Volume 1 / Part 1 — FOREWORD (continued 3)

“... an exact physiological product derived from the lymphoid structures of the body without the use of chemical agents.... So delicate is Protonuclein that any chemical agent is liable to disturb its cellular activity.”

After its examination of the product in 1907 (The Journal, Oct. 5, 1907, p. 1198), the Council concluded that any distinction between the action of Protonuclein and that of ordinary nuclein was purely speculative and highly improbable. “If the active ingredients are really so unstable that they are destroyed by all chemical agents, as claimed, it seems impossible that the activity would be preserved when Protonuclein is given by mouth and therefore subjected to the very profound changes of digestion.”

At that time the importance of thyroid as an ingredient had not been emphasized. The following year, however, Hunt and Seidell (The Journal A. M. A., Oct. 24, 1908) reported the results of an investigation which showed that Protonuclein was a diluted thyroid preparation, as skilfully disguised as in the antifats Rengo and Marmola. Hunt later pointed out (The Journal, Feb. 1, 1913, p. 384) that the amount of nuclein contained in a dose of Protonuclein probably would not have the slightest effect, especially when given by mouth.

The following are extracts from the Protonuclein advertising matter:

“For cancer, infectious fevers (measles, scarlet fever, typhoid and septicaemia) and as a prophylactic.”

“Protonuclein: An ideal prophylactic for all infectious Diseases.”

“A true alterative and tissue builder.”

“The value of Protonuclein depends upon its ability to increase cell power and promote tissue strength. It is therefore needed whenever the organism is below the normal standard, more especially in Anaemia, Typhoid, Neoplasms and as a Prophylactic.”

All the foregoing claims and recommendations are supposed to be based on certain alleged discoveries which the Council has previously characterized as “a tissue of vague speculations ... in direct conflict with the known facts of physiologic chemistry.” As for the third claim, Hunt and Seidell have commented on the danger of recommending thyroid, the most powerful tissue-destroying drug known, as a “tissue builder.”

Protonuclein Beta, it is said:

“... combines the reconstructive action of Protonuclein with the action of the vital principle of the spleen, making it a distinct product for use in all tubercular troubles, including phthisis, localized joint affections and scrofular conditions.”

This product, according to the manufacturers, is based on the work of a certain Dr. Bayle of Cannes, France. Dr. Bayle said that he had treated tuberculous patients with fresh ground up spleen of hogs (25–100 grams per day), mixed with fruit preserve or bouillon; in cases in which this brought on gastro-intestinal disorders, extract of the spleen pulp was administered hypodermically. Bayle reported extraordinary improvements in the physical and mental conditions of his patients even after a few days of this treatment; over 90 per cent. of his tuberculous patients, according to him, improved or were cured. This applied to all types and stages of tuberculosis in man. “With the spleen pulp treatment tuberculous glands disappear like syphilis lesions on administration of mercury and iodids.”

This “spleen specific” of Bayle lacks scientific foundation; Bayle’s own cases were not adequately controlled, and no notice has been taken of Bayle’s report by experts on tuberculosis. Hence it practically lacks both confirmation and contradiction.

The spleen is invaded by tubercle bacilli quite as frequently as are the kidneys and the liver; it has no special toxic action on these bacilli. Nor is there any reason to believe that the end products of gastric and intestinal digestion of spleen pulp, after absorption into the blood, exert such toxic action. It cannot be assumed that these end products indirectly aid the healing processes through improved metabolism, for there is no evidence that they have any specific nutritive or stimulating action after such absorption. Altogether, what we know of the physiology and pathology of the spleen does not warrant us in looking for a “specific” against tuberculosis in this organ.

If, however, the known facts did justify any hope that the spleen might furnish such a specific, manufacturers would not be warranted in exploiting or physicians in prescribing spleen products as a remedy for tuberculosis until control experiments on animals had confirmed the therapeutic value of these products. In a chronic disease like tuberculosis, no conclusions that are scientifically valid can be drawn from clinical cases until many cases have been observed for years under suitable conditions. Right here it may be said that the clinical “evidence” offered in favor of Protonuclein Beta is worthless. The observations which have been reported on this product are not such as to permit any valid final conclusions to be drawn with regard to its value.

The rational method of proving the worth of an alleged new specific such as this is by animal experimentation. So far as we know, neither Dr. Bayle nor the Reed and Carnrick company has performed any such experiments with “spleen pulp” or Protonuclein Beta; nor are we aware that any competent investigator has done so. There is, to the best of our knowledge, no scientific evidence on which to base the claims for Protonuclein Beta.

The Council reaffirms its former action with regard to Protonuclein. The objections made to Protonuclein apply with equal force to Protonuclein Beta. In view of the lack of evidence, the claims for Protonuclein Beta are unwarranted and the product is ineligible to N. N. R. on account of noncompliance with Rules 1, 6 and 8.—(From The Journal A. M. A., Jan. 1, 1916.)

HYDROPSIN

Report of the Council on Pharmacy and Chemistry

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

W. A. Puckner, Secretary.

Hydropsin is marketed by the Ernst Bischoff Company, Inc., New York. Its composition is thus described:

“Hydropsin is the standardized dialysate of Digitalis purpurea, Betula alba, Scilla maritima, Juniperis communis, and Herniaria glabra; or, stated otherwise, it is the juice of these drugs, dialyzed and physiologically standardized.”

“Each fluid dram represents Digitalysatum 7 gtts., and 2 gtts. each of the dialysates of Betula, Herniaria, Juniper and Scilla.”

The composition of Hydropsin must be considered essentially secret since the amounts of the several constituent drugs in a given amount of “dialysate” are not disclosed. The active principle of juniper is a volatile oil which is practically insoluble in water; it is difficult to believe that the “juice” of juniper submitted to dialysis could contain any material amount of the active constituent. No information is given as to the method used whereby the several dialysates are “physiologically standardized.” It therefore remains to be proved that the manufacturer of Hydropsin possesses any method whereby the dialysates of juniper (Juniperis communis), birch (Betula alba, the common European birch) and knot weed (Herniaria glabra) are so standardized. The claim is made that:

“Herniaria has long been recognized as one of the most valuable drugs in the treatment of dropsical affections due to cardiac impairment.”

On the contrary, Herniaria belongs to that large class of drugs which have been tried, found wanting and abandoned. It is a very old remedy, and the claims made for it are an inheritance from the early herbalists, with whom it was very popular. According to King’s American Dispensatory, it was “principally employed to cure hernia (hence its name) and to increase the flow of urine. It was also said to increase the flow of bile.... Internally and externally, it was praised in snake-bites, and the powdered plant was employed to kill maggots on unhealthy sores of horses. It was reputed to ‘crush’ and expel calculi from the kidneys and bladder....”

The Ernst Bischoff Company says that:

“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 indiscriminately used. 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.)

