88 T H E AMERICAN JOURNAL OF

9. Callander, C. L.: Surg ica l a n a t o m y . W. B. S a u n d e r s , Phi lade lphia , 1943.

10. Chr i s tophe r , F.: Tex tbook in Su rge ry . W. ]3. Saunder s , Phi ladelphia , 1943.

11. Grant , J. C. B.: Method of a n a t o m y . Wi l l i ams a n d Wilkins , Bal t imore , 1945.

12. McGregor , A. L.: S y n o p s i s of su rg i ca l ana tomy . Wi l l i ams and Wilkins , Bal t imore , 1943.

13. Lewis, W. H.: Gray ' s a n a t o m y . Lea and Febiger , Phi ladelphia , 1942.

14. Morris , G.: H u m a n ana ' tomy, Blakis ton , Phi ladelphia , 1942.

15. Piersol , G. A.: H u m a n a n a t o m y . Lippincot t , Ph i l a - de.lphia, 1930.

16. Sobot ta , J., and McMurr ich , R.: At las of h u m a n , a n - a tomy. Ste icher t , N e w York, 1928.

17. Spal teholz, W.: At l a s of h u m a n a n a t o m y . Lippincot t , Phi lade lphia , 1937.

18. Boyden, E. A.: The s p h i n c t e r of Oddi in m a n and m a m m a l s . Surg . 1, 2,5, 1937.

19. Dard insk i , V. J.: The a n a t o m y of the m a j o r duodena l papi l la of man . Jour . Ana t . 69, 469, 1935.

20. Dard insk i , V. J.: P a t h o l o g y of t h e m a j o r duodena l papilla. Am. Jour . Pa th . 7, 169, 1931.

21. Ivy, A. C.: Ana ly s i s of bi l iary dyskines ia . Am. J. Roen tgen . 67, 1, 1947.

DIGESTIVE DISEASES V o l u m e 16 N u m b e r 3

22. Rich, A. 1R. and Duff, G. L.: E x p e r i m e n t a l and p a t h o - logical s tud ies on p a t h o g e n e s i s of acu te pancrea t i t i s . Bull. J o h n H o p k i n s i o s p . 58, 212, 1936.

23. Vater , A.: Disse r t~ t io ana tomiea , q u a n o v u m bills di- v e r t i c u l u m et v a l v u l o s u m colli ves icae fillae c o n s t r u e - t ionem, etc., in t i a l l e r ' s D i s p u t a t i o n e m ~ n a t o m i c a r u m se lec ta rum, Go~tingae, 1748, V. 3, 2,59, 1748.

24. Oddi, R.: D 'une d i spos i t ion a s p h i n c t e r speeiale de l 'over ture ' du cana l eholedoque. Ar0h. Ital. Biol. 8, 317, 1887.

25. Zawisch -Ossen i t z , C.: His to logic e x a m i n a t i o n a f t e r a r - tificial d i la ta t ion of V a t e r ' s papil la. Zen t r a lb l a t t f. Chir. 55, 1868, 1928.

26. Ster l ing, J. A.: D ive r t i cu la in tfhe t e rmina l por t ion of t he c o m m o n bile duct. Am. Jour . Pa th . 25, 39, 1949.

27. Luce, T.: Ga l l s tone ileus. Ann. Surg. , 74, 86, 1947.

28. Dobbie, R. F.: F a i l u r e s in s u r g e r y of t he b i l iary t ract . N. Y. S ta te J. Med. 45, 882, 1945.

29. Moore, M. T.: Some u s u a l and some u n u s u a l m e c h - a n i s m s of a b d o m i n a l pain. SouVhern Med. and Surg . 108, 135, 1946.

30. P r i b r am, ]3. D. C.: E t h e r t r e a t m e n t of gall s t ones impac ted in c o m m o n duet. Lancet , 1, 1311, 1939.

31. Peikoff, S. S.: P o s t - c h o l e c y s t e c t o m y syndrome . Mani - toba Med. Rev. 26, 69, 1946.

Effect of Acetyl Salicylic Acid on the Gastric Mucosa of the Shay Rat * By

J O S E P H KATZ, PH.D.

R. L. DRYER; M. S.

W. D. PAUL, M.D.

and

J. I. ROUTH, PH.D.

IOWA CITY, IOWA

T HE EFFECT OF ASPIRIN on the anatomy and physi- ology of the stomach has been investigated by

many workers (1). In 1947, Clark and Adams (2), reported that there was no increase in gastric secretion in Cope pouch dogs receiving oral administration of 95 mgs. of acetyl salicylate per kg. per day. However, if large doses (200 mgs. per kg. per day) were given, sufficient to cause anorexia, nausea, vomiting and gas- tric irritation, an increase in gastric secretion did take place.

