous. Rabbits frequently die in a few minutes after an intravenous injection of a quantity relatively small as compared with the amount of Na2SO4 which can be given in this way. Barium chloride is extremely active as a subcutaneous purgative, but should be used with the greatest caution and in very minute quantities on account of its very poisonous character. I can give no idea of the dose that might be given to a human being without danger. A rabbit usually does not recover from a subcutaneous injection of 3 c.c. m/8 BaCl solution.
The fact that saline purgative solutions applied to the peritoneal surfaces of the intestine act very rapidly may suggest some use in abdominal surgery for this method. If it were desirable to have evacuation of the bowel rapidly follow an abdominal operation this procedure might be resorted to. An isotonic solution (m/6) of sodium sulphate or sodium citrate would be most favorable for this purpose.
The possible uses to which our knowledge of the action of calcium may be put has aroused some discussion. The fact that it suppresses muscular and nervous irritability (Loeb), and as shown in the experiments above, inhibits the muscular and glandular activity of the intestine, as well as the secretory activity of the kidney, makes it seem probable that some practical use may be made of it in certain conditions in the human being. The most important of these conditions is perhaps the persistent diarrhœa which sometimes accompanies disorders of an hysterical or neurasthenic sort. There have already come under my notice several cases of diarrhœa of nervous origin which were quite uncontrolled by morphine preparations. These cases were apparently entirely relieved by calcium chloride given for only a few days. (grs XX t.i.d.) Whether a large number of similar patients will show the same results remains to be seen. The treatment is evidently to be applied to only a small class of patients, roughly those cases of persistent diarrhœa of apparently nervous origin, which cannot be influenced by opiates.
When rectal infusions of NaCl are not retained it is possible by adding CaCl2 to the solution to stop the movements of the rectum which cause their expulsion. Enemata of NaCl containing CaCl2 are retained much better than those of pure NaCl.
The marked action of calcium on the kidney suggests that certain conditions might arise where it could be made use of. In nervous polyuria it can be given with benefit; and although we know practically nothing as to the etiology of diabetes insipidus, it is possible that calcium might be employed with advantage to stop the abnormal flow of urine.
With regard to general conditions such as the muscular and nervous irritability accompanying hysterical and neuraesthenic disturbances little can be said as to the possible value of calcium. Loeb drew attention to the possibilities of its being of use in these diseases, but there is not sufficient evidence to make any statement concerning it. The extreme irritability which is present in some types of insanity might also be tested in this respect.
Calcium might also be of benefit in asthma where the two distressing symptoms are spasmodic contractions of the bronchioles and a hypersecretion from the mucous membrane of the larger and smaller bronchi. Judging by analogy from the experiments described above, calcium should not only relieve the muscular contractions but also inhibit the secretion.
These suggestions are made simply in the hope of stimulating clinical research in this direction.
Wright has recently stated that calcium relieves urticaria, a circumstance which he refers to the influence of calcium on the coagulability of the blood, which he says is diminished in this condition. It seems more probable from the above experiments that the calcium inhibits the secretion or passage of fluid from the lymph vessels to form the vesicles.
CHAPTER XI.
The Action of Purgatives of Vegetable Origin.
This group of purgatives, as far as its general properties are concerned, is so well described in many text-books that it is unnecessary here to go into the details of their preparation and the commoner characteristics of each. Certain points which have come up in connection with my own experiments, however, may be briefly described here.
Cascara Sagrada is prepared in many ways, but the most favorable preparation for experiment is the dried extract. This is the dark yellow powder familiar in commerce. It is found that in shaking this powder in distilled water it is almost entirely insoluble. The result is a dirty yellow mixture, the filtrate from which gives an acid reaction. This suggested neutralizing the mixture or making it alkaline. A small amount of sodium bicarbonate was added, and the powder immediately went into solution, producing a clear dark brown fluid.[92] A similar result was obtained by adding sodium hydrate. It was found that ¹⁄₂ g. of the dried extract could be dissolved in 25 c.c. m/24 NaHCO3. This solution in NaHCO3, is practically neutral. If a few drops of dilute H2SO4 be added a yellow precipitate at once appears giving a mixture or suspension similar to that originally obtained by adding the powder to distilled water. The addition of NaHCO3 will again produce the characteristic dark brown solution. The extract is much more readily soluble in a stronger solution of NaHCO3.
