SO-CALLED SECRETIN PREPARATIONS
Report of the Council on Pharmacy and Chemistry
The Council authorized the following report for publication, and voted to endorse the work of Professor Carlson discussed therein.
W. A. Puckner, Secretary.
The Council has not accepted for inclusion in New and Nonofficial Remedies any preparations said to contain secretin or prosecretin as their active ingredient. A report giving the reasons for the rejection of one (the first of the so-called secretin preparations marketed) was published early last year;[29] an article on secretin, based on work undertaken at the request of the Council on Pharmacy and Chemistry, is now published.[30]
Lest the appearance of this detailed study of secretin, after the rejection of so-called secretin preparations, should be interpreted (as manufacturers whose products have been rejected have endeavored to interpret such action) as a case of first condemning a preparation and then getting the facts, the Council’s methods, and their application in this case, may be briefly stated. The Council maintains that, when a manufacturer places a product on the market, the burden of proof is on that manufacturer to show that the properties of his product are in accordance with his claims for it. As stated in the introduction to N. N. R., “it is ... manifestly impossible for the Council to investigate the composition of every complex pharmaceutical mixture, or to check thoroughly every therapeutic claim; it can give only an unbiased judgment on the available evidence.” Acting on this principle, the Council examined the claims made for Secretogen, an alleged secretin product manufactured by the G. W. Carnrick Company. The conclusion was that these claims were in absolute conflict with the available evidence as to the action of secretin.
It is not necessary to review this subject again. It will suffice to state that the claims made for Secretogen rest on two fundamental propositions: (1) that deficiency of secretin (or, rather, of prosecretin) in the intestinal mucosa is a factor in gastro-intestinal diseases; (2) that secretin given by the mouth is absorbed and produces increased secretion of the pancreatic and intestinal juices and of the bile.
From an examination of the evidence available, including that submitted by the manufacturers, the Council concluded: “1. No evidence has been presented that the absence of secretin is a cause of gastro-intestinal disease. 2. There is no evidence that secretin in any form is physiologically active when administered by mouth.” That these conclusions were justified is shown again by the review given by Carlson of the literature, much of which was also reviewed in the Council’s previous report.
Since the claims of the Carnrick Company were not supported by any satisfactory evidence, no further investigation on the Council’s part was necessary to warrant rejection of the product. The Council did not undertake to determine, for instance, whether or not Secretogen and similar products actually contain secretin; the determination of this point was immaterial here, in view of the conclusiveness of the evidence that secretin given by mouth has no physiologic action.
Since firms other than the G. W. Carnrick Company are manufacturing alleged secretin preparations, and since recommendations for the use of secretin preparations in gastro-intestinal diseases have even crept into textbooks, it seemed desirable to obtain further information on certain points. The Council therefore requested Prof. A. J. Carlson of the University of Chicago to check the results of previous investigators with regard to the action of secretin administered by mouth or directly into the intestine, and, in addition, to investigate the secretin content of certain alleged secretin preparations.
Carlson and his co-workers, like all previous investigators, found that secretin given by mouth, or introduced even in enormous doses directly into the intestine, is entirely inactive. They also found that marked destruction of secretin followed contact for one minute with human gastric juice and that secretin is rapidly oxidized and rendered inert in contact with the air.
Further, they were unable to demonstrate the presence of secretin in samples of Secretogen and another supposed secretin preparation (Duodenin) bought on the open market. In the case of Secretogen there was one exception: one bottle was found which contained a little secretin, but it was necessary to administer (by intravenous injection, of course) the entire contents of the bottle (100 tablets) to obtain “a small but unmistakable secretin reaction.”
In these studies the methods employed were those by which secretin was discovered. It is only by the use of such methods that the presence or absence of secretin can be determined. Apparently the manufacturers who place so-called secretin preparations on the market do not make use of these methods, by which alone even the composition of their products can be determined.
Carlson and his collaborators conclude:
“There is as yet no reliable evidence that lack of secretin is a primary or important factor in any disease. Even should this be established, secretin therapy, to be effective, must be intravenous. Secretin has not yet been prepared in sufficiently pure state to render possible intravenous injection in man without injurious effects. And even when this is attained, the very fleeting action of secretin will in all probability render secretin therapy as futile in all the diseases in which it is theoretically indicated as epinephrin therapy is in Addison’s disease.”
In short, secretin is as ineffective taken by mouth as it would be rubbed on the skin.
The referee recommends that the work of Professor Carlson be endorsed.—(From The Journal A. M. A., Jan. 15, 1916.)
HAS SECRETIN A THERAPEUTIC VALUE? [B][C]
A. J. Carlson, Ph.D., J. E. Lebensohn, M.S., and S. J. Pearlman, B.S.
Chicago
It is well established that acid chyme in the duodenum is the normal stimulus to the secretion of pancreatic juice.[31] Interaction of the acid with the duodenal mucosa liberates into the blood stream a substance which, circulating through the pancreas, excites the latter to activity. This exciting substance has been termed “secretin.” It can be prepared artificially by macerating duodenojejunal mucosa in 0.4 per cent. hydrochloric acid, neutralizing the boiling mixture, and filtering. A few cubic centimeters of the filtrate injected into a vein produce invariably a powerful secretion of pancreatic juice.[32] That a “chemical messenger” is at the basis of the duodenal acid reflex has been proved by even more crucial experiments—transfusion (Wertheimer,[33] Enriquez and Hallion[34]), cross circulation (Fleig,[35] Matuso[36]), and perfusion of the isolated pancreas (Huston[37]).