DIGITALYSATUM

Report of the Council on Pharmacy and Chemistry

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 diuretic par excellence in 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 elsewhere28 expressed 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.)

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 Hallion34), cross circulation (Fleig,35 Matuso36), and perfusion of the isolated pancreas (Huston37).

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 chlorid36). 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 LePage42 found that after the introduction of acid, secretion is secreted into the lumen of the intestine. Matuso36 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 Hallion45), likewise that of succus entericus (Delezenne and Frouin,46 Bottazzi and Gabrielli47), and intestinal peristalsis is stimulated (Enriquez and Hallion,48 Falloise49). 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 Starling50 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 Chapman56). 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 gastrin59 (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 Hamill51 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 Abram64 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 Beddard66 gave secretin a thorough trial in three cases with negative results, and are disposed to attribute the results of Moore to dieting. Dakin and Ransom67 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 Sweet74 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,” Wentworth76 has claimed that in infantile atrophy such is the condition, but Sweet and Pemberton77 have found that the difficulty of preparing secretin from human duodenums is such as to render Wentworth’s findings inconclusive.

Beveridge78 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 authorities79 as also recommending secretin for digestive disorders. Harrower, who is or was connected with the Carnrick Company, in clinical journals80 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. Lalou62 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. Matuso36 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 Hallion83) and intrapleural injections are likewise negligible (Bayliss and Starling55).

Starling63 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 Starling32). This may be due to other secretin stimulants as fats, or to the action of the nervous mechanisms (Meltzer86).

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 Starling32 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 ExperimentQuantity of Gastric Juice Used, C.c.Secretion of Pancreatic Juice in Drops

10 C.c. Secretin Control —Beginning ExperimentThe Secretin After Incubation with Human Gastric Juice10 C.c. Secretin Control —End of Experiment

Dig. Time, HoursSecretion RateDig. Time, HoursSecretion RateDig. Time, HoursSecretion Rate

12 286 04 02 016

221102 71¹⁄₂181 1841

32 401 7 ³⁄₄ 7 ¹⁄₄ 831

41 21 ¹⁄₂11 ¹⁄₄12 ¹⁄₆₀1418

58 20 ¹⁄₂ 1 ¹⁄₄ 3 ¹⁄₆₀ 618

65 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*

PreparationPancreatic Juice Drops

10 c.c. secretin20

10 c.c. secretin digested with 0.5 c.c. gastric juice15

10 c.c. secretin digested with 3 c.c. gastric juice13

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

PreparationPancreatic Juice Drops

Experiment 8:

10 c.c. secretin, five injections of inert depressor substances29

10 c.c. secretin, two injections of completely digested secretin28

10 c.c. secretin, eight injections of inert depressor substances16

10 c.c. secretin16

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 juice27

10 c.c. secretin, after thirty minutes incubation with 1 c.c.

fresh gastric juice11

10 c.c. secretin (control, end of experiment)18

The findings of Lalou, confirmed by us, explain the anomaly that has led Delezenne88 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 TubeRate of Secretion of Pancreatic Juice in C.c. per Hr.

Continuous Secretion Before FeedingContinuous Secretion After Feeding

First HourSecond HourThird HourFirst HourSecond HourThird Hour

150 c.c. active secretin, slightly acid 6.5 3.6 3.920.0 6.0 8.0

150 c.c. active secretin, slightly alkaline13.011.0 5.023.026.012.0

150 c.c. secretin passed through Berkefeld 7.8 7.5 7.423.013.011.0

150 c.c. extract of colon11.612.011.430.019.614.8

150 c.c. extract of gastric mucosa10.0 7.0 8.023.0 7.5 4.0

150 c.c. extract of muscle 6.911.0 6.435.0 5.0 7.0

150 c.c. 0.4% HCl (diluted to 250 c.c.) 6.0 8.0 4.033.036.017.0

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 ExperimentMaterial FedRate of Secretion of Pancreatic Juice in C.c. Per HourIncrease in C.c.

Three Hours Before FeedingThree Hours After Feeding

3Secretin slightly acid 511 6

5Secretin slightly alkaline2430 6

4Secretin passed through Berkefeld1823 5

1Secretin exposed to sun for 4 hrs162913

2Extract of colon (rabbit)192910

3Extract of gastric mucosa1423 9

3Extract of muscle 816 8

2Mixture of gelatin, peptone and salt233310

11 per cent. peptone solution 6 8 2

40.2 per cent. hydrochloric acid133724

3Milk and bread 72013

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 FedRate of Secretion of Pancreatic Juice in C.c. Per Hour

Continuous Secretion Before Feeding*Secretion After Feeding

FirstSecondThirdFirstSecondThird

1150 c.c. secretin 8.7 7.5 6.8 3.0 1.0 4.8

2 4.5 6.510.0 6.0 7.5 7.6

315.6 8.116.0 3.9 4.9 2.9

1150 c.c. 4% HCl (diluted to 250 c.c.) 9.8 7.0 6.065.128.0 7.1

217.418.517.034.018.020.0

* Five gm. Na HCO₃ given at beginning of each first two hours.

COMMERCIAL PREPARATIONS OF SECRETIN

Secretogen and Elixir Secretogen.—The Carnrick Company offers Secretogen90 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. SecretinSecretogen inElixirControl 10 C.c. Secretin

Distilled Water0.4% HCl70% Alcohol0.9% NaCl

1Secretogen, 1 tablet; Elixir, 15 c.c.109000 0059

1Secretogen, 6 tablets.....0........

2Secretogen, Elixir, 15 c.c. 3 tablets; 16000 01(?)16

3Secretogen, 5 tablets.....1(?)........

4Secretogen, 25 tablets 14..1(?)...... 8

5Secretogen, 100 tablets110......21..67

6Secretogen, 100 tablets; Elixir, 125 c.c. 19..5.. 12(?) 8

7Elixir, 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 UsedSecretion of Pancreatic Juice in Drops, Following Intravenous Injection

Control 10 C.c. SecretinDuodenin inControl 10 C.c. Secretin

Distilled Water0.4% HCl70% Alcohol0.9% NaCl

1 3 290001(?)28

1 6.....1(?)......

2 18 16..6....16

3 5 14..000 8

3 25.....1(?)......

4100110..0....67

5150 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.)

ARTICLES REFUSED RECOGNITION

Report of the Council on Pharmacy and Chemistry

Below appear abstracts of the Council’s action on articles refused recognition which were not deemed of sufficient importance to require lengthy reports:

Radio-Rem

The Radium Therapy Company, Schieffelin & Co., selling agents, submitted to the Council radium emanation generators called “Radio-Rem Outfits,” designed to generate respectively 200, 1,000, 2,000, 5,000 and 10,000 Mache units per twenty-four hours.

Those who are well informed on the subject of radium therapy are of the opinion that the administration of small amounts of radium emanation such as generated by certain outfits is without therapeutic value. It has been stated that at the Radium Institute of London the minimum preliminary dose is 185 micro­curies (500,000 Mache units), and as many as 555 micro­curies (1,500,000 Mache units) are employed.

