5 6 A M E R I C A N J O U R N A L OF D I G E S T I V E D I S E A S E S VOLUME VI I I NUMBER 2

B I B L I O G R A P H Y 1. Eyerly, J . B. and Breuhaus, H. C.: A Method of Measuring

Acidity and Protein Digestion Within the Human Stomach. A m . J. Dig. Dis., 6:187, 1939.

2. Kirsner, Joseph B. and Palmer, Waiter Lincoln: The Effect of Various Antacids on the Hydrogen-Ion Concentration of the Gastric Contents. Am. J . Dig. Dis., 7:85, 1949.

3. Mutch, N. : The Silicates of Magnesium. Brit . M. J. , 1:143-205, 254, 1936.

4. Mann, W. N. : Experiments on the Neutralization of HCI by Magnesium Trisilicate. Guy's Hospital Reports, 87:151, 1937.

5. Kraemer, M.: The Use of Hydrated Trisilicate of Magnesium for Peptic Ulcer. Am. J. Dig. Dis., 7:57. Feb., 1940.

6. Reid, C. G. : The Control of Gastric Hyperacidity by Magnesium Trisilicate. Am. J . Dig. D/s., 6:267, 1939.

7. Wyllie, D. : The Influence of Certain Antacids on the Acidity of Human Gastric Juice with Special Reference to Magnesium Trisilicate. Edinburgh M. J. , 47:336, 1940.

8. Greenwald, I . : Gastric Antacids Which Cannot Act as Systemic Alkalis. Proc. Soe. Exp . Biol. and Meal., 20:436, 1023.

9. Shattuck, H. F., Rohdenburg, E. L. and Booker, L. E. : Antacids in the Medical Management of Peptic Ulcer. J . A. M. A., 82: 200, 1924.

10. Kantor, J . L . : Antacid Gastric Therapy with Especial Reference to the Use of Neutral Antacids. J . A. M. A., 81:816, 1923.

11. Freezer, C. R. E., Gibson, C. S. and Matthews, E . : A Contribu- tion to the Study of Alkalis as Therapeutic Agents. Guy's Hospital Reports, 78:191, 1928.

12. Hurst , A. F. and Stewart, M. G.: Gastric and Duodenal Ulcer. Humphrey Milford, Oxford Universi ty Press, London, p. 395, 1929.

13. Mahler, P . : Vergleichende Studien fiber Antacida. Med. Klin. , 30:1520, 1934.

Magnesium Trisilicate N. N. R. Its Position Among Antacids Used to Treat Peptic Ulcer

By

MANFRED KRAEMER, M.D.t NEWARK, N E W JERSEY

I N 1928 Freezer, Gibson and Matthews (1) tabulated the relative efficiencies of the then commonly em-

ployed antacids as follows: (Sodium bicarbonate 100%)

Magnesium oxide 317% Magnesium peroxide 160% Magnesium carbonate 145% Sodium bicarbonate 100% Sodium citrate 61% Tribasic calcium phosphate 61% Potassium citrate 58% Tribasic magnesium phosphate 51% Calcium carbonate 20% Bismuth oxycarbonate 0%

They also found tha t the following amounts of ant- acid had the same effect in countering the acidity of 100 cc. of 0.3% Hydrochloric acid:

Calcium carbonate 3.36 grams Tribasic magnesium phosphate 1.31 grams Potassium citrate 1.17 grams Tribasic calcium phosphate 1.10 grams Sodium citrate 1.10 grams Sodium bicarbonate 0.61 grams Magnesium carbonate 0.47 grams Magnesium peroxide 0.42 grams Magnesium oxide 0.214 grams

Since the appearance of the Freezer, Gibson and Matthews paper, additional antacids have come into common use, especially Aluminum Hydroxide and Magnesium Trisilicate.

Kirsner and Palmer (2) in a series of in vivo ex- periments have tabulated the neutralizing values of these antacids. Unfor tunate ly they did not use equal weights of antacids. The Freezer, Gibson and Mat- thews tables were based on an optimum pH of 7. Kirsner and Palmer considered a pH of 4 to 5 as suffi- ciently alkaline to permit ulcer healing, and their tabulations are based on the production of a pH of 4 t o 5 . ~From the-Gast ro-Intes t inal Clinic, Presbyterian Hospital, Newark,

New Jersey. tChief of Clinic. Presented as pa r t of the Scientific Exhibit at the New York Meeting

of the American Medical Association, June, 1040. Submitted August 25, 1940.