Caravati (3), performed a series of gastroscopic ex- aminations on twenty patients kept on salicylate f~or twenty days. He found no gastritis in nineteen of these patients. If nausea or vomiting occurred, it could be correlated with high salicylate levels in the blood, even though the gastric juice contained little aspirin. The distress after large doses of this drug is attributed to the effect of salicylate on brain centers rather than on the gastric mucosa.

D e p a r t m e n t s of I3 iochemis t ry a n d Medicine, College of Medicine, S ta t e U n i v e r s i t y of Iowa, I o w a City, I o w a

.-I.. *.Aided by G r a n t s f r o m I n s t i t u t e f o r t h e S t u d y of A n a l - gesic Drugs , a n d Br i s to l L a b o r a t o r i e s . S u b m i t t e d J u l y 28, 1948.

The gastroscopic studies of Paul (4), on a large number of patients receiving aspirin in doses as high as 80 grains per day had disclosed no demonstrable hyperemia nor damage to the gastric mucosa. Even if ingested over long periods of time, aspirin was not found to produce chronic gastritis. However, inas- much as 5% of the patients complained of epigastric distress followillg the ingestion of aspirin, Paul at- tributed these symptoms to pylorospasm and increased acid production rather than to gastric lesions.

To corroborate this theory, it was decided to study the effect of high doses of aspirin on the gastric mucosa of a large number of animals. In our work, a modifica- tion of the Shay technique (5, 6), for producing gastric lesions in rats was employed. Theulceration in the gastric mucosa which resulted six hours after ligation of the pylorus in a group of rats receiving two mls. of either 0.01 N HC1, distilled water, or 0.9% NaC1 orally, was compared with the mucosal damage observed in similarly operated rats receiving 2 1/2 grains of aspirin in a two ml. volume of one of the above mentioned carriers. The volume of the gastric contents was measured and the pH, free and total acidity were determined. Attempts were made to

A . J . D . D. M a r c h , 1949 E F F E C T OF ,5~CETYL S A L I C Y L I C A C I D ON T H E S H A Y R A T 89

correlate severity of mucosal lesions with free and total acidity, pH, and rate of gastric secretion.

G E N E R A L P R O C E D U R E

Stock rats of both sexes ranging in weight between 120 and 385 grams and previously maintained on a balanced ration were fasted for 72 hours, water being freely available until one hour prior to the operation. A midline abdominal incision extending from the xiphoid process to approximately one inch below this point was made, under light ether anesthesia. A heavy cotton thread ligature was placed around the pylorus with a mininmm of disturbance to the surrounding viscera and without touching the stomach under any circumstances. The incision was closed at once. A fine rubber catheter attached to a syringe was passed into the stomach and two ml. volumes of the substances under study were administered. Recovery from the operative procedure was prompt and satisfactory.

At the end of six hours, the animals were sacrificed by a sharp ,blow on the head and the stomachs were excised after clamping off the esophagus with a hemostat. The gastric contents were poured into a grad- uated centrifuge tube and were measured after cen- trifuging off the solids. The empty stomachs were opened along the greater curvature and the interior was examined for lesions, using a dissecting micro-

No.

1 2 2 2 3 2 4 2 5 2

6 2

7 2 8 2 9 2

10 2 ]1 2 12 2 13 2 14 2 15 2 16 2 17 2 18 2 19 2 20 2 21 2 22 2 23 2 24 2 25 2 26 2 27 2 28 2 29 2 30 2 31 2

scope. Specimens contaminated with blood or con- taining food were discarded. All total volumes were corrected for the two ml. of substance originally ad- ministered and for the solids found. The free and total acidity of the gastric juice were determined by titrating one ml. volumes with 0.02 N NaOH using T6pfer's solution and phenolphthalein, respectively. Free and total acidity are expressed as milliequiva- lents of HC1 per 100 ml. gastric juice.

