Chapter XII: Introduction: The Council on Pharmacy and Chemistry was established (5)

[37] Huston: Ann. et bull. Soc. roy. de sc. méd. et nat. =70=:178, 1912.

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 2-1/2 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.

[38] Starling: Lancet, London =2=:433, 1905.

_Preparation._--All of the more dissociated acids liberate secretin from intestinal mucosa on boiling. Their action is dependent on the degree of dissociation,[39] carbonic and boric acids being inactive.[40] Secretin can also be prepared with strong soaps (from 10 to 30 per cent. sodium oleate), alcohol (70 per cent.,[41] 0.6 per cent. sodium chlorid[36]). The acid and soap in the duodenum produce secretion; there is no necessary correspondence between the action of a substance in the intestine and that obtained by injection after boiling mucosa with it. The sodium chlorid, bile, maltose and glucose produce some secretion by the latter method yet none by the former.[36] On the other hand, ether, chloral and oil of mustard excite secretion when in the intestine, but no secretin can be prepared from boiled mucosa by their action. The irritation of the lining cell has produced the necessary hydrolysis.[38] In well-controlled experiments, Wertheimer and LePage[42] found that after the introduction of acid, secretion is secreted into the lumen of the intestine. Matuso[36] confirmed their results, and found this a satisfactory method for the preparation of secretin. It is said that secretin can be obtained by merely boiling the mucosa with water, but the results are inconstant.[43]

[39] Frouin and Lalou: Compt. rend. Soc. de biol., =71=:189, 1911.

[40] Camus: Compt. rend. Soc. de biol., 1902, =54=:442, 1902.

[41] Fleig: Jour. de physiol. et de path. gén. =6=:32, 50, 1904.

[42] Wertheimer and LePage: Jour. de physiol. et de path. gén. =4=:1061, 1070, 1902.

[43] Stepp: Jour. Physiol. =43=:441, 1912.

_Action._--Secretin is an excitant not only of the pancreatic juice but also of the liver and the intestinal mucosa. The flow of bile is markedly accelerated (Henri and Portier,[44] Enriquez and Hallion[45]), likewise that of succus entericus (Delezenne and Frouin,[46] Bottazzi and Gabrielli[47]), and intestinal peristalsis is stimulated (Enriquez and Hallion,[48] Falloise[49]). Injections of secretin produce a marked vasodilatation, but the secretory effect is independent of the blood pressure changes. The pancreas is not readily fatigued by secretin. Bayliss and Starling[50] have obtained undiminished flow after eight hours of continuous injection. Our experience confirms this result. Also, equal doses of secretin give corresponding results at various intervals. Moreover, anesthesia does not affect the flow. Secretin is unrecoverable from the glands even after two hours of continuous injection.[51] The juice obtained by secretin has been subject to many studies.[52] It is of high alkalinity (about seventh normal), contains all the pancreatic ferments, and corresponds in all respects to the juice obtained in digestion from permanent pancreatic fistulas.[53]

[44] Henri and Portier: Compt. rend. Soc. de biol. =54=:620, 1902.

[45] Enriquez and Hallion: Presse méd. =1=:105, 1903.

[46] Delezenne and Frouin: Compt. rend. Soc. de biol. =56=:319, 1904.

[47] Bottazzi and Gabrielli: Arch. internat. de physiol. =111=:156, 1905.

[48] Enriquez and Hallion: Bull. gén. de thér. =162=:202, 1911.

[49] Falloise: Bull. de l’Acad. roy. de Belgique =5=:945, 1902.

[50] Bayliss and Starling (Note 2). Matuso (Note 6). Arch. internat. de physiol. =10=:335, 1911.

[51] Dixon and Hamill: Jour. Physiol., 1909, xxxv, 314.

[52] Bayliss and Starling: Jour. Physiol., 1904, xxx, 61. Bierry: Compt. rend. Soc. de biol., 1907, lxii, 433. Bierry and Terroine: Compt. rend. Acad. de sc., 1905, cxli, 146. Lalou: Comp. rend. Acad. de sc., 1910, xxix, 824. Morel: Compt. rend. Soc. de biol., 1909, lxvii, 36. Strassano and Billoro: Compt. rend. Soc. de biol., 1902, liv, 937.

