DIGITALYSATUM

“Betula exerts both an antiseptic and stimulating influence on the urinary passages and is particularly serviceable where a catarrhal condition of the bladder exists. When combined with other diuretics, as in Hydropsin, the drug affords highly satisfactory results in the treatment of ascites, cardiac dropsy and hydrothorax.”

Birch is another drug which has been discarded. Few textbooks on materia medica even mention it. That it can materially affect the action of such powerful drugs as squill and digitalis is exceedingly doubtful.

An unwarranted implication—that in this preparation the powerful drugs digitalis and squill have been deprived of their dangerous qualities—is the assertion:

“Dialysis, removing all resins and colloidals, results in better tolerance on part of sensitive patients, and in more rapid absorption and elimination; which, in turn, means early therapeutic effects and little or no fear of toxic accumulation.”

That removal of colloids and resins materially affects the tolerance of these drugs is improbable. To claim that because of their removal, there need be “little or no fear of toxic accumulation” is utterly without warrant. The claim that one preparation containing digitalis is less likely to produce cumulative effect than any other digitalis preparation is contradicted by a mass of evidence.

It is claimed that Hydropsin affects “favorably all forms of dropsy or Edema that are at all amenable to medical treatment.” There can be no question but that squill and digitalis, or, better, either singly, used in suitable cases, may relieve dropsical effusions; but to claim that such a complex mixture as Hydropsin can favorably affect all forms of dropsy that are amenable to medical treatment is on its face unwarranted.

The claim is made that:

“By reason of its unusual potency and relative harmlessness, Hydropsin may be employed to great advantage in all cases where it is desirable to increase the volume of urine without injury to the renal structures.”

On the basis of the claimed composition, the action of Hydropsin must be essentially that of digitalis or of digitalis and squill. Consequently, if it possesses “unusual potency,” it cannot possess “relative harmlessness,” and vice versa. Neither digitalis nor squill should be employed “in all cases” of nephritis, even if it is “desirable to increase the volume of urine.”

The composition claimed for Hydropsin brands it as an irrational mixture in which potent drugs are combined with, and more or less covered up by, others that are obsolete and inefficient. The name, instead of indicating its composition, suggests diseases in which it may be thoughtlessly and indiscriminatelyused. The claim that the danger of toxic or cumulative action has been removed, if accepted by physicians, tends to uncritical use with possible disastrous results. Hydropsin is ineligible for New and Nonofficial Remedies because of conflict with Rules 1, 2, 6, 8 and 10.—(From The Journal A. M. A., Jan. 8, 1916.)

The Council has adopted the following report and authorized its publication.

W. A. Puckner, Secretary.

Digitalysatum is sold in the United States by Ernst Bischoff Company, Inc., New York. The firm claims that it is a dialysate prepared from the juice of freshly gathered digitalis, containing all the active principles, and representing the fresh plant weight for weight. It is said to be standardized physiologically and to contain 12 per cent. alcohol. Sterisol-Digitalysatum, intended for injection, appears to be the “dialysate” without alcohol, diluted with equal parts of physiologic sodium chlorid solution. The Council some years ago found both products ineligible for New and Nonofficial Remedies because of unwarranted therapeutic claims. The preparations are still being advertised to physicians under claims which imply superiority to all other digitalis preparations. For instance:

“Digitalysatum is the diureticpar excellencein cardiac insufficiency...”“Digitalysatum as a diuretic and cardiac stimulant is in a class by itself, being quick of action, uniform in strength, and well tolerated.”“Digitalysatum differs from other forms of digitalis in these respects:... Digitalysatum is free from fat, resins and colloids, and is therefore well-borne by sensitive patients—the young and the feeble—and is quickly absorbed and eliminated....”

“Digitalysatum is the diureticpar excellencein cardiac insufficiency...”

“Digitalysatum as a diuretic and cardiac stimulant is in a class by itself, being quick of action, uniform in strength, and well tolerated.”

“Digitalysatum differs from other forms of digitalis in these respects:... Digitalysatum is free from fat, resins and colloids, and is therefore well-borne by sensitive patients—the young and the feeble—and is quickly absorbed and eliminated....”

The Council has elsewhere28expressed the conviction that tincture of digitalis produces the full therapeutic effects of digitalis; that, when properly made, the tincture is as stable as any liquid preparation of digitalis now available, and that attempts to enhance the reputation of proprietary products by exaggerating the disadvantages of the official preparation are to be deplored. No adequate evidence is offered of the claimed superiority of action of Digitalysatum.

By implication, the claim is made that Digitalysatum is superior to other digitalis preparations in respect to toxicity:

“Free from fat, resins and colloidals, it is always well borne and is quickly absorbed and eliminated. No case of toxic accumulation (faulty elimination) has ever been reported.”