The comparative table of K i r s n e r and Palmer follows: The antacids are listed in decreasing order of neutralizing capacity:

1. Calcium carbonate 4.0 gin. 2. Calcium carbonate 2.0 gm. 3. "Heavy" powders. 4. Aluminum hydroxide 30 cc. 5. " In termedia te" powders. 6. Tricalsate 4.0 gin. 7. Tribasic calcium phosphate 4.0 gm. 8. Aluminum hydroxide 16 cc. 9. "Simple" powders.

10. Sodium bicarbonate 4.0 gm. 11. Aluminum hydroxide 4 cc. 12. Magnesium trisilicate 1.0 gm. In previous communications (3, 4) I have presented

evidence of the acid removing capacity and clinical value of magnesium trisilicate. These articles cor- roborated the findings of the English workers, Mutch (5) and Mann (6).

In order to determine the theoretical position of magnesium trisilicate among the antacids commonly employed to t rea t peptic ulcer, the following experi- ments were performed: To each of twelve, 400 cc. samples of N/20 hydrochloric acid (the approximate amount and s t rength of acid present in the stomach a f te r a meal) one gram of antacid was added. The mixture was stirred constantly and at intervals of five minutes in successive specimens the residual acid was t i t ra ted against a sodium hydroxide standard in the presence of the unreacted antacid. Brom thymol blue was used as an indicator.

The following antacids were tested: Sodium citrate, magnesium oxide, magnesium carbonate, c a l c i u m carbonate, sodium bicarbonate, tr ibasic calcium phos- phate, bismuth sub-carbonate, aluminum hydroxide gel, and magnesium trisilicate. By re fer r ing to Fig. 1 the acid removing power of these antacids can be com- pared. I t should be noted that the only antacid having a gradual neutralization curve is magnesium trisili- cate.

A 6% emulsion of aluminum phosphate supplied through the kindness of Dr. Richard Johnson, Medical

JouR. n . D. FEBRUARY, 194t

KRAEMER--MAGNESIUM TRISILICATE N . N . R. 57

Director of Frederick Stearns, and a sample of mag- nesium silicate, special (7), received through the courtesy of Dr. W. B. Levin of Baltimore, were also examined. The former did not have as high an acid removing power as aluminum hydroxide gel, and the la t ter did not meet the standards for magnesium tri- silicate set up by Mutch. These findings do not mean that the preparat ions are not valuable as antacids for t r ea t ing peptic ulcer. I also examined g e l a t i n - - a brand advertised for use in t rea t ing peptic ulcer, and found tha t i t had no acid neutral izing value and tha t i ts acid adsorbing power was almost nil. I also tested some commercially used adsorbents like Bentonite and also the amino acids, leucine and cystine. Their acid adsorbing qualities were so small that they could not be used for t rea t ing peptic ulcer. Kaolin, long used empirically and considered an acid adsorbent, was found almost valueless in this capacity. Acid adsorp- tion was determined by the method described in a previous paper.

With our neutralization experiments we have supple-

DISCUSSION The etiology of ulcer is obscure despite the numer-

ous theories which have been promulgated. Therapy seeking to counteract or remove the theoretical causes of ulcer (infection, spasm, amino acid deficiency, etc.) is ineffective. Ber t ram Sippy (8) showed tha t regard- less of the cause of ulcer, constant neutralization of the gastr ic contents resulted in ulcer healing. There have been no real advances in ulcer therapy since his day. Unfortunately the antacids used by Sippy and those since introduced have numerous disadvantages. By re fe r r ing to the tables it is seen that for some preparat ions recommended for t rea t ing peptic ulcer, the acid removing power is almost nil.

The disadvantages of some of these commonly used antacids follow:

1. Sodium Bicarbonate is soluble in water and it therefore leaves the stomach too quickly. I t s sodium ion is absorbed and in the presence of kidney disease alkalosis may result. In susceptible persons it may cause diarrhea. On interaction with the gastr ic hydro-

N o .

2 3

4

5 6 7

- - - - - ~ - - t -

9

to It,

~ l ~ "

I$

A . .

Manufacturer

B . . . . . . . . . .