[53] Bayliss and Starling (Note 23).

_Specificity._--In a maceration of the duodenojejunal mucosa, such as we have in secretin, the known substances are proteoses and peptones, acid amins, bile salts, beta-imidazolethylamin, cholin, gelatin and inorganic salts. These substances, individually and severally, together with their derivatives, are devoid of secretory action. Chemically, secretin, is then a specific entity. But like epinephrin, in its distribution, it is nonspecific. Active preparations have been made from an extraordinary variety of animals among the different classes of vertebrates (Camus,[54] Bayliss and Starling,[55] Chapman[56]). It is likewise found in the new-born and in the fetus.[57] Its action, however, like its chemical composition, is markedly specific. It stimulates the flow of pancreatic juice, bile and succus entericus. Its effect on the gastric glands is negative, and on the saliva likewise.[58] On the other hand, no other extracts produce pancreatic secretion. Dr. Koch, who, in collaboration with Dr. Keeton and Dr. Luckhardt, has done the most recent work on gastrin[59] (a substance that most nearly resembles secretin) and has isolated an extremely active preparation, finds that gastrin injection has likewise no effect on the pancreas. Camus and Gley,[60] with crude preparations, had previously obtained a similar result.

[54] Camus: Jour. de physiol. et de path. gén. =4=:998, 1902.

[55] Bayliss and Starling: Jour. Physiol. =29=:174, 1903.

[56] Chapman: Proc. Linnaean Soc., New South Wales =1=:92, 1905.

[57] Camus: Compt. rend. Soc. de biol. =61=:59, 1906. Hallion and Lequex: Compt. rend. Soc. de biol. =61=:33, 1906.

[58] Derouaux: Arch. internat. de physiol. =3=:44, 1905. Lambert and Myer: Compt. rend. Soc. de biol. =54=:1044, 1902. Starling: Lancet, London =2=:501, 1905.

[59] Keeton and Koch: Am. Jour. Physiol. =37=:481, 1915.

[60] Camus and Gley: Compt. rend. Soc. de biol. =54=:648, 1902.

_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.

[61] Lalou (Note 21). May: Jour. Physiol. =30=:400, 1904.

Secretin is oxidized readily. If left standing uncovered for a summer’s day, the preparation will be inactive.[51] Even if kept in the ice-chest (no other precaution being taken), its activity is lost in a very few days. Sunlight undoubtedly hastens the oxidative process. If care is taken as to sterility, however, and the secretin is kept in the ice-chest, well stoppered and in a dark flask, it will retain its activity for several weeks.

Dixon and Hamill[51] claimed that secretin disappears quantitatively on passage through a Berkefeld filter at 5 mm. pressure. Lalou,[62] using higher pressure, was unable to confirm the finding, but obtained a marked decrease in activity. Our results are in accord with those of Lalou.

[62] Launoy: Arch. internat. de Physiol. =3=:62, 1906. Morel and Terroine: Compt. rend. Soc. de biol. =67=:36, 1909. Zunz: Arch. internat. de physiol. =8=:181, 1909. Lalou: Jour. de physiol. =14=:465, 1912.

_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]

[63] Starling: Proc. Roy. Soc. Med., 8, No. 4, 1914, Therap. and Pharm. Section, p. 29.