The dried extract is thus soluble only in a neutral or alkaline fluid. It is insoluble in distilled water on account of the free acid which is present in the powder.
Cascara extract is readily soluble in the intestinal juice of a rabbit, a characteristic dark brown clear solution being obtained. On the other hand, it is insoluble in the gastric juice, and an alkaline solution added to the gastric juice is at once precipitated.
It was found that the intravenous injection of 1 c.c. of a 2% solution of cascara extract in m/25 NaHCO3 produces within a minute very strong peristaltic movements in the intestine. A similar injection of the same amount of m/25 NaHCO3 alone produces no such result, though stronger solutions of NaHCO3 cause a slight increase in intestinal movements. It is therefore the cascara in solution which produces these strong contractions.
A somewhat larger quantity of the cascara solution injected subcutaneously produces increased peristaltic activity after an interval of several minutes.
If the cascara solution be applied directly to the serous surfaces of the intestine, very strong contractions and peristaltic movements result in 2 or 3 minutes. A solution of m/25 NaHCO3 alone produces very slight movements when applied in this way. These can, however, be readily distinguished from those produced by cascara. The latter are much more powerful, are slower in developing, and can be only partially inhibited by m/6 CaCl2. The movements following the application of pure NaHCO3 solution, however, are weak, they appear almost immediately, and can be entirely suppressed by the application of m/6 CaCl2 solution.
When the cascara solution is placed in the stomach no movements appear in the intestine even after 15-30 minutes. The acid of the gastric juice has evidently precipitated the cascara, which cannot act until it is passed on into the intestine where it may be dissolved in the alkaline juice of the intestine. If instead of placing the solution in the stomach it is injected directly into the small intestine, increased peristaltic movements begin within 5 minutes. Here it evidently remains in solution and is absorbed. It is for this reason that in human beings cascara taken by mouth acts only after several hours. It is precipitated in the stomach and must reach the intestine before it is dissolved and absorbed.
In addition to the increased peristaltic activity caused by the cascara, there seems to be also an increase in the secretion of fluid into the lumen. One or two hours after the injection 20-30 c.c. fluid could be collected from the small intestine. Without the purgative it is rarely possible to obtain more than 5 to 10 c.c.
It was found that calcium chloride has only a very transient effect in inhibiting the increased movements produced by cascara. For 2 or 3 minutes following the injection of CaCl2 the movements were usually quieted, but they rapidly began again and continued as vigorously as before.
The behavior of rhubarb is in every way similar to that of cascara. It is less readily soluble, but the solution acts in a way quite like that described for cascara.
It is further well known that aloin injected subcutaneously causes increased peristalsis. A study has recently been made of certain constituents of the derivatives of the aloes group of purgatives. Esselmont,[93] following the work of Tschirch,[94] experimented with a number of substances obtained from these purgatives. Aloëemodin is present not only in aloes, but also in Cascara sagrada and senna leaves. A small amount of this substance acts as a purgative. Alochrysin, aloingrin, barbaloin, all act as purgatives. Chrysophanic acid, which is found in aloes, rhubarb, and senna is a mild purgative. It is of interest to note that each of these substances is either a di-or tri-oxymethylanthrachinon. They owe their purgative action, according to Tschirch, to their containing the oxymethylanthrachinon group.
Some experiments[95] which I recently made on a jellyfish (Polyorchis) with some of the vegetable purgatives are of interest. They were suggested by the experiments of Loeb[96] on the effect of various salts on the isolated center of the animal and of a related form (Gonionemus). When separated from the margins the bell-like centers of these jellyfish do not beat in pure sea-water. In case of Gonionemus it was found that the addition of one of a number of salts (calcium precipitants) caused the center to beat. This group of salts includes the so-called saline purgatives.
The methods used in the experiments with vegetable purgatives were practically the same as those used by Loeb. The animal was bisected just above the ring of sense organs in order to entirely remove the margin containing the main nervous system. The center was then placed in mixtures of sea-water and solutions of the purgatives. The center never beats in pure sea-water, but was found to beat vigorously in sea-water to which a small quantity of a solution of cascara, rhubarb, aloin, podophyllin, or colocynth had been added. It was necessary to dissolve the cascara and rhubarb extracts in m/24 NaHCO3, since they are not soluble in pure water. The centers do not beat in sea-water to which pure m/24 NaHCO3 has been added in quantities equivalent to those added with the purgative solution.