C ,.

D

E . ,

F

G

T A B L E l.~Analysis of l'ariou~ grund.*

Sample

I 2 3

1 2 3

I 2

I 2

( I )

MgO

% 22.43 22.34 21.71

20.99

20.12 20.77 21.12

19.97 21.04

17.29 16.16

15.94

13.61

(2~

SiOs

% 50.19 50.01 48.92

46.72

44 19 45.05 44.93

47.68 51.99

52.71 53 70

52.94

59.73

o f t e r e d u~* '" M a n e s i u m T r h i l i c a t r "'

(31

Loss on Ig- nition

% 23.17 24.70 27.40

29.22

(4)

Fe=03 AlzO:*

& CaO

% 1.39 2.50 1.54

2.15

0.92 0.87 1.19

t.41 |.53

1.28 2.07

1,25

I 04

32.94 32.31 31.67

30.29 25.86

26.91 25.86

36.90

23.74

Rat io MgO : SiO,

(Theore- tical. I : 2.24)

(gravimetric)

1:2.24 I :2.24 1 : 2.25

1 : 2.22

1:2.20 I :2.17 1 : 2.13

I : 2.39 1 : 2.47

I : 3.05 I : 3.32

! : 3.32

I : 4 . 3 9

(6)

C o n t a m i - nat ion with

Silica (SiO, in excess of

true formula)

% Nil Nil

+ 0.44

- 0.89

- - 1.7 - 3,1 - 4.9

+ 6.69 +10.2

+36.7

(7) Antac id

Value (N/20 HCI neutral ized

by I gr~mrr~, Ignited Wt.,

in 4 hours at 37 ~ C.)

r 300.8 300.7 303

3O8

36~" 315 300

288 242

205 242 +48.2

+48.2 236

173 + 95.9

i

(r Adsorpt ion

(Methy lene - blue ad-

sorb.'d ~ r gramme. 18- nited Wt.) in 14 day~

at sat urat io l0

m8. 271 281 282

240

282 272 250

276 256

256 234

264

180

mented the tables of Freezer, Gibson and Matthews so tha t all of the now commonly used antacids are in- cluded. Their relative efficiencies follow: Sodium bi- carbonate - - 100%

Sodium bicarbonate 100% Magnesium oxide 372% Calcium carbonate 177% Magnesium Trisilicate 100% Tribasic Calc. Phos. 31% Bismuth Sub. Carb 19% Aluminum hydroxide gel 13% Sodium citrate 1%

We found tha t the following amounts of antacids have the same effect in counteracting the acidity of 100 cc. of .3% hydrochloric acid:

Sodium citrate Aluminum hydroxide gel Bismuth Sub. Carb Tribasic Calc. Phos. Magnesium Trisilicate Magnesium Carbonate Calcium Carbonate Magnesium oxide

100 grams 13.3 grams

9.5 grams 5.8 g rams 1,7 grams 1.05 g rams 1.03 grams

.48 grams

chloric acid, carbon dioxide is released with un- comfortable increase in intra-gastr ic tension and an- noying belching. I t st imulates a marked secondary acid rise. Bicarbonate of soda should not be used for treating peptic ulcer.

2. Magnesium Oxide is the most powerful antacid we prescribe. I t causes the highest secondary acid rise. I t may be quite Iaxative even when used in small amounts.

3. Magnesium Carbonate is also laxative in action and causes a secondary acid rise. As in the case of sodium bicarbonate the evolution of carbon dioxide gas is a decided disadvantage.

4. Calcium Carbonate is a good antacid and were it not for its constipating action and for its release of carbon dioxide in the stomach, it would approach the ideal in antacid therapy.

5. Sodium and Potassium Citrates have little neu- tralizing power. They are valueless in treating peptic ulcer.

6. The Tribasic Phosphates of Calcium and Mag- nesium were suggested by Kantor (9). They are in- efficient antacids. They may produce alkalosis. Consti-

58 AMERICAN J O U R N A L

pation or diarrhea may result from their use. They could be abandoned.