CLINICAL USE OF SECRETIN

_Diabetes Mellitus._--Moore, Edie and Abram[64] were the first to suggest a therapeutic value for secretin, having obtained favorable results with secretin administration in diabetes. They argued that the internal secretion of the pancreas _may_ be stimulated by secretin, and that some cases of diabetes _may_ be due to lack of this necessary excitant. Owing to the importance of the question, their announcement was followed quickly by numerous investigations by other observers. Previously, Spriggs, at the suggestion of Starling, had tried intravenous injections of secretin free from depressor substance in a diabetic patient, and had obtained negative results. Moore, Edie and Abram gave their secretin by mouth over long periods. Of the five cases cited in their first paper, two were negative. The third was that of a man, aged 25, who received daily 30 c.c. of secretin. After a latent period of three weeks, the sugar suddenly fell, and after four months the urine was sugar-free. Six months later a relapse occurred with the development of phthisis and death. The other two patients were a boy, aged 7, and a girl, aged 9, whose urine in from three to five weeks became sugar free during the secretin treatment in spite of severe diabetes. One of these patients later relapsed.[65] Bainbridge and Beddard[66] gave secretin a thorough trial in three cases with negative results, and are disposed to attribute the results of Moore to dieting. Dakin and Ransom[67] cited one case, secretin being given for twelve weeks, with negative results; Foster,[65] nine cases, all negative; Charles,[68] three cases, all negative. Crofton,[69] however, gave secretin a trial in one case with favorable results. Moore, Edie and Abram, in a later paper,[70] report a large number of cases tried with the majority of results negative, though in some cases an improvement in the digestion, and in certain cases an increase of weight was noted.

[64] Moore, Edie and Abram: Biochem. Jour., =1=:28, 1906.

[65] Foster: Jour. Biol. Chem., =2=:297, 1906.

[66] Bainbridge and Beddard: Biochem. Jour., =1=:429, 1906.

[67] Dakin and Ransom: Jour. Biol. Chem., =2=:305, 1906.

[68] Charles: Med. Press and Cir., =133=:578, 1906.

[69] Crofton: Lancet, London, =176=:607, 1909.

[70] Moore, Edie and Abram: Biochem Jour., =3=:82, 1908.

One method of testing the basis of Moore’s theory would be by examining the prosecretin content of the intestine in diabetics. Bainbridge and Beddard found, in the paper referred to,[66] that from five of the six cases of diabetics examined postmortem, little or no secretin could be prepared; but in a subsequent report of seven cases,[71] they found only one in which the secretin obtained was scanty. The failure to obtain secretin in some cases they claim is probably due to the rapid postmortem degeneration of diabetic tissue. Evans,[72] in Starling’s laboratory, found that in dogs made recently diabetic by total pancreatectomy, but little secretin could be obtained. Hedon and Lisbonne,[73] and Pemberton and Sweet[74] report, on the contrary, that the duodenum of diabetic dogs is rich in prosecretin. Bainbridge and Beddard,[71] working on a diabetic cat, likewise found prosecretin to be present in normal quantity.

[71] Bainbridge and Beddard: Biochem. Jour. =3=:82, 1908.

[72] Evan: Jour. Physiol. =44=:461, 1912.

[73] Hedon: Compt. rend. Soc. de biol. =74=:375, 1913.

[74] Pemberton, Ralph, and Sweet, J. E.: Further Studies on the Influence of the Ductless Glands on the Pancreas, Arch. Int. Med., May, 1910, p. 466.

_Digestive Disturbances._--Secretin for digestive disturbance was first used in the “acid duodenal medication” of Enriquez.[75] This consisted in the giving of tartaric acid in thick keratin capsules, the acid not being liberated until the duodenum was reached, where it provoked the formation of secretin. “The secretin mechanism,” he says, “is probably capable of pathologic disturbance as would result, for example, with diminished acidity of chyme, disturbance of the normal motility of the stomach or pylorus, or diminished prosecretin in the mucosa. Such a condition would produce disturbance of the pancreatic, biliary and intestinal secretions, and interfere with intestinal movements, with a clinical syndrome of intestinal dyspepsia as a result, among the chief and most constant symptoms of which would be constipation.” “The acid duodenal medication” was submitted to wide clinical use, and very favorable results in certain obstinate cases of constipation were reported. In regard to “diminished prosecretin in the mucosa,” Wentworth[76] has claimed that in infantile atrophy such is the condition, but Sweet and Pemberton[77] have found that the difficulty of preparing secretin from human duodenums is such as to render Wentworth’s findings inconclusive.

[75] Enriquez: Bull. du Lab. de biol. Appliq. 2, No. 2-No. 8, 1904.