In consideration of these facts the Council voted not to accept any radium emanation generator which produces less than 2 micro­curies of emanation during twenty-four hours. Accordingly, while accepting Radio-Rem Outfit No. 5, claimed to produce 10,000 Mache units (3.7 micro­curies) and Radio-Rem Outfit No. 4, claimed to produce 5,000 Mache units (1.8 micro­curies), the Council voted not to accept Radio-Rem Outfit No. 3, claimed to produce 2,000 Mache units (0.74 micro­curie), Radio-Rem Outfit No. 2, claimed to produce 1,000 Mache units (0.37 micro­curie), and Radio-Rem Outfit C, claimed to produce 200 Mache units (0.07 micro­curie).

This report having been submitted to Schieffelin & Co. and their reply considered, the Council authorized publication of the report. [See also Reports of Council on Pharmacy and Chemistry, 1916, p. 631.]

Olio-Phlogosis

Olio-Phlogosis, a liquid preparation to be applied externally by means of a cotton pad, is advertised by the Mystic Chemical Company, Kansas City, Mo., thus:

“Doctor: Don’t fail to use Olio-Phlogosis liberally for Pneumonia, Bronchitis and Pleurisy. It works quickly. Olio-Phlogosis is as far ahead of all medicated kaolin plasters as these plasters were ahead of the old-time moist and soggy poultices.”

A pamphlet advises the use of Olio-Phlogosis in

“... all cases of Inflammation and Congestion, such as Pneumonia, Bronchitis, Pleurisy, Croup, Boils, Carbuncles, Rheumatism, Swollen Glands, Peritonitis, Ovaritis, as a Surgical Dressing, Mamitis [Mastitis (?)] Vaginitis and Metritis (on cotton tampon to deplete these parts), Septic Wounds, Old Ulcers, Chilblain, Eczema, Neuralgia, Inflammation of the Eyes and Ears, Alveolar Inflammation, Burns, Scalds, Etc.”

According to the information sent to the Council by the Mystic Chemical Company, Olio-Phlogosis has the following composition per gallon:

Ol. Eucalyptus Gaultheria drs. 8

Ol. Abies Canadensis drs. 8

Ol. Abies Canadensis drs. 2

Ol. Thyme (white) drs. 2

Resublimated Iodin crystals grs.32

Resorcin drs. 1

Acid Boracic C. P. drs. 2

Quinine Bisulphate drs. 4

Sodium Thiosulphate drs. 3¹⁄₂

Glycerin C. P. q. s. ad gal. 1

A nonquantitative formula which appears on the label of a sample bottle sent to a physician enumerates the same ingredients except the sodium thiosulphate.

The A. M. A. Chemical Laboratory reports that no free iodin could be detected in the preparation.

Apparently, then, Olio-Phlogosis is essentially a skin irritant applied by means of cotton; it can be expected to be just about as effective as the old-fashioned cotton pneumonia jacket, used in conjunction with an aromatic skin irritant, such as camphorated oil or wintergreen or menthol ointment. The odor may have some psychic effect, and it is possible that some of the oily matter may be absorbed by the skin. That such small amounts, even if absorbed, can produce any considerable systemic effect, however, is highly improbable, and the advice that this preparation be relied on in pneumonia, pleurisy, peritonitis, etc., is pernicious. In the few cases of pneumonia in which heat is indicated, the plain cotton pad will usually be found sufficient. If the physician consider the addition of a skin irritant desirable, it is easy to select one from the official preparations. It will be far more rational to do so than to invoke the aid of a mystic name and a complex formula to which the patient and his family, at least, will be led to give unmerited credit.

The claims made for Olio-Phlogosis are unwarranted; its composition is complex and irrational, and the nondescriptive but thera­peutically suggestive name is likely to lead to uncritical use. The Council voted that the product be refused recognition for conflict with Rules 6, 8 and 10, and that this report be published.—(From The Journal A. M. A., Aug. 19, 1916.)

THE HYPOPHOSPHITE FALLACY

Report of the Council on Pharmacy and Chemistry

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

W. A. Puckner, Secretary.

The introduction of hypo­phosphites into medicine was due to an erroneous and now discarded theory as to the cause of tuberculosis of which one Dr. J. F. Churchill of London, and later of Paris, was the promulgator and propagandist.92 This theory was that the so-called “tuberculosis diathesis” was due to a deficiency of phosphorus in the blood. Believing that the hypo­phosphites, while nontoxic, were capable of further oxidation in the organism, Churchill recommended them as the best means of supplying the supposedly lacking phosphorus. It is now known that tuberculosis is not due to a deficiency of phosphorus. Of more importance is the fact, now known, that little phosphorus, if any, is assimilated from the hypo­phosphites—far less than from phosphorus compounds of ordinary food.93 There is no justification for giving hypo­phosphites for the sake of their phosphorus content. For various reasons, however—partly from force of habit and partly because of the power of advertising—many physicians still prescribe hypo­phosphite preparations, and consequently, they are still included in the Pharmacopeia and in textbooks on materia medica and therapeutics. They are put out in the form of “specialties” and of proprietary preparations, and are lauded extravagantly by the manufacturers of the latter.

Although the overwhelming weight of evidence was against the probability that the hypo­phosphite preparations are of value as therapeutic agents, the Council thought it well to investigate the subject. Dr. W. McKim Marriott of Baltimore was therefore requested to review the evidence for and against the therapeutic usefulness of the hypo­phosphites and to conduct such experiments as seemed necessary. His report has already appeared in The Journal.94

Dr. Marriott found that nine observers (Paquelin and Joly, Vermeulen, Boddaert, Massol and Gamel, Panzer, Delaini and Berg), who endeavored to test the alleged utilization of the hypo­phosphites in the organism, reported that there is complete, or practically complete, elimination of hypo­phosphites in the urine, with little or no effect on the body. Only one experimenter (Patta) claimed that a considerable amount of ingested hypo­phosphite was retained in the body; however, he used a method now known to be inaccurate and made obvious errors in calculation, so that his conclusions were unwarranted.

Since the evidence was even to this extent contradictory, Marriott performed a series of experiments. The methods of this study and details of results are described in his paper, in which he also discusses the experiments of some other observers. Marriott writes:

“None of the subjects of the experiment [Marriott’s] experienced any effect whatsoever from the administration of the drug.... Almost all of the ingested hypo­phosphite is promptly eliminated unchanged....