7. Bismuth Salts also have little neutralizing value and are constipating. They were supposed to cure peptic ulcer by forming a protective coating over the ulcer base. This impression has proved erroneous. Sippy originally used Bismuth Sub-Carbonate in his "A" powder, but he soon recognized the disadvantages of this salt and substituted Calcium Carbonate for it. Blind adherence to custom, perpetuates the use of Bismuth salts. Powder "A" in most hospitals is still a mixture of Bismuth Sub-Carbonate and Soda Bi-

OF D I G E S T I V E D I S E A S E S VOLUMB VIII NUMBER 2

found extreme constipation and fecal impaction fre- quently result when aluminum hydroxide is used in quantities sufficient to give adequate neutralization and to control symptoms.

Aluminum Hydroxide Gel may be efficacious even if used in amounts inadequate for neutralizing gastric acid. I believe that this improvement in ulceration is due to astringent action both of Aluminum Hydroxide and of the Aluminum Chloride formed. This astrin- gency may have the same effect in the stomach as aluminum acetate preparations have on skin and skeletal muscle wounds and ulcerations. A disad-

Figure I

~agnesium oxide

Alkali Excess

400 --

o

f<

4 g

2OO

.............................. C a l c i u ~ C a r b o n a t e Eagnesium Carbonate

Ea~nesium Trisilicste

Sodium Bicarbonate

I00

50

I0 20 50 40 50

Time in Einutes

Tribasic Calcium Phos.

Bismuth Sub-Carbonate Aluminum Hydroxide

Cream Sodium Citrate

6O

carbonate. The use of Bismuth salts for treating peptic ulcer should be abandoned.

8. Aluminum Hydroxide Gel is today extensively employed to treat ulcer. Introduced in 1929, by Bur- rill Crohn (10) it has been popularized by Einsel, Adams and Myers (11), Woldman and Rowland (12) and others. When added to an excess of acid the ad- sorbtive power of Aluminum Hydroxide Gel is nil, as it is completely changed to soluble aluminum chloride. Despite claims of advertisers it cannot promote ulcer cure by coating action, since change to solution is almost instantaneous. That it is a poor antacid is evi- denced by reference to Fig. 1. I f used as an antacid it must be prescribed in very large amounts. I have

vantage of Aluminum Gels is that they are too ex- pensive for constant and routine use.

A theoretical ideal antacid should possess the follow~ ing properties :

1. It should be of low cost. 2. I t should be tasteless and not astringent to the mouth mucosa. 3. A small amount should neutralize a large amount of acid. 4. It should adsorb pepsin. 5. It should be neither consti- pating nor laxative. 6. It should be insoluble so as not to leave the stomach too quickly. 7. I t should have a prolonged action and not stimulate a secondary acid rise. 8. The cation should be unabsorbable so that alkalosis cannot occur. 9. No distressing gases should evolve after its interaction with hydrochloric acid.

JOUR. D. D, W O L D M A N AND R O W L A N D - - - A L U M I N U M HYDROXIDE D R I P T R E A T M E N T OF P E P T I C U L C E R 5 9 FEBRUARY, 1941

Magnesium Trisilicate approaches this theoretical ideal as closely as 'any antacid I have used or investi- gated. I t s clinical efficacy was described in previous publications. In susceptible individuals it does have a slight s t imulat ing action on the colon with increase in the number of bowel movements but I have not en- countered the i r r i ta t ing watery movements which so often follow the use of Magnesium oxide or carbon- ate. Magnesium Trisilicate has a prolonged neutrali- zing action in vivo an shown by Reid (13). Unfor tu- nately many brands offered as magnesium trisilicate do not match up to the standards set down by Mutch. I have demonstrated the difference in neutralizing power between two widely used preparat ions (4).

Table I taken f rom Mutch (14) shows tha t each of seven brands offered as Magnesium Trisilicate were in fact different products. Acceptance by N. N. R. should result in a uniformity of the products offered for sale.

SUMMARY AND CONCLUSIONS 1. The neutralizing powers of various antacids

used in t rea t ing peptic ulcer have been compared. 2. The disadvantages of usually employed antacids

have been discussed. 3. A theoretical ideal antacid was postulated. 4. Magnesium Trisilicate was described in its re-

lation to other antacids and as an approach to the ideal.

R E F E R E N C E S 1. Freezer, C. R. E., Gibson, C. S. and Matthews, E. : A Contribution

to the Study of "Alkalis" as Therapeutic Agents. Guy's Hospi- tal Reports, 8:191, 1928.