[76] Wentworth, A. H.: The Cause of Infantile Atrophy, J. A. M. A., July 20, 1907, p. 204.

[77] Sweet, J. E., and Pemberton, Ralph: Experimental Observations on Secretin, Arch. Int. Med., February, 1908, p. 231.

Beveridge[78] suggests the use of secretin in (_a_) pyloric stenosis, (_b_) pancreatic insufficiency, (_c_) hepatic stimulation and cirrhosis of the liver (_d_) to stimulate peristalsis in colonic stasis, (_e_) in gastro-enterostomy and short-circuiting of the intestines. He claims to have used it in over a hundred cases with “brilliant results,” and cites four typical histories. The G. W. Carnrick Company, which manufactures “Secretogen,” an alleged secretin preparation, cites a number of authorities[79] as also recommending secretin for digestive disorders. Harrower, who is or was connected with the Carnrick Company, in clinical journals[80] has ardently advocated the use of secretin for a large number of maladies.

[78] Beveridge: Am. Med. =20=:255, 1914.

[79] Lockwood, G. R.: Diseases of Stomach, 1913, Chapter on Achylia. Bassler, Anthony: Am. Jour. Gastro-Enter., 1914; Kemp, R. C.: Diseases of Stomach, Intestine and Pancreas, 1912. Reed, Boardman: Am. Jour. Gastro-Enter., October, 1912. Ewald (Therapie der Gegenwart, 1915, p. 5) reports favorable results with Secretogen in one of thirteen cases.

[80] Harrower: Pediatrics =25=:430, 1913; New York M. J. =118=:315, 1913; Arch. f. Verdauungskr. =20=:577, 1914.

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.

[81] Flieg: Arch. gén. de méd. =191=:1482, 1903.

[82] Wertheimer and Duvillier: Compt. rend. Soc. de biol. =68=:535, 1910.

_The destructive action of the digestive enzymes leads us to believe that it is in inactive form that secretin is absorbed._ Like epinephrin, it cannot pass through the digestive tract. Bayliss and Starling state that it is destroyed by one hour’s tryptic digestion. Lalou[62] worked with the action on secretin of pepsin, dog’s gastric juice, pancreatic juice, succus entericus and erepsin, and found in each case a destructive effect, even almost after mixing; and after five minutes over 75 per cent. of the activity had disappeared. Matuso[36] introduced 30 c.c. of active secretin into the intestine, removed it five minutes later, and found that no activity remained.

Other methods of administration have been tried. Subcutaneous injections are practically negative (Matuso,[36] Hallion[83]) and intrapleural injections are likewise negligible (Bayliss and Starling[55]).

[83] Hallion: Presse méd. =20=:433, 1912.

Starling[63] finds that continued intravenous injections of secretin in a healthy dog produces after a time severe symptoms of collapse, which, he believes, are due to change in the intestinal mucous membrane caused by the entry and non-neutralization of the strongly alkaline pancreatic juice.

Intestinal digestion seems little affected in achylia gastrica (Stockton,[84] Ehrman and Lederer,[85] Bayliss and Starling[32]). This may be due to other secretin stimulants as fats, or to the action of the nervous mechanisms (Meltzer[86]).

[84] Stockton: In Osier and McCrae’s Modern Medicine =3=:19, 1914.

[85] Ehrman and Lederer: Deutsch. med. Wchnschr. =35=:879, 1909.

[86] Meltzer, S. J.: The Factors of Safety in Animal Structure and Animal Economy, J. A. M. A., Feb. 23, 1907, p. 655.

THE DESTRUCTION OF SECRETIN BY HUMAN GASTRIC JUICE

We have carried out in detail experiments on the digestive effect of human gastric juice on secretin. Our results in every respect confirm the findings of Lalou,[62] who worked with commercial pepsin and dog’s gastric juice, but are even more striking because of the much superior quality of pure human gastric juice.