“These experiments [Forbes’] demonstrate conclusively that the hypo­phosphites possess no specific value as a source of phosphorus for the body. This is not to be wondered at in view of the fact that 85 per cent. of the phosphorus ingested in the form of hypo­phosphite is excreted unchanged, and there is no proof that even the remaining 15 per cent. is available to the organism. It is doubtful if there are any conditions in which the body suffers from lack of phosphorus. Even should such conditions exist, phosphorus, in the form that it occurs in the ordinary foods, or as phosphates, is more efficient in supplying the deficit than hypo­phosphites that must be oxidized before utilization and which are only about 15 per cent. oxidized, if at all. For example, half a glass of milk contains more available phosphorus than three large doses of hypo­phosphites of 15 grains each, as great a dosage as is usually given.

“What, then, is the therapeutic value of hypo­phosphites? There is no reliable evidence that they exert a physiologic effect; it has not been demonstrated that they influence any pathologic process; they are not ‘foods.’ If they are of any use, that use has never been discovered.”

In view of the foregoing, it seemed to the Council advisable to examine the claims under which a few of the proprietary hypo­phosphite preparations are marketed. The following are representative:

FELLOWS’ SYRUP OF HYPOPHOSPHITES

No very exact information concerning the composition is furnished by the manufacturers (Fellows Medical Mfg. Co., New York). They say that the product

“... contains the chemically pure hypo­phosphites of iron, quinin, strychnin, calcium, manganese and potassium, agreeably blended in the form of a bland, stable syrup with a slightly alkaline reaction....

“Each fluid drachm contains the equivalent of 1-64th of a grain of pure strychnin.”

The Fellows’ Hypo­phosphites advertising furnishes something like a barometer of the popular status of hypo­phosphites. In one circular (undated, but, from certain references contained in it, presumably issued ten or fifteen years ago) we read:

“It is an indubitable fact that the hypo­phosphites have earned the distinction of having their therapeutic value more completely established than have any other remedial agents.... it is only by accepting the current view, which was originally advanced by Mr. Fellows, that we can satisfactorily account for the incontestable fact that the hypo­phosphites are of supreme importance in the treatment of a very extensive variety of affections.... the hypo­phosphites increase the consumption of oxygen and the elimination of carbon dioxide. In this manner, they stimulate nutrition and promote constructive metamorphosis.... It is now universally conceded that the widespread utility of the hypo­phosphites is due to the fact that they substantially improve metabolic processes, thus increasing the disease-resisting capacity of all the tissues.”

The circular, continuing, emphasizes the “incomparable phosphorus-contributing properties” of Fellows’ Syrup, its “extraordinary reconstructive properties” and “the magnificent results which invariably attend its employment in the treatment of anemia, chronic bronchitis, chlorosis, neurasthenia, mollities ossium, delayed union of fractures, rickets, convalescence,” etc.

A circular bearing the copyright date 1914, on the other hand, admits that:

“The theories for the favorable action of Fellows Syrup of Hypo­phosphites have undergone several changes.”

The same circular further maintains, however, that:

“... the fact has never been challenged that in Fellows Syrup of Hypo­phosphites we have one of the most efficient, most complete, most all-around tonics and roborants in the materia medica.”

No attempt is made to base this assertion on the therapeutic action of the constituents. In other words, the old theory, which formed the basis for the popularity of Fellows’ Syrup, has been thrown overboard, but no substitute is deemed necessary; the momentum already acquired is apparently regarded as sufficient to insure its continued sale.

Fellows’ Syrup of Hypo­phosphites is a semisecret, unscientific preparation—an affront to sound therapy—exploited by means of extravagant and misleading statements.

SYRUPUS ROBORANS (SYRUP HYPOPHOSPHITES COMP. WITH QUININ, STRYCHNIN AND MANGANESE)

Little information concerning this preparation seems to be furnished at present by the manufacturers, Arthur Peter & Co., Louisville, Ky. According to an old circular, it contains, in each fluidounce,

Grains

“Hypophos. Potass.1¹⁄₂

Hypophos. Manganese1

Hypophos. Lime1

Hypophos. Iron1¹⁄₂

Hypophos. Quinin ⁶⁄₁₆

Hypophos. Strichnin ¹⁄₁₆

“¹⁄₁₂₈ grain Strychnia to Teaspoonful.”

Further, according to the same circular:

“The Hypo­phosphites are especially useful in all diseases where there is a lack of nutrition.... They are the best of all remedies in Rachitis, non-union of fractures, Osteomalacia and Syphilitic Periostitis.”

As for Syrupus Roborans itself:

“This elegant preparation is ... the best general tonic and reconstructive known.”

The unwarranted therapeutic claims formerly made for it seem to be no longer circulated. Syrupus Roborans is an unscientific, shotgun mixture.

SCHLOTTERBECK’S SOLUTION HYPOPHOSPHITES OF LIME AND SODA (LIQ. HYPOPHOSPHITUM, SCHLOTTERBECK’S)

The Schlotterbeck & Foss Co., Portland, Maine, the manufacturers, say of their preparation:

“This solution contains 30 grains of the combined Hypo­phosphites of Lime and Soda to the ounce. It contains No Sugar, No Acid and it is Perfectly Neutral.”

“Indications for use.—Galactostasis, Imperfect Metabolism, Neurasthenia, Nervous Dyspepsia, Insomnia, Convalescence, Acetonuria, Cyclic Vomiting in Infants, Diabetes, Starvation, Deficiency of Lime, Mother’s Teeth during Pregnancy, Dentition of Infants, Rachitis, Furunculosis, Vomiting of Pregnancy, Obesity.”

“Migraine is often caused by conditions for which this Solution is one of the most satisfactory remedies:”

“In Insomnia due to advancing age, it will often act as a hypnotic....”

Of the hypo­phosphites the Schlotterbeck & Foss Company say:

“If ‘damning it with faint praise’ on the part of some of the leading medical authorities, or utterly condemning it as useless, on the part of others, would kill a medicine, the Hypo­phosphites would long since have disappeared as medicinal agents. Negative testimony in regard to the value of a drug does not settle anything.”

Of their own preparation they say:

“When we get the results that ought to follow the administration of Hypo­phosphites, we have proved that Schlotterbeck’s Solution enters the system unchanged.”

“This Solution is primarily a blood and nerve tonic and chemical food.”

Schlotterbeck’s Solution of Hypo­phosphites of Lime and Soda is a semisecret preparation marketed under claims that are both unwarranted and misleading.

ROBINSON’S HYPOPHOSPHITES

According to the manufacturers, the Robinson-Pettet Company, Louisville, Ky., each fluidounce of this preparation contains:

“Hypo­phosphites Soda2 gr.

Hypo­phosphites Lime1¹⁄₂gr.

Hypo­phosphites Iron1¹⁄₂gr.

Hypo­phosphites Quinin ³⁄₄gr.

Hypo­phosphites Strychnine¹⁄₁₆gr.”

It is claimed to be

“Nutritive, Tonic Alterative. A Standard Remedy in the treatment of Pulmonary Phthisis, Bronchitis, Scrofulous Taint, General Debility, etc. Stimulates Digestion, promotes Assimilation.”

The declared composition of the preparation is unscientific, and the therapeutic claims are unwarranted.