A solution of ¹⁄₄ g. cascara extract was made in 50 c.c. m/24 NaHCO3. It was found that a mixture of 25 c.c. sea-water + 2 c.c. of this cascara solution was the most favorable for producing rhythmical contractions in the isolated center of Polyorchis. Contractions lasted 10-15 minutes.
A solution of rhubarb extract of the same strength was made. The optimal mixture in this case is 25 c.c. sea-water + 0.5 c.c. or 1 c.c. rhubarb solution. In this mixture the contractions develop quickly and last 15 minutes or more.
With aloin the concentration of the purgative needed to produce optimal results was somewhat greater than in cascara or rhubarb. Colocynth and podophyllin act similarly, but the contractions soon cease.
These vegetable purgatives thus act on the jellyfish, Polyorchis, in a way quite similar to that described by Loeb for saline purgatives.
Pilocarpine, though not used as a purgative on account of its special action on other organs of the body, has a powerful action also on the intestine. Its influence on the intestine is much like that of barium chloride. It causes violent contractions of the musculature of the gut and very active peristaltic movements. This is the case in whatever way the substance is administered. A few drops of a ¹⁄₁₀% solution of pilocarpine hydrochlorate in distilled water poured on the serous surfaces of the rabbit’s intestine brings about almost immediately violent peristaltic movements. In addition to this there is an increase in the amount of fluid secreted into the intestine, 20-30 c.c. gathering in the small intestine in an hour. The evacuation of faeces takes place in about three-quarters of an hour. These may be of a semifluid character, and with larger doses resemble the faeces produced by BaCl2. The antagonism between pilocarpine and CaCl2 is incomplete. CaCl2 is capable of inhibiting only temporarily the movements caused by pilocarpine.
It is interesting to note the marked purgative effect of pilocarpine in a small fresh-water crustacean (Sida crystallina). This animal, which has been spoken of in previous chapters belongs to the Cladocera. The intestine extends in a fairly straight line throughout the body, bending downward at the post abdomen to open to the outside. At the anterior end is a slight dilatation which may represent the stomach. From this there open two diverticula or coeca which seem to be of a glandular nature, and are sometimes spoken of as digestive glands. They are usually filled with a greenish fluid. The intestine is always filled with brown faeces which are normally expelled in small quantities, only at considerable intervals. Slight peristaltic waves are commonly seen in the lower part of the intestine.
These animals were placed in various solutions, and it was found[97] that pilocarpine hydrochlorate, aloin, cascara, as well as barium chloride, sodium citrate, sulphate, and fluoride, caused an increased peristaltic activity of the intestine, and a rapid expulsion of faeces, so that in a very short time the entire intestine was empty. At the same time the intestine becomes filled with a greenish fluid similar to that seen in the diverticula. This fluid may be also expelled and replaced again. It is evidently secreted by the intestine or by the diverticula as a result of the purgative action. Very dilute solutions of pilocarpine are sufficient to bring about this effect. In a 1% solution the action is very rapid, and evacuation of faeces may be brought about by a mixture of 1 c.c. 0.1% pilocarpine in 10 c.c. water. This takes place within 20 minutes.
An attempt was made to determine whether or not CaCl2 is capable of inhibiting the action of pilocarpine. The experiments on rabbits in this respect were unsatisfactory. It was found that the greatest dilution at which expulsion of faeces in Sida could be caused in a short period of time was 1 c.c. 0.1% pilocarpine + 10 c.c. water. Animals were placed in a mixture of 1 c.c. 0.1% pilocarpine + 10 c.c. m/6 CaCl2. These behaved exactly as though the water had not been replaced by CaCl2. In other words, the presence of the CaCl2 did not delay at all the action of the pilocarpine. This was repeated many times, and it seems that in Sida at least the action of pilocarpine is not at all antagonized by calcium chloride. In a mixture, however, of 10 c.c. 1% atropin sulphate + 1 c.c. 0.1% pilocarpine no evacuation of faeces took place and there was no increase in peristalsis.