PROPERTIES OF SECRETIN
Prosecretin.—Secretin is soluble in water, yet a watery extract of intestinal scrapings is without action,[32] even after being submitted to acid treatment.[38] Starling therefore holds that secretin exists in the intestinal mucosa in an inactive form, as “prosecretin.” The content of the intestine in prosecretin decreases from the duodenum down, so that one is unable to demonstrate any prosecretin in the last 21⁄2 feet of the ileum. Prosecretin is insoluble in water, acetone, absolute alcohol or ether. Secretin, on the other hand, is readily soluble in water, normal salt solution and diluted alcohol (70 per cent.), but likewise insoluble in absolute alcohol and ether.
Preparation.—All of the more dissociated acids liberate secretin from intestinal mucosa on boiling. Their action is dependent on the degree of dissociation,[39] carbonic and boric acids being inactive.[40] Secretin can also be prepared with strong soaps (from 10 to 30 per cent. sodium oleate), alcohol (70 per cent.,[41] 0.6 per cent. sodium chlorid[36]). The acid and soap in the duodenum produce secretion; there is no necessary correspondence between the action of a substance in the intestine and that obtained by injection after boiling mucosa with it. The sodium chlorid, bile, maltose and glucose produce some secretion by the latter method yet none by the former.[36] On the other hand, ether, chloral and oil of mustard excite secretion when in the intestine, but no secretin can be prepared from boiled mucosa by their action. The irritation of the lining cell has produced the necessary hydrolysis.[38] In well-controlled experiments, Wertheimer and LePage[42] found that after the introduction of acid, secretion is secreted into the lumen of the intestine. Matuso[36] confirmed their results, and found this a satisfactory method for the preparation of secretin. It is said that secretin can be obtained by merely boiling the mucosa with water, but the results are inconstant.[43]
Action.—Secretin is an excitant not only of the pancreatic juice but also of the liver and the intestinal mucosa. The flow of bile is markedly accelerated (Henri and Portier,[44] Enriquez and Hallion[45]), likewise that of succus entericus (Delezenne and Frouin,[46] Bottazzi and Gabrielli[47]), and intestinal peristalsis is stimulated (Enriquez and Hallion,[48] Falloise[49]). Injections of secretin produce a marked vasodilatation, but the secretory effect is independent of the blood pressure changes. The pancreas is not readily fatigued by secretin. Bayliss and Starling[50] have obtained undiminished flow after eight hours of continuous injection. Our experience confirms this result. Also, equal doses of secretin give corresponding results at various intervals. Moreover, anesthesia does not affect the flow. Secretin is unrecoverable from the glands even after two hours of continuous injection.[51] The juice obtained by secretin has been subject to many studies.[52] It is of high alkalinity (about seventh normal), contains all the pancreatic ferments, and corresponds in all respects to the juice obtained in digestion from permanent pancreatic fistulas.[53]
Specificity.—In a maceration of the duodenojejunal mucosa, such as we have in secretin, the known substances are proteoses and peptones, acid amins, bile salts, beta-imidazolethylamin, cholin, gelatin and inorganic salts. These substances, individually and severally, together with their derivatives, are devoid of secretory action. Chemically, secretin, is then a specific entity. But like epinephrin, in its distribution, it is nonspecific. Active preparations have been made from an extraordinary variety of animals among the different classes of vertebrates (Camus,[54] Bayliss and Starling,[55] Chapman[56]). It is likewise found in the new-born and in the fetus.[57] Its action, however, like its chemical composition, is markedly specific. It stimulates the flow of pancreatic juice, bile and succus entericus. Its effect on the gastric glands is negative, and on the saliva likewise.[58] On the other hand, no other extracts produce pancreatic secretion. Dr. Koch, who, in collaboration with Dr. Keeton and Dr. Luckhardt, has done the most recent work on gastrin[59] (a substance that most nearly resembles secretin) and has isolated an extremely active preparation, finds that gastrin injection has likewise no effect on the pancreas. Camus and Gley,[60] with crude preparations, had previously obtained a similar result.
Lability.—Neutral secretin is but feebly attacked by a temperature of 100 C. If heated in an autoclave (so as to prevent oxidation), this temperature can be continued for thirty minutes without any change in its activity. Increasing the temperature increases the speed of destruction, so that at 140 C. the destructive action is marked.[61] Autoclaving at 15 pounds for fifteen minutes, as an ordinary sterilization of culture mediums, produces, we found, a distinct though not serious decrease in activity. Secretin acidified to fifth-normal with hydrochloric acid loses 60 per cent. of its activity on fifteen minutes boiling. Secretin, alkalinized to fifth-normal with sodium hydroxid loses 95 per cent. of its activity in five minutes’ boiling; decreases to a trace in thirty minutes, and disappears entirely in sixty minutes. At room temperature, with fifth-normal alkalinity, 80 per cent. of secretin is destroyed in eight hours.[61] The destruction probably means a secondary cleavage of the secretin molecule itself.