EUPEPTIC HYPOPHOSPHITES

Nelson, Baker & Co., Detroit, Mich., who market Eupeptic Hypo­phosphites, call this preparation:

“A superior combination containing the Hypo­phosphites of Potassium, Calcium, Iron and Manganese, and the bitter tonics, Quinin and Strychnin, agreeably associated with natural digestive ferments of the pancreatic secretion. It is thus a general reconstructive tonic.... The remedy is of especial value in the treatment of mental and nervous affections.... It is indicated in pulmonary tuberculosis, in all wasting diseases, in debilitated conditions generally and in all exhaustion from over work.”

On the basis of the manufacturer’s statement, Eupeptic Hypo­phosphites must be regarded as a semisecret, unscientific, shotgun preparation, exploited through unwarranted therapeutic claims.

MCARTHUR’S SYRUP OF THE HYPOPHOSPHITES COMP. (LIME AND SODA)

So far as the recent literature and trade package are concerned, no information as to the composition of this product is furnished beyond what is conveyed in the name. The advertising for McArthur’s Syrup, like that for Fellows’ Syrup and Peters’ Syrupus Roborans, has been modified as time has passed. A few years ago it was advertised under such claims as the following:

“... Has Stood the Test during many years for unequaled efficacy in the treatment of Tuberculosis.... Indicated also as a Tonic and Tissue Builder in convalescence from Fevers, in Nervous Diseases, Rickets, Senile Debility and Bronchitis.”

“Its use is indicated in ... diseases of the chest, chronic cough, throat affections, general debility, brain exhaustion, cholera infantum and wasting diseases of children.”

At present no definite claims seem to be made for it; the manufacturers evidently find the magic name of hypo­phosphites sufficient to evoke the spell for which the advertisement writer’s aid was once sought. A testimonial contained in a circular which seems to be still used illustrates both the kind of aura which surrounds hypo­phosphites in the minds of physicians who are still living in the past, and the kind of logic which has made the reputation of this and many other equally worthless preparations.

“Just about six years ago I had a severe attack of La Grippe which almost killed me. Left me with Asthma (Catarrh) and a severe cough. Did not get out of the house for three months. Took over a dozen bottles McArthur’s Hypophos.—came out all right and since then worked hard, but last Fall took another cold, but worked on, used McArthur’s Hypophos., am using it now, am on my 12th bottle.

“I have five or six patients whom I have put on McArthur’s Hypophos., but I do not prescribe the single bottle, but wholesale no less than half dozen bottles. One patient is on his 24th bottle with orders to get another half dozen and keep it up all winter. I have given the same order to all (keep it up all winter) and I myself intend to do the same, for with its use I have lost no time—rain or shine I am doing my work. I know what it has done for me and what it is doing for my patients.”

It would be hard to find a more characteristic example of the naïve mental processes of the simple folk who in all good faith write testimonials for worthless medicines. This well-meaning practitioner (a homeopath, by the way), because he “came out all right” after an attack of grip, returns all praise to McArthur’s Hypo­phosphites, which he has taken “wholesale.” Not the faintest doubt of the validity of his post hoc ergo propter hoc argument seems to glimmer across his consciousness.

McArthur’s Syrup of the Hypo­phosphites is an irrational preparation. While its faults are fewer and less glaring than those of some other proprietaries, the circulation of such a testimonial as the one just quoted is sufficient of itself to cast suspicion on the product.

BORCHERDT’S MALT OLIVE WITH HYPOPHOSPHITES, MALTZYME WITH HYPOPHOSPHITES AND MALTINE WITH OLIVE OIL AND HYPOPHOSPHITES

These preparations are now described in the appendix to New and Non­official Remedies. Borcherdt’s Malt Olive with Hypo­phosphites (Borcherdt Malt Extract Company, Chicago) is said to contain in each 100 c.c., 0.64 gm. each of calcium and sodium hypo­phosphites, with malt extract, olive oil and glycerine. Maltzyme with Hypo­phosphites (Malt-Diastase Company, New York) is said to contain, in each 100 c.c., 0.4 gm. each of calcium, sodium and potassium hypo­phosphites and 0.005 gm. each of iron and manganese hypo­phosphites, with maltzyme. Maltine with Hypo­phosphites (Maltine Company, Brooklyn, N. Y.) is said to contain in each 100 c.c., 0.64 gm. each of calcium and sodium hypo­phosphites and 0.42 gm. of iron hypo­phosphite, with maltine. Maltine with Olive Oil and Hypo­phosphites (Maltine Company, Brooklyn, N. Y.) is said to contain, in each 100 c.c., 0.6 gm. each of calcium and sodium hypo­phosphites, with maltine and olive oil. In general, no therapeutic claims are made for these mixtures so far as the hypo­phosphites are concerned. The addition of hypo­phosphites to such mixtures is irrational and, since it tends to perpetuate the hypo­phosphite fallacy, detrimental to sound therapeutics.

THE COUNCIL’S ACTION

The Council endorsed the conclusions of the work of Dr. Marriott referred to above, and noted: (1) that the therapeutic use of hypo­phosphites (except possibly in some cases as a convenient means of administering the positive element in the salt, as ammonium in ammonium hypo­phosphite or calcium in calcium hypo­phosphite) is irrational; (2) that the merits of each hypo­phosphite salt submitted for consideration under the foregoing exception must be judged individually, and (3) that Fellows’ Syrup of Hypo­phosphites, Peters’ Syrupus Roborans, Schlotterbeck’s Solution Hypo­phosphites of Lime and Soda, Robinson’s Hypo­phosphites, the Eupeptic Hypo­phosphites of Nelson, Baker & Co., and McArthur’s Syrup of the Hypo­phosphites are ineligible for inclusion in New and Non­official Remedies, and that Borcherdt’s Malt Olive with Hypo­phosphites, Maltzyme with Hypo­phosphites, Maltine with Hypo­phosphites, and Maltine with Olive Oil and Hypo­phosphites be deleted from the appendix of N. N. R. Of these preparations, all are in conflict with Rule 10; Fellows’ Syrup, Schlotterbeck’s Solution, Robinson’s Hypo­phosphites and Nelson, Baker & Co.’s Eupeptic Hypo­phosphites are in conflict with Rule 6; the Fellows, Schlotterbeck, and Nelson, Baker preparations are also in conflict with Rule 1.—(From The Journal A. M. A., Sept. 2, 1916.)

PULVOIDS CALCYLATES

Report of the Council on Pharmacy and Chemistry

Pulvoids Calcylates 5 grains was submitted by the Drug Products Company, Inc., New York, under the following claims as to composition:

“When ingested represents the following chemical formulas: C

6

H

4

OH COO

2

Ca.2H

2

O + Sr.(C

7

H

5

O

3

)

2

+ 2H

2

O.”