Our findings are summarized in Table I which covers observations on a total of 66 rats, of which 31 served as controls and 35 received aspirin. To uniformly de- scribe the severity of the gastric ulceration the follow- ing integer and decimal notation has been adopted:

Designation

1.0

2.0

3.0

4.0

5.0

0.1

0.2

0.3

0.4

0.5

TABLE I

Pathology

H e m o r r h a g e o f v e s s e l s i n g a s t r i c m u c o s a and i n c i p i e n t u l c e r a t i o n

M a n y s m a l l p u n c t a t e u l c e r s

S e v e r a l e r o d e d u l c e r a r e a s

D e e p l y p i t t e d a r e a s o f u l c e r a t i o n w i t h n e c r o s i s

P e ~ ' f o r a t i o n o f g a s t r i c w a l l

I s c h e m i a l o c a l i z e d i n r u m e n

H y p e r e m i a in r u m e n

P e t e c h i a e a n d v a s o d i l a t a t i o n i n b o d y

E r o s i o n a n d t h i n n i n g o f w a l l o f tureen w h i c h b e c o m e s m o r e t r a n s p a r e n t t h a n u s u a l

I s e h e m i a in b o d y

Changes in the Stomach of Control Rats

Treatment

cc. 0.01 N H,C1 3,5 cc . 0.01 N H C 1 4.0 cc . 0.01 N H C 1 4.0 c e. 0.01 N ,HCI 4.0 cc . D i s t i l l e d H 2 0 1.0

cc . Di, s t i l l e d H 2 0 2.0 cc . D i s t i l l e d t t 2 0 3.0

cc . 0 . 9% N ~ C I 4.5 cc . 0 . 9% N a C 1 1.2 cc . 0 . 9% / q a C 1 4.3 cc . 0 . 9% N a C l 3.5 cc . 0 . 9% N a C l 2.1 c'c. 0 . 9% N a C 1 2.3 ce . 0 .9% N a C 1 4.0 cc . 0 . 9% N a C 1 4.0 cc . 0 .9% Na~C1 4.3 co. 0 .9% N a C 1 4.3 cc . 0 . 9% N a C 1 0.0 ce . 0 .9% N a C ' l 4.3 cc . 0 . 9% N a C 1 4.3 cc . 0 .9% N ~ C 1 4.3 cc . 0 . 9% N a C 1 5.0 cc . 0 . 9% N a C 1 4.2 c c . 0 . 9% NwC1 4.0 co. 0 .9% N a C 1 5.0 cc . 0 .9% N a C 1 1.2 cc . 0 . 9% N a C 1 4.2 c c. 0 . 9 % N a C 1 5.0 cc . 0 .9% N a C I 4.2 cc . 0 . 9 % N a C I 4.0 c o . 0 . 9 % N~0CI 4.3

A v e r a g e

Gastric Juice Analysis

Gastric Rate of Free Total pH Pathology Secretion Acidity Acidity

ml,/hr./100 gm~ mil|i-eq, HCT/100 ml.

0,32 19.0 52.0 2,9 0.48 42.0 72.0 2.2 0.31 22.2 50.0 2.4 0.62 29.8 78.2 2.6 0.27 51.6 100.8 2.7 0.00 0.56 46.0 91.8 2.3 0.45 72.2 82.8 2.1 0.15 17.0 46.0 2.8 0.83 94.2 144.2 2,0 0.30 47.6 90,0 2.7 0.38 12.0 38.0 3.1 0.32 10.0 96.0 3.2 0.57 40.0 104.0 2.1 0.42 56.0 96.0 2.1 0.72 44.0 92.0 1.8 0.48 25.0 33.0 1.4 0.70 47.8 116,0 1.2 0.00 0.72 21.2 64.4 1.5 0.76 40.0 82.0 1.2 0.68 52.3 109,6 1.5 0.34 23.2 81.2 2.8 0.60 12.0 59.6 3.0 0.59 43.0 73.0 1.7 0.31 19.0 39.0 2.9 0.29 0.0 48.0 3.9 0.23 11.0 87.0 3.1 0.63 15.0 68,0 2.6

0.40

90

No.

THE AMERICAN JOURNAL OF DIGESTIVE DISEASES

Table I Continued Changes in the Stomach of Rats Receiving Aspirin

Gastric Juice Analysis,

Treatment Gastric Rate of Free Total pH Pathology Secretion Acidity Acidity

ml./hr./lOO.gm, milli-eq. HCI/100

1 2 1/2 grains aspirin 0.3 0.35 2 2 1/2 grains aspirin 0.2 0.69 3 2 1/2 grains aspirin 0.2 0.25 4 2 1/2 grains aspirin 2.2 0.51 5 2 1/2 grains aspirin 1.2 0.40 6 2 1/2 grains aspirin 2.3 0.76 7 2 1/2 grains aspirin 0.2 0.50 8 2 1/2 grains aspirin 2.3 0.09 9 2 1/2 grains :aspirin 2.3 0.45