Secretin is oxidized readily. If left standing uncovered for a summer’s day, the preparation will be inactive.[51] Even if kept in the ice-chest (no other precaution being taken), its activity is lost in a very few days. Sunlight undoubtedly hastens the oxidative process. If care is taken as to sterility, however, and the secretin is kept in the ice-chest, well stoppered and in a dark flask, it will retain its activity for several weeks.
Dixon and Hamill[51] claimed that secretin disappears quantitatively on passage through a Berkefeld filter at 5 mm. pressure. Lalou,[62] using higher pressure, was unable to confirm the finding, but obtained a marked decrease in activity. Our results are in accord with those of Lalou.
Analogy to Epinephrin.—The analogy of secretin to epinephrin does not generally receive enough emphasis. Both substances are nonspecific in distribution, but specific chemically, and especially physiologically, epinephrin acting on the myoneural junctions, secretin on intestinal digestion. They are both relatively simple substances of low molecular weight, and subject to rapid oxidation whereby their properties disappear. The action in both cases is very transient. They are the two examples of what Starling calls the “acute hormones,” in which it is essential that reaction take place immediately, and shall disappear as soon as the exciting cause is removed.[63]
CLINICAL USE OF SECRETIN
Diabetes Mellitus.—Moore, Edie and Abram[64] were the first to suggest a therapeutic value for secretin, having obtained favorable results with secretin administration in diabetes. They argued that the internal secretion of the pancreas may be stimulated by secretin, and that some cases of diabetes may be due to lack of this necessary excitant. Owing to the importance of the question, their announcement was followed quickly by numerous investigations by other observers. Previously, Spriggs, at the suggestion of Starling, had tried intravenous injections of secretin free from depressor substance in a diabetic patient, and had obtained negative results. Moore, Edie and Abram gave their secretin by mouth over long periods. Of the five cases cited in their first paper, two were negative. The third was that of a man, aged 25, who received daily 30 c.c. of secretin. After a latent period of three weeks, the sugar suddenly fell, and after four months the urine was sugar-free. Six months later a relapse occurred with the development of phthisis and death. The other two patients were a boy, aged 7, and a girl, aged 9, whose urine in from three to five weeks became sugar free during the secretin treatment in spite of severe diabetes. One of these patients later relapsed.[65] Bainbridge and Beddard[66] gave secretin a thorough trial in three cases with negative results, and are disposed to attribute the results of Moore to dieting. Dakin and Ransom[67] cited one case, secretin being given for twelve weeks, with negative results; Foster,[65] nine cases, all negative; Charles,[68] three cases, all negative. Crofton,[69] however, gave secretin a trial in one case with favorable results. Moore, Edie and Abram, in a later paper,[70] report a large number of cases tried with the majority of results negative, though in some cases an improvement in the digestion, and in certain cases an increase of weight was noted.
One method of testing the basis of Moore’s theory would be by examining the prosecretin content of the intestine in diabetics. Bainbridge and Beddard found, in the paper referred to,[66] that from five of the six cases of diabetics examined postmortem, little or no secretin could be prepared; but in a subsequent report of seven cases,[71] they found only one in which the secretin obtained was scanty. The failure to obtain secretin in some cases they claim is probably due to the rapid postmortem degeneration of diabetic tissue. Evans,[72] in Starling’s laboratory, found that in dogs made recently diabetic by total pancreatectomy, but little secretin could be obtained. Hedon and Lisbonne,[73] and Pemberton and Sweet[74] report, on the contrary, that the duodenum of diabetic dogs is rich in prosecretin. Bainbridge and Beddard,[71] working on a diabetic cat, likewise found prosecretin to be present in normal quantity.
Digestive Disturbances.—Secretin for digestive disturbance was first used in the “acid duodenal medication” of Enriquez.[75] This consisted in the giving of tartaric acid in thick keratin capsules, the acid not being liberated until the duodenum was reached, where it provoked the formation of secretin. “The secretin mechanism,” he says, “is probably capable of pathologic disturbance as would result, for example, with diminished acidity of chyme, disturbance of the normal motility of the stomach or pylorus, or diminished prosecretin in the mucosa. Such a condition would produce disturbance of the pancreatic, biliary and intestinal secretions, and interfere with intestinal movements, with a clinical syndrome of intestinal dyspepsia as a result, among the chief and most constant symptoms of which would be constipation.” “The acid duodenal medication” was submitted to wide clinical use, and very favorable results in certain obstinate cases of constipation were reported. In regard to “diminished prosecretin in the mucosa,” Wentworth[76] has claimed that in infantile atrophy such is the condition, but Sweet and Pemberton[77] have found that the difficulty of preparing secretin from human duodenums is such as to render Wentworth’s findings inconclusive.
Beveridge[78] suggests the use of secretin in (a) pyloric stenosis, (b) pancreatic insufficiency, (c) hepatic stimulation and cirrhosis of the liver (d) to stimulate peristalsis in colonic stasis, (e) in gastro-enterostomy and short-circuiting of the intestines. He claims to have used it in over a hundred cases with “brilliant results,” and cites four typical histories. The G. W. Carnrick Company, which manufactures “Secretogen,” an alleged secretin preparation, cites a number of authorities[79] as also recommending secretin for digestive disorders. Harrower, who is or was connected with the Carnrick Company, in clinical journals[80] has ardently advocated the use of secretin for a large number of maladies.