“Strontium Di-Salicylate 2¹⁄₂ grs. and our especially prepared Salt of Calcium and Acid Salicylic adjusted in such nascent form, that these pulvoids upon ingestion will promptly form Calcium Neutral Di-Salicylate 2¹⁄₂ gr.”

“A combination of Calcium and Strontium Di-Salicylate, in seemingly true chemical union.”

These statements are rather vague, possibly because they are an attempt to mystify. The product, however, may be assumed to be a mixture (not a chemical combination) of calcium salicylate and strontium salicylate. The therapeutic claims made for the preparation are:

“Superior to ordinary salicylates. Can be taken continuously and indefinitely without gastric irritation, insuring maximum efficiency.”

“Reports show surprisingly good results, even where the sodium salt fails.”

As there is no evidence to show that strontium salicylate, calcium salicylate or a mixture of the two salts has any advantage over sodium salicylate, these claims cannot be accepted. The name and the statement of composition are objectionable in that they do not reveal the identity of the drugs in “Calcylates” and in suggesting that this preparation possesses radical advantages over salicylates in other forms.

The Drug Products Company was told that the facts just mentioned rendered “Pulvoids Calcylates” ineligible for New and Non­official Remedies. The company in its reply objected to the Council’s conclusions, and in support of its position submitted testimonials from a number of physicians. The reply of the company embodied no facts or arguments which had not been considered by the Council’s referee, and the testimonials from physicians contained no evidence to show that the combination has any real advantage over sodium salicylate.

The Council therefore declared “Pulvoids Calcylates” ineligible for New and Non­official Remedies for the following reasons: Unwarranted therapeutic claims are made for the mixture (Rule 6); the name does not describe the composition (Rule 8), and the mixture is an unessential modification of an established remedy (sodium salicylate) (Rule 10).—(From The Journal A. M. A., Sept. 9, 1916.)

SULFURYL MONAL

Report of the Council on Pharmacy and Chemistry

Sulfuryl Monal is said to be manufactured by Monal Frères, manufacturing chemists of Nancy, France. It is sold in the United States by George J. Wallau, Inc., New York City. According to the label:

“Each PastilleContains: Sulfuryl (combined polysulphurets)

= 0.35 centigr.”

Liberates: Nascent sulphurretted Hydrogen

= 2 cub. cent.”

The Chemical Laboratory of the American Medical Association was requested to check the amount of available hydrogen sulphid. An original bottle of Sulfuryl Monal was used; this contained tablets having the taste of licorice extract and an odor of hydrogen sulphid. The tablets were found to liberate about 6 c.c. hydrogen sulphid to each tablet.

Among the claims made for the preparation are:

“Dissolved by the saliva, Sulfuryl Monal reaches the stomach where, under the influence of the gastric juice, it generates nascent sulphuretted hydrogen. Professor Albert Robin’s remarkable researches have proven that it is in the nascent state that drugs produce the greatest effect with the smallest dose.... Being thus eliminated by the entire respiratory tract: the lungs, bronchi and the throat, the sulphurretted hydrogen passes from the interior to the exterior, that is to say, goes right through these organs which are, as a consequence, thoroughly cleansed, antisepticized and freed of the pathogenic micro-organisms.... Then, again, part of the sulphuretted hydrogen, liberated in the stomach, is eliminated by the mouth and acts as an antiseptic and disinfectant of the mucous membranes of the throat and mouth. Hence Sulfuryl Monal is a perfect protective agent against contagious diseases.... Numerous clinical tests have demonstrated its real efficacy in diseases of the throat and of the respiratory tract: laryngitis, pharyngitis, hoarseness, granulations, tonsillitis, colds, bronchitis, pulmonary catarrh, asthma, emphysema, grippe, whooping cough, simple and infectious pneumonia, and in the first stage of pulmonary tuberculosis.”

The sulphids are practically ignored in modern textbooks. There is a rather extensive clinical literature on the subject, particularly in connection with sulphur waters; this, however, offers no good evidence for the therapeutic value of sulphids. Probably the tradition in their favor is largely due to the old popular idea that a disagreeable taste or odor is a mark of a good remedy.95

When hydrogen sulphid is introduced into the body, the small amounts that appear in the expired air are insufficient for quantitative demonstration and it is highly improbable that the amount thus excreted has any germicidal action, or that enough is excreted in the lungs to cause irritation and a reaction. The claim that Sulfuryl Monal is “a perfect protective agent against contagious diseases” is unwarranted; the recommendation for its use in “simple and infectious pneumonia, and in the first stage of pulmonary tuberculosis” is dangerous and vicious. The Council declared Sulfuryl Monal ineligible for New and Non­official Remedies and authorized publication of this report.

[Editorial Note..—With one exception, this product does not appear to be advertised in medical journals. We find, however, in the gallery of nostrums that grace the advertising pages of the International Journal of Surgery, that Sulfuryl Monal has its place. According to an advertisement that has been running some months in this publication, “affections of the throat and respiratory organs respond promptly” to Sulfuryl Monal whose “effects are rapid and certain” even in “incipient tuberculosis.” This pre­posterous pro­nounce­ment is no worse than many others appearing in the same journal, but it is bad enough to indicate how uncritical must be the physicians who support—by sub­scrip­tion or con­tri­bu­tion—pub­li­ca­tions that are still debasing scientific medicine.]—(From The Journal A. M A., Sept. 16, 1916.)

MARK WHITE GOITER SERUM AND MARK WHITE IODINIZED OIL

Report of the Council on Pharmacy and Chemistry

The “Mark White Goiter Serum Laboratories” of Chicago asked the Council to consider its products “Mark White Goiter Serum” and “Mark White Iodinized Oil.” The “serum” was claimed to be an “antibody blood serum from a goat with thyroidosis” while the “Iodinized Oil” was said to contain “about 4 grains of iodin” to “each c.c.” The therapeutic indications for the treatment were given as:

“Simple or Exophthalmic Goiter, Hyperthyroidism-dosis, Thyrosis, Thyroidosis, Thyrotoxicosis, Dementia.”

An ampule (2 c.c.) of the “serum” is to be injected into the thyroid to be followed one week later by an ampule (2 c.c.) of the “Iodinized Oil.” Repetition of this “treatment” once or twice a month is advised.

The Council asked for more specific information as to the composition of the remedies, particularly as to the preparation and nature of the serum; it also asked for evidence of the therapeutic value of the preparations. In reply, Mark White wrote:

“All that I can say regarding the serum is that it is made from the blood of goats with thyroid affection, and it has been found that the serum from these goats has antibodies which control, or has curative effect upon thyroid affections when injected into thyroid glands of either humans or animals. As to the iodinised oil, it is only an adjunct or side treatment which is not always used or indicated, and will only be furnished to the physician for use in case in his judgment his patient needs it. We shall also advise the use of quinin ... when indicated....”