2. Kirsner, J . B. and Palmer, W. L. : The Effect of Various Ant- acids on the Hydrogen-Ion Concentration of the Gastric Con- tents. Am. J. Dig. Dis., 7:85, 1940.

3. Kraemer, M.: The Use of Hydrated Magnesium Trisilicate in Peptic Ulcer. Am. J. Dig. DIS., 5:422, 1938.

4. Kraemer, M. : The Use of Hydrated Trisilicate of Magnesium for Peptic Ulcer. Am. J. Dig. Dis.. 7:57, 1940.

5. Mutch, N.: The Silicates of Magnesium. Synthetic Magnesium Trisilicate. Hydrated Magnesium Trisilicate. Br. Med. J., 3916, 3917, 3918; 143, 205, 254, 1936.

6. Mann, W. N. : Experiments on the Neutralization of Hydrochloric Acid by Magnesium Trisilicate. Guy's Hospital Repo~ts, 87:151, 1937.

7. Levin, M. B.: Peptic Ulcer Therapy. Am. J. Dig. Dis. and Nutrlt., 4'.'574, 1937.

8. Sippy, B. W.: Gastric and Duodenal Ulcer. Medical Cure by an Efficient Removal of Gastric Juice Corrosion. J. A. M. A., 64:1625, 1915.

9. Kantor. J. L. : Antacid Gastric Therapy, with Especial Reference to the Use of Neutral Antacids. J . A. M. A., 81:816, 1923.

10. Crohn, B. B. : The Clinical Use of Colloidal Aluminum Hydroxide as a Gastric Antacid. J. Lab. Clin. Med., 14:610, 1929.

11. Einsel, I. H., Adams, W. L. and Myers, V. C.: Aluminum Hydrox- ide in the Trea tment of Peptic Ulcer. Am. J. Dig. Dis. und Nutrit. , 1:513, 1934.

12. Woldman, E. E. and Rowland, V. C.: A New Technique for the Continuous Control of Acidity in Peptic Ulcer by the Aluminum Hydroxide Drip. Am. J. Dig. Dis. a~l Nutrit . , 2:733, 1935.

13. Reid, C. G.: The Control of Gastric Hyperacidity by Magnesium Trisilicate. Am. J. Dig. Dis., 6:267, 1939.

14. Mutch, N. : Magnesium Trisilicate, Br. Med. J., 4006:735, 1937.

A One Flask Apparatus for the Aluminum Hydroxide Drip Treatment oF Peptic Ulcer

By

EDWARD E. WOLDMAN, M.D. and

VERNON C. ROWLAND, M.D. CLEVELAND, OHIO

W H E N one is passing a gelatinous suspension down a tube one cannot easily regulate the flow

by constricting this tube because of the tendency to clogging and obstruction. In order to avoid this diffi- culty we have devised a siphon re leaseappara tus .

The older three flask method for the adminis trat ion of the continuous aluminum hydroxide drip may be simplified to a single Kelly infusion flask with a gravi ty out-flow f rom the lower end and a regulated a i r in-flow through the upper end. A t ight fitting cork, or better, a rubber cap overlapping the upper opening connects the Kelly flask with a curved glass tube and rubber connection to an inverted Murphy drip tube filled with water. The lat ter is used simply to visualize the rate of flow. The a i r inflow is con- trolled by a fine screw clip or valve on rubber tubing, allowing about fifteen bubbles a minute to rise through the liquid. The system, of course, must be a i r tight. I f rubber overlaps glass at all points the possibility of a i r leaks is eliminated. A vacuum is then established at once in the tubing when the grav i ty flow is started. The out-flow of aluminum hydroxide into the stomach

Submitted August 15, 1940.

is precisely at the same rate as the a i r in-flow through the screw clip or valve.

DIAGRAM The technique of s tar t ing

the drip is as follows: 1. Fill the Kelly flask to

the top with a 1% suspension of colloidal aluminum hydrox- ide while clamp (A) is closed.

2. F i l l t h e i n v e r t e d Murphy drip tube with water while clamp (B) is closed.

3. Inser t the rubber stop- per securely into the mouth of the Kelly flask and connect the i n v e r t e d M u r p h y drip tube to the short rubber tube with screw clip as indicated in the diagram.

4. Attach Kelly flask to a hook or standard 2 to 3 feet above the level of the patient 's stomach.

i