PHYSIOLOGIC CONSIDERATIONS
Throughout its clinical use, secretin has been given by mouth; but its direct introduction into the intestine of a dog under anesthesia in even enormous quantities is without effect. This fact, first observed by Bayliss and Starling,[32] was confirmed by Fleig,[81] and Matuso,[36] and our personal experiments have convinced us of its truth. Matuso found that ordinary secretin and that obtained from intestinal lumen gave equally negative results. Large quantities of active secretin, moreover, acidified to 0.2 per cent. hydrochloric acid, and left in the ileum for fifteen minutes, were still negative. Wertheimer and Duvillier,[82] in a previous paper on this subject, had likewise found that acid solutions of secretin (which might be considered more normal for the intestine than when neutral), when introduced into the ileum gave negative or inconstant results. They conclude that it is more likely that the pancreas does not respond to such minimal stimuli, than that the secretin is not absorbed.
The destructive action of the digestive enzymes leads us to believe that it is in inactive form that secretin is absorbed. Like epinephrin, it cannot pass through the digestive tract. Bayliss and Starling state that it is destroyed by one hour’s tryptic digestion. Lalou[62] worked with the action on secretin of pepsin, dog’s gastric juice, pancreatic juice, succus entericus and erepsin, and found in each case a destructive effect, even almost after mixing; and after five minutes over 75 per cent. of the activity had disappeared. Matuso[36] introduced 30 c.c. of active secretin into the intestine, removed it five minutes later, and found that no activity remained.
Other methods of administration have been tried. Subcutaneous injections are practically negative (Matuso,[36] Hallion[83]) and intrapleural injections are likewise negligible (Bayliss and Starling[55]).
Starling[63] finds that continued intravenous injections of secretin in a healthy dog produces after a time severe symptoms of collapse, which, he believes, are due to change in the intestinal mucous membrane caused by the entry and non-neutralization of the strongly alkaline pancreatic juice.
Intestinal digestion seems little affected in achylia gastrica (Stockton,[84] Ehrman and Lederer,[85] Bayliss and Starling[32]). This may be due to other secretin stimulants as fats, or to the action of the nervous mechanisms (Meltzer[86]).
THE DESTRUCTION OF SECRETIN BY HUMAN GASTRIC JUICE
We have carried out in detail experiments on the digestive effect of human gastric juice on secretin. Our results in every respect confirm the findings of Lalou,[62] who worked with commercial pepsin and dog’s gastric juice, but are even more striking because of the much superior quality of pure human gastric juice.
Methods.—The human gastric juice was obtained from Mr. V., the gastric fistula case of our laboratory. The chemical and digestive characters of his juice are discussed in a recent paper.[87] In the different experiments, different samples of gastric juice were used. The secretin employed was always freshly prepared. Digestion was carried out in the incubator at 38 C. with the reaction of 0.4 per cent. acid, and the end of the period was marked by either boiling the mixture or (in the first two experiments) by turning the mixture alkaline. The action of the preparation, we proved, was not influenced by the method used. The dogs on which the preparations were tested were prepared for carotid blood pressure, injection into the external jugular vein, and cannula in the pancreatic duct, essentially the methods of Bayliss and Starling[32] being employed. The preparations were injected at body temperature after being neutralized and filtered. Except for the addition of normal salt solution instead of gastric juice, the control injections of secretin were submitted to exactly the same treatment as the other preparations.
Results.—Our results are embodied in Table 1. We assured ourselves before beginning the series that incubation of secretin with boiled gastric juice produced no change. It is to be noted in the table that each experiment is a unit complete in itself, beginning and ending with a control injection of secretin. Special attention is called to the marked destruction that follows contact of human gastric juice with secretin for merely one minute. In Experiment 4, using 1 c.c. of human gastric juice, the action fell to 14 drops from an original secretion of 21; in Experiment 5, using 8 c.c. of gastric juice, the action fell to 6 drops from an original secretion of 20. Of interest also is the rate at which we get complete destruction of secretin. This is practically 2 hours for 2 c.c. with secretin giving originally 110 drops (Experiment 2, Fig. 1), or 30 minutes for 5 c.c. with a secretin giving originally 53 drops (Experiment 6). These results are practically parallel, though they were obtained with different samples of gastric juice and in different experiments.