I0 2 1/2 grains aspirin 2.3 0.33 11 2 1/2 grains aspirin 1.2 0.22 12 2 1/2 grains aspirin 1.2 0.22 13 2 1/2 grains aspirin 3.2 0.14 14 2 1/2 grains aspirin 4.2 0.15 15 2 1/2 grains aspirin 1.2 0.19 16 2 1/2 grains aspirin 0.2 0.15 17 2 1/2 grains aspirin 0.2 0.24 18 2 1/2 grains aspirin 1.2 0.21 19 2 1/2 grains aspirin 0.3 0.54 20 2 1/2 grains aspirin 0.3 0.29 21 2 1/2 grains aspirin 0.0 22 2 1/2 grains aspirin 0.2 23 2 1/2 grains aspirin 0.0 24 2 1/2 grains aspirin 1.0 25 2 1/2 grains aspirin 4.0 26 2 1/2 grains aspirin 0.3 27 2 1/2 grains aspirin 0.2 28 2 1/2 grains aspirin 0.2 29 2 I/2 grains ~tspirin 1.2 30 2 1/2 grains aspirin 0.0 31 2 1/2 grains aspirin 0.2 32 2,1/2 grains aspirin 0.0 33 2 1/2 grains aspirin 0.0 34 2 i/2 'grains aspirin 0.0 35 2 1/2 grains aspirin 0.5

Average

The integer describes the severity of the lesions; the larger the number , the greater the damage. The decimal, on the other hand, merely indicates our general observations regarding the state of the mucosa and no at tempt has been made to correlate the degree of damage with the magni tude of the decimal.

In table I I is given a summary of gastric path- ology by g roups :

No. of

rats Treatment

ml.

0.0 133.8 3.8 0.0 211.2 3.3 0.0 105.6 3.8 0.0 102.8 3.1 0.0 128.6 3.9 0.1 129.2 3.1 0.0 102.2 3.3 0.0 119.4 3.6 0.0 121.8 3.3 0.0 192.4 4.0 0.0 76.0 3.4 0.0 58.0 3.4 0.0 64.6 3.5 0.0 44.6 3.'~ 0.0 62.0 3.2 0.0 64.5 3.5

0.0 68.4 3.4 0.0 66.2 3.4 0.0 49.0 3.5 0.0 60.0 3.7

Volume 15 Number 8

0.09 0.0 22.4 4.4 0.24 0.0 15.0 5.6 0.28 0.0 23.0 5.1 0.34 0.0 24.8 5.1 0.28 0.0 13.8 5.7 0.23 0.0 19.8 5.2 0.76 0.0 20.4 5.2 0.27 0.0 29.4 5.0 0.30 0.0 29.4 5.0 0.39 0.0 77.6 4.8 0.32

It is evident that 30 out of 31 control rats showed gastric lesions of vary ing extent, while only 15 out of 35 rats receiving aspir in had any grossly visible ulceration. Moreover, 20 of the rats receiving aspirin showed no ulceration at all. These findings seem to be in close agreement with those of Pauls, Wick and MacKay (7) , who reported recently that when the salts of o-hydroxybenzoic acid were adminis tered to rats with ligated pylorus, the format ion of ulcers was

TABLE I I

4 2 ml. 0.01 N HC1 3 2 ml. distilled water

24 2 ml. 0.9% NaCI 35 2 1/2 grains aspirin in 2 ml. H20

prevented. They found that the most effective route

of adminis t ra t ion is by vein, but the protective ac-

t ion results also a f te r oral or intraperi toneal admini -

stration. The meta and para sodium salts are less ac- tive. Acetyl salicylic acid afforded almost as much protection~ as the or tho-hydroxybenzoic acid. The only difference between our technique and the one

Pathological Index 0 1 2 3 4 5

1 3 1 1 1

1 2 2 1 15 3 20 7 5 1 2

employed by Pauls and co-workers was that their animals were fasted 48 hours instead of 72 and they sacrificed "their rats nine hours af ter pyloric l igation instead of after six as we did.

Analysis of our data shows that the gastric contents of the rats receiving aspir in had almost no free acidity and that the pH was considerably higher than in the

A. J. D. D. March, 1949 BLEEDING PER A N O 91

case of the control animals. Rates of secretion in both the control and experimental groups show a range of values which has almost exactly the same upper and lower limits. The average value for rate of secretion was calculated for both control and ex- perimental groups, and it was found that the experi- mental average was 20% lower than the control average. Aspirin thus appears to have an anti-secre- tory effect under the experimental conditions we have employed. Whether the decrease in free acidity and in the rate of secretion is responsible for the less- ened incidence of ulceration in the rats receiving aspirin awaits further study using larger numbers of animals, inasnmch as ~hese Observations are less

R E F E

1. Schnedorf , 3-. S., Bradley, W. D., and Ivy, A. 12.: The effect of acetyl salicylic acid upon gas t r i c ac t iv i ty a n d the mod i fy ing ac t ion of ca lc ium g lucona te and sod ium b ica rbona te . Am. J. Dig. Dis., 3, 239, 1936.