_Methods._--The human gastric juice was obtained from Mr. V., the gastric fistula case of our laboratory. The chemical and digestive characters of his juice are discussed in a recent paper.[87] In the different experiments, different samples of gastric juice were used. The secretin employed was always freshly prepared. Digestion was carried out in the incubator at 38 C. with the reaction of 0.4 per cent. acid, and the end of the period was marked by either boiling the mixture or (in the first two experiments) by turning the mixture alkaline. The action of the preparation, we proved, was not influenced by the method used. The dogs on which the preparations were tested were prepared for carotid blood pressure, injection into the external jugular vein, and cannula in the pancreatic duct, essentially the methods of Bayliss and Starling[32] being employed. The preparations were injected at body temperature after being neutralized and filtered. Except for the addition of normal salt solution instead of gastric juice, the control injections of secretin were submitted to exactly the same treatment as the other preparations.

[87] Carlson: Am. Jour. Physiol. =38=:248, 1915.

_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

=====================================================================
| | Secretion of Pancreatic Juice in Drops
| +--------+--------------------------------------+--------
No. |Quan-|10 C.c.c| The Secretin After Incubation |10 C.c.
of | tity|Secretin| with Human Gastric Juice |Secretin
Exper-|of |Control +-----+------+-----+------+-----+------+Control
iment|Gas- |--Begin-| | | | | | |--End of
| tric| ning |Dig. |Secre-|Dig. |Secre-|Dig. |Secre-|Experi-
|Juice|Experi- |Time,| tion |Time,| tion |Time,| tion | ment
|Used,| ment |Hrs. |Rate |Hrs. |Rate |Hrs. |Rate |
|C.c. | | | | | | | |
------+-----+--------+-----+------+-----+------+-----+------+--------
1 | 2 | 28 |6 | 0 |4 | 0 |2 | 0 | 16
2 | 2 | 110 |2 | 7 |1-1/2| 18 |1 | 18 | 41
3 | 2 | 40 |1 | 7 | 3/4| 7 | 1/4 | 8 | 31
4 | 1 | 21 | 1/2| 11 | 1/4| 12 | 1/60| 14 | 18
5 | 8 | 20 | 1/2| 1 | 1/4| 3 | 1/60| 6 | 18
6 | 5 | 53 | 1/2| 2 | .. | .. | .. | .. | ..
------+-----+--------+-----+------+-----+------+-----+------+--------

We also tried the effect of keeping the digestive time _constant_ and varying the amount of gastric juice employed. Increasing the quantity of gastric juice used increases the quantity of secretin destroyed (Table 2).

TABLE 2.--EXPERIMENT 7*

Pancreatic
Preparation Juice Drops
10 c.c. secretin 20
10 c.c. secretin digested with 0.5 c.c. gastric juice 15
10 c.c. secretin digested with 3 c.c. gastric juice 13
10 c.c. secretin digested with 10 c.c. gastric juice 8

* The digestive time was kept constant at fifteen minutes. (The gastric juice used had been _diluted_ with stomach washings.)

The reader will observe in Table 1 that the results obtained from the control injection of secretin at the beginning of the experiment is uniformly greater than that obtained after several injections of digested secretin.

In view of the established fact that equal quantities of secretin can generally be relied on to produce results,[21] 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

Pancreatic
Preparations Juice Drops

Experiment 8:

10 c.c. secretin, five injections of inert depressor substances 29
10 c.c. secretin, two injections of completely digested secretin 28
10 c.c. secretin, eight injections of inert depressor substances 16
10 c.c. secretin 16

Experiment 9:

10 c.c. secretin (control, beginning of experiment) 21
10 c.c. secretin, after thirty minutes incubation with 1 c.c.
_boiled_ gastric juice 27
10 c.c. secretin, after thirty minutes incubation with 1 c.c.
_fresh_ gastric juice 11
10 c.c. secretin (control, end of experiment) 18

The findings of Lalou, confirmed by us, explain the anomaly that has led Delezenne[88] to put forward the antisecretin theory.

[88] Delezenne and Pozerski: Jour. de Physiol., =14=:540, 1912.

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.

[89] Pawlow: Ergeb. de Physiol., O., p. 266, 1902.