TABLE 1.—THE DESTRUCTION OF SECRETIN BY HUMAN GASTRIC JUICE
| No. of Experiment | Quantity of Gastric Juice Used, C.c. | Secretion of Pancreatic Juice in Drops | |||||||
| 10 C.c. Secretin Control —Beginning Experiment | The Secretin After Incubation with Human Gastric Juice | 10 C.c. Secretin Control —End of Experiment | |||||||
| Dig. Time, Hours | Secretion Rate | Dig. Time, Hours | Secretion Rate | Dig. Time, Hours | Secretion Rate | ||||
| 1 | 2 | 28 | 6 | 0 | 4 | 0 | 2 | 0 | 16 |
| 2 | 2 | 110 | 2 | 7 | 11⁄2 | 18 | 1 | 18 | 41 |
| 3 | 2 | 40 | 1 | 7 | 3⁄4 | 7 | 1⁄4 | 8 | 31 |
| 4 | 1 | 21 | 1⁄2 | 11 | 1⁄4 | 12 | 1⁄60 | 14 | 18 |
| 5 | 8 | 20 | 1⁄2 | 1 | 1⁄4 | 3 | 1⁄60 | 6 | 18 |
| 6 | 5 | 53 | 1⁄2 | 2 | .. | .. | .. | .. | .. |
We also tried the effect of keeping the digestive time constant and varying the amount of gastric juice employed. Increasing the quantity of gastric juice used increases the quantity of secretin destroyed (Table 2).
TABLE 2.—EXPERIMENT 7*
| Preparation | Pancreatic Juice Drops |
| 10 c.c. secretin | 20 |
| 10 c.c. secretin digested with 0.5 c.c. gastric juice | 15 |
| 10 c.c. secretin digested with 3 c.c. gastric juice | 13 |
| 10 c.c. secretin digested with 10 c.c. gastric juice | 8 |
* The digestive time was kept constant at fifteen minutes. (The gastric juice used had been diluted with stomach washings.)
The reader will observe in Table 1 that the results obtained from the control injection of secretin at the beginning of the experiment is uniformly greater than that obtained after several injections of digested secretin.
In view of the established fact that equal quantities of secretin can generally be relied on to produce results,[62] one might suggest that the injections of the split products of secretin have inhibited to some degree the action of the pancreas. We can submit the data in Table 3 in support of this view, showing among other things that the action of secretin is not influenced by previous injections of inert depressor substances, though it by the injection of the cleavage products of secretin. (The various injections in the experiments were made at about fifteen-minute intervals).
We have carefully analyzed the reaction in blood pressure that follows the injection of the various preparations. We find no constant effect. Digested secretin gives a fall in blood pressure that is at times less, at times equal, and at other times greater (Fig. 1) than that produced by the original preparation.
Besides the bearing that it has on the therapeutic use of secretin, this destructive action of the digestive enzymes is also of prime physiologic interest. Failure to realize it has led to misconceptions as to the intrinsic nature of secretin.
TABLE 3.—EXPERIMENTS 8 AND 9
| Preparation | Pancreatic Juice Drops |
| Experiment 8: | |
10 c.c. secretin, five injections of inert depressor substances | 29 |
10 c.c. secretin, two injections of completely digested secretin | 28 |
10 c.c. secretin, eight injections of inert depressor substances | 16 |
10 c.c. secretin | 16 |
| Experiment 9: | |
10 c.c. secretin (control, beginning of experiment) | 21 |
| 10 c.c. secretin, after thirty minutes incubation with 1 c.c. | |
boiled gastric juice | 27 |
| 10 c.c. secretin, after thirty minutes incubation with 1 c.c. | |
fresh gastric juice | 11 |
10 c.c. secretin (control, end of experiment) | 18 |
The findings of Lalou, confirmed by us, explain the anomaly that has led Delezenne[88] to put forward the antisecretin theory.
SECRETIN HAS NO ACTION WHEN GIVEN BY MOUTH
It is a constant claim that so many and complex are the factors concerned in physiologic processes, that it is not unusual for clinical deductions to establish themselves in the face of a priori laboratory dicta. We considered it desirable, therefore, to test the action of secretin, orally administered, in the most direct manner, and the one freest from possible criticism. With this in view, we performed a series of experiments on normal unanesthetized dogs having permanent pancreatic fistulas.
Method.—In the operations for permanent pancreatic fistulas we followed closely the technic developed by Pawlow,[89] and with excellent results. The dogs maintain themselves in splendid condition if proper care is taken. This consists in feeding them only with bread and milk, and giving sodium bicarbonate daily. The dogs were given this treatment in the evening so that experimental procedure might be carried on in the day with empty stomach under constant conditions. Freshly prepared secretin in large quantities was given by stomach tube to these dogs, and the response of the pancreas studied and compared with the response obtained from control preparations. The same preparation was generally not given on consecutive days.