The Council was referred for further information to a paper by Rachel Watkins, M.D., published in the Illinois Medical Journal. It is to be noted, incidentally, that the letterheads used by White in his correspondence bore in one corner the notation “Rachel Watkins, M.D., Practice Limited to Goiter and Other Disorders of the Thyroid Glands,” and in the other, “Mark White, Goiter Research.”

The information regarding the composition of this goiter treatment, as furnished in Dr. Watkins’ paper, was to this effect:

“The medical treatment consists of the administration of a blood serum derived from a thyrodized goat. Formula: Iodine 0.16 grams [according to a correction by Mark White, this should read 0.26 gm.], oil 0.25 c.c., serum q. s. 1 c.c.”

This description of the treatment differs from that furnished to the Council by Mark White in that here the iodin and oil appear to be combined with the serum. Dr. Watkins’ “formula” implies that the iodin is a routine medication, thus contradicting White’s statement, which, in turn, is at variance with the statements made in submitting the treatment.

Photographic reproductions (greatly reduced) of some of the letterheads used by the Mark White concern during the past five years.

The Council does not accept any biologic product until its sale in interstate commerce has been authorized by the secretary of the treasury in accordance with the federal law regulating the sale of viruses, serums, toxins and analogous products. The sale of the Mark White Goiter Serum has not been so authorized; consequently even if the preparation complied with other rules of the Council it could not be accepted.

In addition, however, this treatment conflicts with other Council rules. The statements regarding its composition are indefinite and contradictory (Rule 1); the evidence presented to support the therapeutic claims is insufficient in itself and does not appear to have been checked by any disinterested authority (Rule 6). Moreover, the recognized variation in the morphology and pathology of the types of goiter render it impracticable to treat cases of goiter by any routine procedure.

The foregoing report was submitted to the Mark White Goiter Serum Laboratory. In reply, a letter signed “Mark White, V.M.D.,” was received, which read, in part:

“... we hope at some future time to be able to give you more detailed information, but as you possibly appreciate that we have experienced for some time a demand on the part of many physicians that we furnish to them our therapy, which necessitates us furnishing it before all the detailed work has yet been accomplished, and I trust that you will be so kind as to bear patiently with us until we are better in a position to make a complete scientific application and report to you.”

White wrote further:

“The serum and iodized oil may be mixed for immediate use, but could not be put up only separate for the use of the profession and the therapy furnished Dr. Watkins she mixed as used.”

This statement throws no light on the discrepancies in the statements with regard to the place of the iodinized oil in the treatment, namely: (a) the original statement that the oil was to be given a week after the serum; (b) White’s statement (quoted earlier in this report) that the oil “is only an adjunct or side treatment” and “is not always used or indicated”; (c) the statement in Dr. Watkins’ paper that the oil and the serum are given in combination.

The Council declared the Mark White Goiter Serum and Mark White Iodinized Oil ineligible for New and Non­official Remedies and authorized publication of this report.

Editorial Note on the Mark White “Serum”

As some of our readers will remember, on April 26, 1913, The Journal called attention to the Mark White preparation which at that time was being exploited from Denver. The Propaganda Department has in its files a number of letters sent out from the Mark White concern at various times. One mailed in May, 1911, on the embossed stationery of “The Mark White Goiter Institute,” Exchange Building, Denver, was evidently a general letter sent to physicians, calling their attention to “the most important medical discovery of the age.” “Dr. Mark White, a graduate of the University of Pennsylvania,” said the letter, had discovered “a simple and harmless remedy” that would cure goiter. “Because of the desire to preserve the secrecy of this remedy it is given only at the office here.” It was then suggested that the doctor might send those of his patients who were suffering from thyroidism to the “Mark White Goitre Institute.” If he would do so he would be “given a commission of $10, in cases of the $50 fee with the additional $5 for each $50 increase.” It closed with some casuistic arguments, presumably for the purpose of overcoming the physician’s scruples, summing up the matter with the statement:

“No right thinking man will allow a narrow and self-seeking system of ethics to stand between him and his duty to the sick and suffering.”

About 1912 the name of the concern seems to have been changed, for we have in our files a letter addressed to a layman on the stationery of the “Mark White Goitre Treatment Company.” According to this letterhead the product this concern had for sale was “Goitreine” discovered by Mark White, “President and General Manager.” Mr. White’s letter to the sufferer from goiter assured him that if he would take “Goitreine” he might “be practically sure of an immediate and permanent cure.” “Goitreine,” according to White, “has absolutely and permanently cured 90 per cent.” of all cases of goiter in which it has been used—“and the other ten showed remarkable improvement.” It was efficacious for all forms of goiter and “cannot possibly harm.”

The person who received this assurance might have had his confidence in it shaken had he seen a copy of the Denver News for May 23, 1911, in which was reported a case of collapse and death in a woman following an injection given in White’s office. The paper stated that the death certificate was signed by one W. A. Gray and gave “fatty degeneration of the heart and goiter” as the cause of death. Gray, it seems, was the licensed physician employed by Mark White to administer “Goitreine”—if that is what White happened to be calling his product at that time. For here it may be stated, parenthetically, that Mark White is not a physician; he is a veterinarian.

In February, 1913, Mark White sent a circular letter to a number of medical publications with the request that it be printed in full in the next issue, “to cover one full page of space.” The letter White wanted printed was addressed to doctors offering to “enter into a copartnership agreement” with such physicians who would be willing to treat “patients with goiter affections on a 50 per cent. commission basis.”

“You would be expected to make a cash charge to the patient for the treatment, remitting on the same day our 50 per cent. to us, when ordering the treatment, giving the treatment in no cases for less than $50.00.”

About the same time that Mark White made this “fifty-fifty” offer, he sent in an advertisement to be published in the classified column of The Journal. At that time he was told his advertisement was not acceptable; we now reprint it, however, free of charge. Here it is:

“WANTED—ONE OR MORE PHYSICIANS in each vicinity to administer and represent our new medical treatment for GOITER. Good margin of profit. Write for copy of contract. The Mark White Goitre Treatment Co., Denver, Colo.”

In 1914, White moved to Chicago. At least the card which we reproduce so indicates. At that time, as will be seen, “Dr. Mark White” was “personally associated” with Peter S. Clark, M.D. According to the same card Dr. F. D. Paul of Rock Island, Ill., seems to have been his “associate” for that particular locality. In this connection, it is worth noting that a Rock Island paper, in one of its issues during July, 1913, devoted a good deal of space to “Dr. Mark White” who was at that time in Rock Island “directing Dr. Frank D. Paul in the administering of the treatment.” There was nothing to indicate that this notice was an advertisement or that the editorial appearing in the same issue puffing White’s “important cure,” was paid for.

When exploited from Denver the Mark White “goiter cure” was advertised in the daily papers. Here is a photographic reproduction (reduced) of an advertisement that appeared in the Denver Post, Sept. 1, 1912.