TABLE 4.--DETAIL OF TYPICAL EXPERIMENTS

Dogs with pancreatic fistulas, showing that secretin given by mouth has no action on the pancreas

===================================================================
| Rate of Secretion of Pancreatic
| Juice in C.c. per Hr.
+------------------+------------------
| Continuous | Continuous
| Secretion | Secretion
Material Fed by Stomach Tube | Before Feeding | After Feeding
|-----+------+-----+-----+------+-----
|First|Second|Third|First|Second|Third
|Hour | Hour |Hour |Hour | Hour |Hour
-----------------------------+-----+------+-----+-----+------+-----
150 c.c. active secretin, | | | | | |
slightly acid | 6.5| 3.6 | 3.9 | 20.0| 6.0 | 8.0
150 c.c. active secretin, | | | | | |
slightly alkaline | 13.0| 11.0 | 5.0 | 23.0| 26.0 | 12.0
150 c.c. secretin passed | | | | | |
through Berkefeld | 7.8| 7.5 | 7.4 | 23.0| 13.0 | 11.0
150 c.c. extract of colon | 11.6| 12.0 |11.4 | 30.0| 19.6 | 14.8
150 c.c. extract of gastric | | | | | |
mucosa | 10.0| 7.0 | 8.0 | 23.0| 7.5 | 4.0
150 c.c. extract of muscle | 6.9| 11.0 | 6.4 | 35.0| 5.0 | 7.0
150 c.c. 0.4% HCl | | | | | |
(diluted to 250 c.c.) | 6.0| 8.0 | 4.0 | 33.0| 36.0 | 17.0
-----------------------------+-----+------+-----+-----+------+-----

_Results._--We have data from six dogs with a total of seventy-six experiments. As shown in Table 4, the administration of secretin causes an increase in the flow of pancreatic juice, _but_ the administration of inert substances as extracts of colon, gastric mucosa or muscle causes a like increase. The activity of the secretin may be reduced to a low value by exposure to sunlight, or filtering through a Berkefeld filter, yet the response of the pancreas is not correspondingly reduced. The secretion that occurs in the control cases, every one will admit, is but secondary to the production of gastric juice with its accompanying hydrochloric acid, that is, excited by virtue of the extractives and water in the preparations. Such, we can prove, is the only action of secretin. A mixture of gelatin, peptone and salt water, the chief incidental constituents of a secretin preparation, gives as striking results as ever obtained from secretin administration. Yet the objection may be made that the response of the pancreas that is due to the incidental constituents of secretin is maximal, and that the secretin consequently has no opportunity to display its particular potency. But, as inspection of the accompanying tables illustrate, the administration of hydrochloric acid shows that the response is by no means maximal. Let us cite a striking experiment. For three hours before the administration of hydrochloric acid, the secretion in cubic centimeters was respectively 29.4, 11.75 and 35.4 c.c.; for the three hours after, respectively 88.0, 49.0 and 40.5 c.c.

TABLE 5.--SUMMARY OF EXPERIMENTS

Dogs with pancreatic fistula, weight 14 kg. Secretin given by mouth

====================================================================
| |Rate of Secretion|
| | of Pancreatic |
| | Juice in |
No. of | | C.c. Per Hour |Increase
Experi-| Material Fed +--------+--------+ in
ment | | Three | Three | C.c.
| | Hours | Hours |
| | Before | After |
| |Feeding |Feeding |
-------+---------------------------------+--------+--------+--------
3 |Secretin slightly acid | 5 | 11 | 6
5 |Secretin slightly alkaline | 24 | 30 | 6
4 |Secretin passed through Berkefeld| 18 | 23 | 5
1 |Secretin exposed to sun for 4 hrs| 16 | 29 | 13
2 |Extract of colon (rabbit) | 19 | 29 | 10
3 |Extract of gastric mucosa | 14 | 23 | 9
3 |Extract of muscle | 8 | 16 | 8
2 |Mixture of gelatin, peptone and | 23 | 33 | 10
| salt | | |
1 |1 per cent. peptone solution | 6 | 8 | 2
4 |0.2 per cent. hydrochloric acid | 13 | 37 | 24
3 |Milk and bread | 7 | 20 | 13
-------+---------------------------------+--------+--------+--------

It is possible by large doses of sodium bicarbonate given shortly before the administration of a preparation so to depress the stomach that it does not respond with the usual production of hydrochloric acid. Under these conditions the administration of secretin is uniformly negative, but the administration of hydrochloric acid on the contrary still serves to increase the pancreatic secretion (Table 6).