TABLE 4.—DETAIL OF TYPICAL EXPERIMENTS
Dogs with pancreatic fistulas, showing that secretin given by mouth has no action on the pancreas
| Material Fed by Stomach Tube | Rate of Secretion of Pancreatic Juice in C.c. per Hr. | |||||
| Continuous Secretion Before Feeding | Continuous Secretion After Feeding | |||||
| First Hour | Second Hour | Third Hour | First Hour | Second Hour | Third Hour | |
150 c.c. active secretin, slightly acid | 6.5 | 3.6 | 3.9 | 20.0 | 6.0 | 8.0 |
150 c.c. active secretin, slightly alkaline | 13.0 | 11.0 | 5.0 | 23.0 | 26.0 | 12.0 |
150 c.c. secretin passed through Berkefeld | 7.8 | 7.5 | 7.4 | 23.0 | 13.0 | 11.0 |
150 c.c. extract of colon | 11.6 | 12.0 | 11.4 | 30.0 | 19.6 | 14.8 |
150 c.c. extract of gastric mucosa | 10.0 | 7.0 | 8.0 | 23.0 | 7.5 | 4.0 |
150 c.c. extract of muscle | 6.9 | 11.0 | 6.4 | 35.0 | 5.0 | 7.0 |
150 c.c. 0.4% HCl (diluted to 250 c.c.) | 6.0 | 8.0 | 4.0 | 33.0 | 36.0 | 17.0 |
Results.—We have data from six dogs with a total of seventy-six experiments. As shown in Table 4, the administration of secretin causes an increase in the flow of pancreatic juice, but the administration of inert substances as extracts of colon, gastric mucosa or muscle causes a like increase. The activity of the secretin may be reduced to a low value by exposure to sunlight, or filtering through a Berkefeld filter, yet the response of the pancreas is not correspondingly reduced. The secretion that occurs in the control cases, every one will admit, is but secondary to the production of gastric juice with its accompanying hydrochloric acid, that is, excited by virtue of the extractives and water in the preparations. Such, we can prove, is the only action of secretin. A mixture of gelatin, peptone and salt water, the chief incidental constituents of a secretin preparation, gives as striking results as ever obtained from secretin administration. Yet the objection may be made that the response of the pancreas that is due to the incidental constituents of secretin is maximal, and that the secretin consequently has no opportunity to display its particular potency. But, as inspection of the accompanying tables illustrate, the administration of hydrochloric acid shows that the response is by no means maximal. Let us cite a striking experiment. For three hours before the administration of hydrochloric acid, the secretion in cubic centimeters was respectively 29.4, 11.75 and 35.4 c.c.; for the three hours after, respectively 88.0, 49.0 and 40.5 c.c.
Fig. 1.—Tracings (reduced two-thirds) showing failure of Secretogen, Elixir Secretogen, and Duodenin to stimulate the flow of pancreatic juice even when administered intravenously in amounts three times greater than that recommended to be given by mouth. Dog: light ether anesthesia; cannula in the pancreatic duct; a, carotid blood pressure; b, flow of pancreatic juice in drops; c, signal showing where the intravenous injections were made. Tracing A: Reading from left to right, the five intravenous injections are: (1) three tablets of Secretogen digested with 15 c.c. 0.4 per cent. hydrochloric acid and neutralized; (2) three tablets of Secretogen boiled in 15 c.c. 0.4 per cent. hydrochloric acid and neutralized; (3) three tablets of Secretogen in 15 c.c. 0.9 per cent. sodium chlorid; (4) three tablets of Secretogen in 15 c.c. of 70 per cent. alcohol; (5) 15 c.c. Elixir Secretogen. Tracing B: reading from left to right, the four intravenous injections are: (1) 5 c.c. secretin made fresh from dog’s duodenal mucosa; (2) three tablets of Duodenin digested in 15 c.c. 0.4 per cent. hydrochloric acid and neutralized; (3) three tablets of Duodenin boiled in 15 c.c. 0.4 per cent. hydrochloric acid and neutralized; (4) three tablets of Duodenin in 15 c.c. sodium chlorid (0.9 per cent.).
TABLE 5.—SUMMARY OF EXPERIMENTS
Dogs with pancreatic fistula, weight 14 kg. Secretin given by mouth
| No. of Experiment | Material Fed | Rate of Secretion of Pancreatic Juice in C.c. Per Hour | Increase in C.c. | |
| Three Hours Before Feeding | Three Hours After Feeding | |||
| 3 | Secretin slightly acid | 5 | 11 | 6 |
| 5 | Secretin slightly alkaline | 24 | 30 | 6 |
| 4 | Secretin passed through Berkefeld | 18 | 23 | 5 |
| 1 | Secretin exposed to sun for 4 hrs | 16 | 29 | 13 |
| 2 | Extract of colon (rabbit) | 19 | 29 | 10 |
| 3 | Extract of gastric mucosa | 14 | 23 | 9 |
| 3 | Extract of muscle | 8 | 16 | 8 |
| 2 | Mixture of gelatin, peptone and salt | 23 | 33 | 10 |
| 1 | 1 per cent. peptone solution | 6 | 8 | 2 |
| 4 | 0.2 per cent. hydrochloric acid | 13 | 37 | 24 |
| 3 | Milk and bread | 7 | 20 | 13 |
It is possible by large doses of sodium bicarbonate given shortly before the administration of a preparation so to depress the stomach that it does not respond with the usual production of hydrochloric acid. Under these conditions the administration of secretin is uniformly negative, but the administration of hydrochloric acid on the contrary still serves to increase the pancreatic secretion (Table 6).
TABLE 6.—SECRETIN IN EXPERIMENTAL “ACHYLIA GASTRICA”
| Exp. No. | Material Fed | Rate of Secretion of Pancreatic Juice in C.c. Per Hour | |||||||
| Continuous Secretion Before Feeding* | Secretion After Feeding | ||||||||
| First | Second | Third | First | Second | Third | ||||
| 1 |  | 150 c.c. secretin |  | 8.7 | 7.5 | 6.8 | 3.0 | 1.0 | 4.8 |
| 2 | 4.5 | 6.5 | 10.0 | 6.0 | 7.5 | 7.6 | |||
| 3 | 15.6 | 8.1 | 16.0 | 3.9 | 4.9 | 2.9 | |||
| 1 |  | 150 c.c. 4% HCl (diluted to 250 c.c.) |  | 9.8 | 7.0 | 6.0 | 65.1 | 28.0 | 7.1 |
| 2 | 17.4 | 18.5 | 17.0 | 34.0 | 18.0 | 20.0 | |||
* Five gm. Na HCO3 given at beginning of each first two hours.