2. Clark, B. B. and Adams , W. L.: The effect of aeetyl salicylic acid on ga s t r i c secret ion. Gas t roen te ro logy , 9, 461, 1947.

3. Carava t i , C. M.: Gasgrie endoscopy and sec re to ry find- ings d u r i n g sa l i cy l i sm Gas t roen te ro logy , 6, 7, 1946.

4. Paul, W. D.: The effects of aeetyl salicylic acid (a~- p i r in) on the ga s t r i c mucosa . J o u r n a l of the I o w a S ta t e Medical Society, p. 1, April, 1945.

R E

evident on an individual than on a group or statistical basis.

CONCLUSIONS

1. While 30 out of 31 rats receiving oral admini- stration of two ml. volumes of 0.01 N HC1, distilled water, or 0.9% NaCI showed gastric lesions six hours after pyloric ligation, only 15 out of 35 animals receiving 2 1/2 grains of aspirin showed evidence of gastric damage.

2. The rats receiving aspirin showed a lower rate of secretion of gastric juice and had almost no free acidity in the gastric content.

N C E S

5. Shay, H., Komarov , S. A., Fels, S. S., Meranze, D., G r u e n , stein, M., and Siplet, H.: A s imple m e t h o d for the un i - fo rm p roduc t ion of gas t r i c u lce ra t ion in the rat . Gas - t roeniero logy , 5, 43, 1945.

6. Shay, H., Komarov , S. A., Siplet, H., and Gruens t e in , M.: An eva lua t ion of some an tac id and an t ipep t i e agen t s in t he p r even t ion of gas t r i c u l ce ra t ion in the rat . Am. 3-. Dig. Dis., 14, 99, 1947.

7. Pauls , F., Wick, A. N., and MacKay, E. M.: Inh ib i t ion of gas t r i c u lce ra t ion in the r a t by o - h y d r o x y b e n z o i c (sa l i - cylic) acid. Science, 107:19, 1948.

Bleeding Per-Ano

EDW ARD T. W H I T N E Y , M.D.*

BOSTON, MASSACHUSETTS

T t IE PRESENT RADIO AND NEWSPAPER PUBLICITY

being given the subject of cancer has caused many more patients with bleeding per-ano to seek diagnosis than of yore.

In the past, the discovery of some blood following a bowel movement usually suggested the presence of some hemorrhoids and the advice of a friendly drug- gist was solicited. Now, however, with the popular and widespread emphasis on the possibility of ma- lignancy being present with any sign of blood from an orifice, the hideous spectre of cancer is evoked in the layman's mind and he immediately hastens over to his doctor or to the proctologist fully con- vinced that "he is not long for this world." Yet it is a fact that nearly every proctological ailment is accompanied by bleeding either routinely or on oc- casion and as will be seen there are a great number of such ailments. Therefore consideration of this subject practically constitutes a review of the whole of proctology. But the latter is a specialized branch of medicine which is seldom taught to undergradu- ates and consequently has become a popular post-

*Surgeon-in-charge, Recta l Clinic, Bos ton D i s p e n s a r y , Boston, Mass . D ip lomate of the A m e r i c a n Board of Proctology.

S u b m i t t e d J u n e 28, 1948.

graduate or extension course. Some years ago, in order to simplify and condense this subject of bleeding per-ano, we compiled the accompanying table (Table 1). Its use soon revealed it to be an outline of Proc- tology brought together under an interesting heading. Consequently, it has been employed as such ever since.

An examination of this table will show that bleed- ing per-ano (and, concurrently, the subject of Proc- tology) can be divided into four major components the latter being the four general disorders which produce bleeding in the sigmoid, rectum and anus (second column). Each of these four general dis- orders are brought about by certain disturbances of function of the part involved as enumerated in the third column of the table while these disturbances of function are, in turn, found to be the result of certain pathological states as listed in the last column.

It will be seen, therefore, that there are about a hundred ailments, disturbances of function or path- ological entities to be taken into consideration when- ever a patient complains of this type of bleeding. I t might seem that this would be very confusing and require an exacting search before the correct diagnosis could be made. However, experience has shown that a pretty good approach has been achieved