TABLE 6.--SECRETIN IN EXPERIMENTAL “ACHYLIA GASTRICA”

====+=================================================================
| | Rate of Secretion of Pancreatic Juice
| | in C.c. Per Hour
| +--------------------+-------------------
Exp.| Material Fed |Continuous Secretion| Secretion After
No. | | Before Feeding* | Feeding
| +------+------+------+------+------+-----
| |First |Second|Third |First |Second|Third
----+------------------------+------+------+------+------+------+-----
1 |} {| 8.7 | 7.5 | 6.8 | 3.0 | 1.0 | 4.8
2 |} 150 c.c. secretin {| 4.5 | 6.5 | 10.0 | 6.0 | 7.5 | 7.6
3 |} {| 15.6 | 8.1 | 16.0 | 3.9 | 4.9 | 2.9
| | | | | | |
1 |} 150 c.c. 4% HCl {| 9.8 | 7.0 | 6.0 | 65.1 | 28.0 | 7.1
2 |} (diluted to 250 c.c.){| 17.4 | 18.5 | 17.0 | 34.0 | 18.0 | 20.0
----+------------------------+------+------+------+------+------+-----

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

COMMERCIAL PREPARATIONS OF SECRETIN

_Secretogen and Elixir Secretogen._--The Carnrick Company offers Secretogen[90] for use in a large number of conditions. The following indications for the use of the preparation purport to be based on clinical tests covering a period of several years: dyspepsia, and the indigestions generally, fermentative disorders, gastric catarrh, flatulence, nausea; pancreatic insufficiency, intestinal indigestion; gastric secretory deficiencies, apepsia; constipation and hepatic torpor; intestinal stasis; diarrhea; infantile diarrhea, “summer complaint,” marasmus, inanition and malnutrition; gastric atony and dilatation; cholecystitis and gallstones; nephritis, neurasthenia, cachexia and cancer; epilepsy and high blood pressure. Testimonials are presented as to results in most of these conditions.

[90] Secretogen, Report of the Council on Pharmacy and Chemistry, J. A. M. A., May 1, p. 1518, 1915.

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

=======================================================================
| | Secretion of Pancreatic Juice in Drops,
| Quantity of | Following Intravenous Injection
Exp.| Secretogen +--------+---------------------------+------+--------
No.| and Elixir | | Secretogen in | |
| Secretogen |Control +---------+----+-------+----+ |Control
| Used* |10 C.c. |Distilled|0.4%| 70% |0.9%|Elixir|10 C.c.
| |Secretin| Water |HCl |Alcohol|NaCl| |Secretin
----+-------------+--------+---------+----+-------+----+------+--------
1 |Secretogen, | | | | | | |
| 1 tablet; | 109 | 0 | 0 | 0 | 0 | 0 | 59
| Elixir, | | | | | | |
| 15 c.c. | | | | | | |
1 |Secretogen, | | | | | | |
| 6 tablets | ... | .. | 0 | .. | .. | .. | ..
2 |Secretogen, | | | | | | |
| 3 tablets; | 16 | 0 | 0 | 0 | 0 | 1(?)| 16
| Elixir, | | | | | | |
| 15 c.c. | | | | | | |
3 |Secretogen, | | | | | | |
| 5 tablets | ... | .. |1(?)| .. | .. | .. | ..
4 |Secretogen, | | | | | | |
| 25 tablets | 14 | .. |1(?)| .. | .. | .. | 8
5 |Secretogen, | | | | | | |
| 100 tablets | 110 | .. | .. | .. | 21 | .. | 67
6 |Secretogen, | | | | | | |
| 100 tablets;| 19 | .. | 5 | .. | 1 | 2(?)| 8
| Elixir, | | | | | | |
| 125 c.c. | | | | | | |
7 |Elixir, | | | | | | |
| 50 c.c. | ... | .. | .. | .. | .. | 1(?)| ..
----+-------------+--------+---------+----+-------+----+------+--------

* One to three tablets is (according to the label) the therapeutic dose of Secretogen; 4 to 12 c.c. the dose of Elixir Secretogen.