COMMERCIAL PREPARATIONS OF SECRETIN
Secretogen and Elixir Secretogen.—The Carnrick Company offers Secretogen[90] for use in a large number of conditions. The following indications for the use of the preparation purport to be based on clinical tests covering a period of several years: dyspepsia, and the indigestions generally, fermentative disorders, gastric catarrh, flatulence, nausea; pancreatic insufficiency, intestinal indigestion; gastric secretory deficiencies, apepsia; constipation and hepatic torpor; intestinal stasis; diarrhea; infantile diarrhea, “summer complaint,” marasmus, inanition and malnutrition; gastric atony and dilatation; cholecystitis and gallstones; nephritis, neurasthenia, cachexia and cancer; epilepsy and high blood pressure. Testimonials are presented as to results in most of these conditions.
A quantity of “Secretogen” and “Elixir Secretogen” was bought in the open market, and the preparations were tested on suitably prepared dogs. The tablets were ground, thoroughly macerated with the solvent used (water, normal salt solution, alcohol, or 0.4 per cent. hydrochloric acid), and filtered. If hydrochloric acid was used, the pulverized tablets were boiled with it, in the manner that secretin is made from duodenal mucosa, and the preparations neutralized previous to injection. The injections were made in from 15 to 20 c.c. of the solvent. All the operations were carried on immediately before the experiment, and as rapidly as possible, so as to avoid oxidation. The Elixir Secretogen was injected directly, without dilution.
TABLE 7.—SUMMARY OF TYPICAL EXPERIMENTS SHOWING THE ABSENCE OF SECRETIN IN “SECRETOGEN”AND “ELIXIR SECRETOGEN” EXCEPT IN OCCASIONAL TESTS WHEN ADMINISTERED IN ENORMOUS DOSES
Dogs under ether anesthesia
| Exp. No. | Quantity of Secretogen and Elixir Secretogen Used* | Secretion of Pancreatic Juice in Drops, Following Intravenous Injection | ||||||
| Control 10 C.c. Secretin | Secretogen in | Elixir | Control 10 C.c. Secretin | |||||
| Distilled Water | 0.4% HCl | 70% Alcohol | 0.9% NaCl | |||||
| 1 | Secretogen, 1 tablet; Elixir, 15 c.c. | 109 | 0 | 0 | 0 | 0 | 0 | 59 |
| 1 | Secretogen, 6 tablets | ... | .. | 0 | .. | .. | .. | .. |
| 2 | Secretogen, Elixir, 15 c.c. 3 tablets; | 16 | 0 | 0 | 0 | 0 | 1(?) | 16 |
| 3 | Secretogen, 5 tablets | ... | .. | 1(?) | .. | .. | .. | .. |
| 4 | Secretogen, 25 tablets | 14 | .. | 1(?) | .. | .. | .. | 8 |
| 5 | Secretogen, 100 tablets | 110 | .. | .. | .. | 21 | .. | 67 |
| 6 | Secretogen, 100 tablets; Elixir, 125 c.c. | 19 | .. | 5 | .. | 1 | 2(?) | 8 |
| 7 | Elixir, 50 c.c. | ... | .. | .. | .. | .. | 1(?) | .. |
* One to three tablets is (according to the label) the therapeutic dose of Secretogen; 4 to 12 c.c. the dose of Elixir Secretogen.
Results.—In only one case was a slight response obtained, the others gave none. Small and large doses were equally inert (Table 7, Figs. 2, 3). The preparations, though inert, always produced a depression in blood pressure, sometimes even greater than that caused by active secretin. Among our many tests, one bottle was found, however, to be a little different from the rest (Experiment 4). Its entire content, 100 tablets, had been ground and boiled in 0.9 per cent. sodium chlorid. The extract on injection was found to have a small but unmistakable secretin reaction, equivalent to about 2 c.c. of the control secretin used. But repeated experiments were unable to duplicate this result. The “Secretogen” and “Elixir Secretogen” were all supposedly fresh preparations, the retail drug store informing us that a fresh supply was obtained from the wholesale house each week.
Secretogen, then, contains practically no secretin, and even if it did contain secretin, it can have no effect on the pancreas when taken by mouth. The indications for Secretogen, therefore, are based on false premises, and the testimonials are worthless.
Fig. 2.—Tracings (reduced one-half) showing no stimulation of the pancreas by Secretogen, Elixir Secretogen, and Duodenin, even when administered intravenously in quantities one hundred times greater than the therapeutic dose by mouth. Dog: Light ether anesthesia; cannula in the pancreatic duct; a, carotid blood pressure; b, flow of pancreatic juice in drops. Tracing A: at x, intravenous injection of 10 c.c. secretin prepared from duodenal mucosa of dog. Tracing B: at x, intravenous injection of 100 tablets of Secretogen digested with 0.4 hydrochloric acid and neutralized. Tracing C: at x, intravenous injection of 100 tablets of Secretogen, prepared as in Tracing B. Tracing D: at x, intravenous injection of 50 c.c. Elixir Secretogen. Tracing E: at x, intravenous injection of 100 tablets of Duodenin (dissolved in 0.9 per cent. sodium chlorid).