Dr. W. A. Gray, who has already been mentioned as White’s associate in Denver, seems to have been doing business in Illinois some time in 1913 and a Princeton (Ill.) paper had some uncomplimentary things to say about him. Finally in July, 1913, this item appeared in a Princeton paper.

“Dr. W. A. Gray, the goiter specialist who operated last winter at Princeton and Walnut until he became embroiled with Dr. Mark White, a Denver veterinary and originator of the cure, over a division of the spoils, has opened a goiter institute in Chicago under his own name. Advertisements of the Dr. Gray Goiter Institute appeared Sunday morning in the Chicago Examiner and other morning papers. Dr. Gray and Mark White broke off their relations after their disagreement at Walnut, and Dr. Gray slightly changed the ingredients of the goiter cure and started off on his own hook.”

One of Gray’s advertisements in Chicago newspapers made the claim that “Dr. Gray’s New Medical Treatment removes the cause of goiter in seven days.”

Photographic reproduction (reduced) of the “professional” card used by “Dr. Mark White” after he came to Chicago.

The Tulsa (Okla.) associate of “Dr.” White seems to have been Dr. J. H. Morgan and the Tulsa papers of June, 1914, tell of “Dr.” White’s visit to that city “for the purpose of instructing Dr. J. H. Morgan in the technique of his new medical treatment for nervous disorders and goiter.” Some months later—in December, 1915—the following little item appeared in a Tulsa paper:

“Dr. Mark White was found guilty in the county court yesterday of practicing medicine without a license and was fined $50. Doctor White is a goiter specialist.”

In September, 1915, Mr. Thomas S. Hogan, the efficient counsel for the Illinois State Board of Health, instituted action against Mark White for practicing medicine without a license. The case was tried Oct. 15, 1915, and the jury, after being out four hours, returned a verdict of “not guilty.” Attorney Hogan attributes the failure to obtain a conviction to the testimony of Dr. Rachel Watkins, who said she had a partnership arrangement with White in carrying on the medical business. It was about this time that Mark White seems to have issued some new letterheads. These bore in their upper left hand corner the device “Rachel Watkins, M. D., Practice Limited to Goiter and Other Disorders of the Thyroid Glands,” while the upper right hand corner read “Mark White, Goiter Research.”

On Dec. 9, 1915, Rachel Watkins, M. D., of Chicago, read a paper entitled “A Serum Treatment for Physiologically Defective Thyroids, With Clinical Reports” before the Stock Yards Branch of the Chicago Medical Society. The “serum treatment” discussed was Mark White’s “Goitreine” which, in the course of its checkered career, had lost its original name by the wayside. This paper appeared in the December, 1915, issue of the Illinois Medical Journal.

Probably emboldened by the ease with which a component part of the American Medical Association “fell for” a paper exploiting a “goiter cure,” Dr. Watkins requested that she be permitted to read a paper on the same subject before the Section on Pharmacology and Therapeutics at the Detroit meeting of the American Medical Association last June. The request was refused. Dr. Watkins is apparently no longer connected with White and in fact has protested against the use of her name by White in connection with his “goiter cure.”

[After the above was in type and ready for the pages of The Journal, attention was called to the Official Bulletin of the Chicago Medical Society of Sept. 16, 1916. This Bulletin contained a full page advertisement of the Mark White “goiter cure.” The advertiser referred to the preparation as having been “announced to the Chicago Medical Society” and declared it to be “an ethical therapeutic agent.” Mark White was described as “a medical research student” but no hint was given that he is a veterinarian. After again emphasizing that “this therapy is ethically proven” physicians were invited to “visit our goats when convenient” and the advertisement closed with the modest claim that “this thyroid therapy has equal curative therapeutic value in these cases as quinin in malaria.” And this sort of pseudo-scientific claptrap is presented to a presumably learned profession through its own official Bulletin—but what’s the use of commenting!]—(From The Journal A. M. A., Sept. 23, 1916.)

KORA-KONIA

Report of the Council on Pharmacy and Chemistry

Kora-Konia is a “dusting powder” which at present is advertised to the medical profession through medical journals, circulars, post cards and sample packages. It is put out by the “House of Mennen,” which sells various toilet preparations such as talcum powder, shaving soap, etc. On the trade package is the statement:

“Indicated in the treatment of Acne, Dermatitis, Eczema Intertrigo; in obstinate cases of chafing, prickly heat, nettle rash, chicken pox, measles, scarlatina and irritations of the skin; as a soothing absorbent and antiseptic dusting powder and as an umbilical dressing.”

While a circular asserts that:

“Kora-konia is indicated in the treatment of acne, dermatitis, eczema and eczematous conditions of the utmost severity,... eruptive fevers,...”

What purports to be a physician’s testimonial reads:

“I used Kora-Konia in a new born case of inherited syphilis and the eruption soon cleared up.”

Germicidal powers are claimed for Kora Konia in a medical journal advertisement. In view of the various claims made and the fact that it is advertised to the medical profession, the Chemical Laboratory of the American Medical Association was asked to analyze Kora-Konia. This was done and the chemists reported as follows:

LABORATORY REPORT

Kora-Konia is a white powder, slightly greasy to the touch. Qualitative tests showed the presence of boric acid, zinc, magnesium, a solid fatty acid and material insoluble in hydrochloric acid containing magnesium and aluminum. Starch was not found. Quantitative determinations gave the following results:

Acid-insoluble material (talc)48.3 per cent.

Magnesium (Mg⁺⁺) soluble in dilute acid 1.2 per cent.

Zinc (Zn⁺⁺) 4.5 per cent.

Stearic acid (impure)39.2 per cent.

Boric acid 3.0 per cent.

Carbon dioxide (CO₂) 1.5 per cent.

From this analysis it is concluded that Kora-Konia has essentially the following composition:

Zinc stearate U. S. P.44 per cent.

Talc48 per cent.

Magnesium carbonate U. S. P. 5.0 per cent.

Boric acid 3.0 per cent.

Essentially this dusting powder consists of the well-known substances talc and zinc stearate in about equal proportions to which small quantities of magnesium carbonate and boric acid have been added. Inasmuch as the claim is made, by inference at least, that Kora-Konia represents original investigation carried out “with the cooperation of the medical profession” it should be stated that the preparation of commercial zinc stearate was described and recommended as a dusting and toilet powder nearly twenty-five years ago.96

There is nothing new or original in any one of these substances or in the combination. The extravagant and unwarranted claims made for this simple dusting powder are undoubtedly leading the public as well as some thoughtless physicians, to place undeserved confidence in it. In view of the small amount of boric acid present in the powder, its antiseptic powers must be slight and its germicidal powers almost nil. The Council declared Kora-Konia ineligible for New and Non­official Remedies and authorized publication of this report.—(From The Journal A. M. A., Sept. 30, 1916.)

THE THERAPEUTIC VALUE OF THE GLYCEROPHOSPHATES

Report of the Council on Pharmacy and Chemistry

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