_Results._--In only one case was a slight response obtained, the others gave none. Small and large doses were equally inert (Table 7, Figs. 2, 3). The preparations, though inert, always produced a depression in blood pressure, sometimes even greater than that caused by active secretin. Among our many tests, one bottle was found, however, to be a little different from the rest (Experiment 4). Its entire content, 100 tablets, had been ground and boiled in 0.9 per cent. sodium chlorid. The extract on injection was found to have a small but unmistakable secretin reaction, equivalent to about 2 c.c. of the control secretin used. But repeated experiments were unable to duplicate this result. The “Secretogen” and “Elixir Secretogen” were all supposedly fresh preparations, the retail drug store informing us that a fresh supply was obtained from the wholesale house each week.

Secretogen, then, contains practically no secretin, and even if it did contain secretin, it can have no effect on the pancreas when taken by mouth. The indications for Secretogen, therefore, are based on false premises, and the testimonials are worthless.

_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.”

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

=================================================================
| | Secretion of Pancreatic Juice in Drops,
| | Following Intravenous Injection
Exp.| Number +--------+-------------------------------+----------
No. |Duodenin| Control| Duodenin in | Control
| Tablets| 10 C.c.+---------+------+-------+------+ 10 C.c.
| Used |Secretin|Distilled| 0.4% | 70% | 0.9% | Secretin
| | | Water | HCl |Alcohol| NaCl |
----+--------+--------+---------+------+-------+------+----------
1 | 3 | 29 | 0 | 0 | 0 | 1(?)| 28
1 | 6 | ... | .. | 1(?)| .. | .. | ..
2 | 18 | 16 | .. | 6 | .. | .. | 16
3 | 5 | 14 | .. | 0 | 0 | 0 | 8
3 | 25 | ... | .. | 1(?)| .. | .. | ..
4 | 100 | 110 | .. | 0 | .. | .. | 67
5 | 150 | 19 | .. | 0 | .. | 0 | 8
----+--------+--------+---------+------+-------+------+----------

In regard to both Secretogen and Duodenin, we assume that the manufacturers have tried to put secretin in them, but have been unable because they have failed, in all likelihood, to check their methods by physiologic standardization. These firms do not give any details as to the procedure they employed in their manufacture of secretin. Desiccated secretin of extreme potency has been prepared by various physiologists,[91] 1 mg. (1/64 grain) of which is active when given intravenously. It is difficult to conceive that any of these methods were used in the preparation of Secretogen or Duodenin.

[91] Stepp (Note 13). Dale and Laidlow: Jour. Physiol. =44=:11, 1912. Launoy and Ochslin: Comp. rend. Soc. de biol., =74=:338, 1913.

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. 3-1/2
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.

[92] Churchill, J. F.: De la cause immédiate et du traitement spécifique de la phthisie pulmonaire et des maladies tuberculeuses, Paris, 1858.

[93] The Hypophosphite Fallacy, J. A. M. A., April 25, 1914, p. 1346.

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]

[94] Marriott, W. McKim: The Therapeutic Value of the Hypophosphites, J. A. M. A., Feb. 12, 1916, p. 486.

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. 1-1/2
Hypophos. Manganese 1
Hypophos. Lime 1
Hypophos. Iron 1-1/2
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 Soda 2 gr.
Hypophosphites Lime 1-1/2 gr.
Hypophosphites Iron 1-1/2 gr.
Hypophosphites Quinin 3/4 gr.
Hypophosphites Strychnine 1/16 gr.”

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.