Duodenin.—This is a preparation manufactured by Armour & Company, which purports to be “secretin plus enterokinase.” The claims for this product are similar to those for Secretogen, but somewhat less sweeping. According to the manufacturers, “Duodenin (Armour) is recommended in the treatment of intestinal disorders where an increased flow of pancreatic, hepatic and intestinal secretion is desired. It is of specific value in proteid digestion on the theory that secretin and enterokinase stimulate the pancreas and activate its secretion.”
Fig. 3.—Tracings (reduced one-half) showing practically complete destruction of secretin by the gastric juice. Dog under light ether anesthesia; cannula in the pancreatic duct; a, carotid blood pressure; b, record of flow of pancreatic juice in drops. Time, twenty-five minutes. Tracing A: intravenous injection of 10 c.c. secretin (prepared fresh from dog’s duodenal mucosa) at x. Tracing B: intravenous injection (at x) of 10 c.c. of the same secretin as in Tracing A, after being digested in normal human gastric juice at 37 C. for two hours.
We bought a quantity of Duodenin in the open market, and carried out on this product the same series of experiments as that used in the case of Secretogen. The results were similarly negative (Table 8).
TABLE 8.—SUMMARY OF TYPICAL EXPERIMENTS SHOWING THE ABSENCE OF
SECRETIN IN “DUODENIN”
Dogs under ether anesthesia
| Exp. No. | Number Duodenin Tablets Used | Secretion of Pancreatic Juice in Drops, Following Intravenous Injection | |||||
| Control 10 C.c. Secretin | Duodenin in | Control 10 C.c. Secretin | |||||
| Distilled Water | 0.4% HCl | 70% Alcohol | 0.9% NaCl | ||||
| 1 | 3 | 29 | 0 | 0 | 0 | 1(?) | 28 |
| 1 | 6 | ... | .. | 1(?) | .. | .. | .. |
| 2 | 18 | 16 | .. | 6 | .. | .. | 16 |
| 3 | 5 | 14 | .. | 0 | 0 | 0 | 8 |
| 3 | 25 | ... | .. | 1(?) | .. | .. | .. |
| 4 | 100 | 110 | .. | 0 | .. | .. | 67 |
| 5 | 150 | 19 | .. | 0 | .. | 0 | 8 |
In regard to both Secretogen and Duodenin, we assume that the manufacturers have tried to put secretin in them, but have been unable because they have failed, in all likelihood, to check their methods by physiologic standardization. These firms do not give any details as to the procedure they employed in their manufacture of secretin. Desiccated secretin of extreme potency has been prepared by various physiologists,[91] 1 mg. (1⁄64 grain) of which is active when given intravenously. It is difficult to conceive that any of these methods were used in the preparation of Secretogen or Duodenin.
CONCLUSIONS
1. Secretin is quickly destroyed by gastric juice and by trypsin.
2. Secretin is not absorbed in active form from the alimentary tract.
3. The presence of secretin or prosecretin cannot be demonstrated in the commercial preparations “Secretogen,” “Elixir Secretogen” and “Duodenin” even when the therapeutic dose of the preparations is given intravenously. In the case of “Secretogen,” intravenous injection of 100 times the therapeutic dose reveals occasionally an insignificant trace of secretin.
DISCUSSION OF RESULTS
It is, of course, objectionable that preparations containing no secretin should be advertised to the medical profession as containing this substance. The more important blunder, however, consists in the attempt to offer such preparations for oral administration, because even chemically pure secretin would be equally ineffective when taken by mouth. There is as yet no reliable evidence that lack of secretin is a primary or important factor in any disease. Even should this be established, secretin therapy, to be effective, must be intravenous. Secretin has not yet been prepared in sufficiently pure state to render possible intravenous injection in man without injurious effects. And even when this has been attained, the very fleeting action of secretin will in all probability render secretin therapy as futile in all the diseases in which it is theoretically indicated as epinephrin therapy is in Addison’s disease.
But there remains the alleged favorable effect from secretin therapy by mouth in various diseases in man. It is, perhaps, impertinent for laboratory men to comment on these clinical results. The ordinary “testimonials” need not be considered, but we should like to ask the serious worker who thinks he has actually obtained good results from secretin therapy how certain he is of the causal relation between the giving of secretin or alleged secretin and the abatement of the disease.
When a therapeutic measure not only lacks a positive basis in physiology and pathology but runs contrary to all the well-established experimental facts in these fundamental medical sciences, is it too much to ask that positive clinical findings be subjected to more than usual critical analysis before acceptance? “Clinical tests,” it is said, “covering a period of several years have proved that neither the condition in the stomach during digestion nor those in the intestine prevent the secretin from entering intact into the circulation.” When we meet claims such as this, should we not scrutinize the “tests” as well as the men who make them?
We are indebted to Dr. J. H. Moorehead for assistance in part of the surgical work.—(From The Journal A. M. A., Jan. 15, 1916.)