That Digitalysatum is free from the dangers of toxic cumulation is highly improbable; in fact, it is inconsistent with the statement that the preparation contains all the constituents found in the fresh plant. Even if instances of cumulative action have not been reported this does not prove that such cumulative action does not occur. The tincture of digitalis has the systemic side-effects of digitalis in no greater degree than the various proprietary preparations. Attempts to create the impression that Digitalysatum possesses all the virtues of digitalis without its chief disadvantage are to be condemned as likely to lead to incautious use of the preparation.

These exaggerated claims are in the main made indirectly, but they are none the less inimical to sound therapy. The Council therefore declared Digitalysatum ineligible for New and Nonofficial Remedies and voted that this report be published.—(From The Journal A. M. A., Jan. 8, 1916.)

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;29an 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 checkthe 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.)

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.31Interaction 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.32That a “chemical messenger” is at the basis of the duodenal acid reflex has been proved by even more crucial experiments—transfusion (Wertheimer,33Enriquez andHallion34),cross circulation (Fleig,35Matuso36), and perfusion of the isolated pancreas (Huston37).

Prosecretin.—Secretin is soluble in water, yet a watery extract of intestinal scrapings is without action,32even after being submitted to acid treatment.38Starling 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 21⁄2feet 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,39carbonic and boric acids being inactive.40Secretin can also be prepared with strong soaps (from 10 to 30 per cent. sodium oleate), alcohol (70 per cent.,410.6 per cent. sodiumchlorid36). 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.36On 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.38In well-controlled experiments, Wertheimer andLePage42found that after the introduction of acid, secretion is secreted into the lumen of the intestine.Matuso36confirmed 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,44Enriquez andHallion45), likewise that of succus entericus (Delezenne and Frouin,46Bottazzi andGabrielli47), and intestinal peristalsis is stimulated (Enriquez and Hallion,48Falloise49). 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 andStarling50have 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 evenafter two hours of continuous injection.51The juice obtained by secretin has been subject to many studies.52It 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,54Bayliss and Starling,55Chapman56). It is likewise found in the new-born and in the fetus.57Its 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.58On 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 ongastrin59(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,60with 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.61Autoclaving 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.61The 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.51Even 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 andHamill51claimed that secretin disappears quantitatively on passage through a Berkefeld filter at 5 mm. pressure. Lalou,62using higherpressure, 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

Diabetes Mellitus.—Moore, Edie andAbram64were 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 pancreasmaybe stimulated by secretin, and that some cases of diabetesmaybe 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.65Bainbridge andBeddard66gave secretin a thorough trial in three cases with negative results, and are disposed to attribute the results of Moore to dieting. Dakin andRansom67cited one case, secretin being given for twelve weeks, with negative results; Foster,65nine cases, all negative; Charles,68three cases, all negative. Crofton,69however, gave secretin a trial in one case with favorable results. Moore, Edie and Abram, in a later paper,70report 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,66that 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,71they 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,72in Starling’s laboratory, found that in dogs made recently diabetic by total pancreatectomy, but little secretin could be obtained. Hedon andLisbonne,73and Pemberton andSweet74report, on the contrary, that the duodenum of diabetic dogs is rich in prosecretin. Bainbridge and Beddard,71working 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.75This 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,”Wentworth76has claimed that in infantile atrophy such is the condition, but Sweet andPemberton77have found that the difficulty of preparing secretin from human duodenums is such as to render Wentworth’s findings inconclusive.

Beveridge78suggests 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 ofauthorities79as also recommending secretin for digestive disorders. Harrower, who is or was connected with the Carnrick Company, in clinicaljournals80has ardently advocated the use of secretin for a large number of maladies.

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,32was confirmed by Fleig,81and Matuso,36and 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,82in 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.Lalou62worked 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.Matuso36introduced 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,36Hallion83) and intrapleural injections are likewise negligible (Bayliss andStarling55).

Starling63finds 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,84Ehrman and Lederer,85Bayliss and Starling32). This may be due to other secretin stimulants as fats, or to the action of the nervous mechanisms (Meltzer86).

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,62who 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.87In 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 andStarling32being 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 withboiledgastric 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 followscontact 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 getcompletedestruction 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 ExperimentQuantityofGastricJuiceUsed,C.c.Secretion of Pancreatic Juice in Drops10 C.c.SecretinControl—BeginningExperimentThe Secretin After Incubation with Human Gastric Juice10 C.c.SecretinControl—End ofExperimentDig. Time, HoursSecretion RateDig. Time, HoursSecretion RateDig. Time, HoursSecretion Rate122860402016221102711⁄218118413240173⁄471⁄483141211⁄2111⁄4121⁄60141858201⁄211⁄431⁄6061865531⁄22..........

We also tried the effect of keeping the digestive timeconstantand 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*

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