JOUR. D . D . VOLUME 10 FEBRUARY, 1943 NUMBER 2

Clinical Experiments With Riboflavin, Inositol and Calcium Pantothenate By

M A R T I N G. V O R H A U S , M.D., M I C H A E L L. G O M P E R T Z , M.D.

and

A A R O N F E D E R , M.D. N E W YORK, N E W YORK

D U R I N G the pas t f e w yea r s , t h e unso lved p r o b l e m s of n u t r i t i o n a l def ic iency s t a t e s h a v e been v i g o r -

ous ly and succes s fu l ly a t t a c k e d by the b i o c h e m i s t s and o t h e r i n v e s t i g a t o r s in r e l a t ed fields of science. N e w v i t a m i n s have been i so la ted , s y n t h e s i z e d and a d m i n i s - t e r ed to a n i m a l s u n d e r v a r y i n g e x p e r i m e n t a l con- d i t ions . A l t h o u g h t h e p r e l i m i n a r y r e p o r t s of t he se s tud ie s seem c o n f u s i n g and a t t i m e s c o n t r a d i c t o r y , t h e y a re of g r e a t i n t e r e s t to t he c l in ic ian . T h e y cha l l enge h i m to c l a r i f y and c o r r e l a t e t h i s new knowl- edge and to e v a l u a t e i ts use in h u m a n def ic iency s ta tes . I t is t he p u r p o s e of t h i s r e p o r t to de sc r ibe such c l in ica l i n v e s t i g a t i o n s .

T h e t h e r a p e u t i c va lue of r ibo f l av in in cases of chei - l i t i s led us to s t u d y i ts e f fec t in t he t r e a t m e n t of de- c u b i t u s w i t h u l c e r a t i o n (7 ) . Cases w e r e accep ted i r r e s p e c t i v e of t he s e v e r i t y o f t h e a s soc i a t ed con- d i t ions . No case s h o w i n g a n y c l in ica l i m p r o v e m e n t on o r d i n a r y w a r d c a r e was inc luded in th i s se r ies . S ix cases a r e d e s c r i b e d in de ta i l of w h i c h t h r e e w e r e con- t ro l l ed r ig id ly . In t h e s e t h r e e cases no o t h e r v i t a m i n s u p p l e m e n t was g i v e n and no local t r e a t m e n t of the u lcer was p e r m i t t e d . In t h e o t h e r t h r e e cases t he o r i g i n a l d i sease r e q u i r e d a d d i t i o n a l t r e a t m e n t wh ich m a y be i n t e r p r e t e d as h a v i n g had some inf luence upon t h e decub i tus . T h i s a d d i t i o n a l t r e a t m e n t is d e s c r i b e d in de ta i l .

C A S E R E P O R T S

Case 1. S. G., white male, aged 69, d iagnos is - - inoper - able carcinoma of the sigmoid. Pal l ia t ive t ransverse colos- tomy was per formed on 1-9-41 and short ly the rea f te r a decubital ulcerat ion direct ly over the sacrum was noted. The ulcer progressed steadily and on 1-22-41 measured 6.4 x 5.2 cms. The base was pale and unheal thy but the surrounding tissues seemed normal. The usual oral dose of 5 mgms. of riboflavin was s tar ted at tha t t ime and con- t inued daily thereaf te r . A f t e r four days of the rapy the ulcer measured 5.7 x % cm. and f rom then on continued improvement was seen, unti l on 2-19-41 (a f t e r 28 days of riboflavin the rapy) , the ulcer was completely healed. Three days la ter the pat ient was t r ans fe r red to another hospital with no evidence of the previous sacral ulcer.

Case 2. A. J., white female, aged 66, d iagnos i s - -a r t e r io - sclerotic hear t disease with decompensation, bundle branch block. Admi t ted 4-22-40. Decubital ulcers which became progress ively worse were observed on each buttock. On 5-3-40 an ulcerat ion measur ing 2.5 x 1/.2 cm. was noted on the left buttock, and on the r ight buttock a smaller ulcer measur ing 1.2 x 0.5 cm. On this day the daily oral dose of 5 mgms. of riboflavin was begun. In three days be- g inning improvement was noted and by 5-8-40 (five days la ter) the lef t buttock ulcer measured only 1 cm. in length and the r ight ulcer was almost healed. Gradual heal ing

-X-Read before the Amer ican G~st ro-Enterologica l Associat ion a t At- lant ic City on J u n e 9, 1942.

F rom the Medical Service of the Hospi ta l for J o i n t Diseases. The lnos i to l and the Calcium Pan to thena te were suppl ied by the

Abbot t Laborator ies .

continued unti l by 5-24-40, a f te r three weeks of t rea tment , both ulcers were ent i re ly healed and the skin of the buttocks appeared normal. This pat ient was observed unti l d ischarge on 6-2-40 and no evidence of the previous decubitus was noted.

Case 3. M. R., white male, aged 60, d i agnos i s - - a r t e r io - sclerotic gangrene of lef t lower extremity . Enormous de- cubital ulcerat ion, shaped like an inverted t r iangle and in- volving about one-third of lower back was seen. Skin and subcutaneous t issue were missing over ent ire ulcerated area which var ied in depth f rom one to three cms. Chei- litis at angles of the lips and outer canthi of both eyes were noted. On 4-8-40, nine days a f te r admission, 5 mgms. of riboflavin daily were given orally. Pa t i en t was under observat ion unti l death on 4-15-40. Dur ing these seven days the puru len t discharge f rom the ulcer ceased. Necro- sis diminished and small areas of g ranu la t ion were ob- served. A t the t ime of death the ulcer was found to be reduced more than one-third in a rea and the cheilit is of the lips and canthi of the eyes had disappeared.

Case 4. J. C., whi te male, aged 44, d iagnos i s - - th rombo- phlebitis of infer ior vena cava with marked b rawny indu- ra t ion of ent i re body below the costal marg ins complicated by suppura t ion in lef t thigh, probably secondary to the deep thrombophlebit is . On 2-24-40 beginnng bed sore in sacral region noted. On 3-5-40 incision and dra inage of abscess in lef t thigh. Progress ive development of bed sore which became la rger and deeper. On 3-20-40 this round ulcer over the sacrum measured 2.25 cms. in d i ame te r ; i ts edge was beveled and its base appeared unheal thy. F ive mgms. of riboflavin by mouth s tar ted and continued daily. Fe r rous sul fa te and a whole B complex p repara t ion were also given. In three days the ulcer began to improve. On 3-25-40 it had decreased to 1.75 cms., on 3-29-40 fu r t he r decrease to 1 cm. was noted. On 4-2-40 ( th i r teen days la ter) the ulcer was completely healed. A t the t ime of the pat ient ' s discharge f rom the hospital (4-23-40) the sacral a rea appeared heal thy and had remained f ree of ulceration.

Case 5. G. S., white female, aged 58, d iagnos is - -obl ique f r ac tu re of lef t femur. Admit ted 4-12-40. On 4-30-40 pressure erosion was first noted in sacral region and over lef t la tera l epicondylar region of the thigh. Dur ing the next ten days these lesions became progress ively worse. At tha t t ime the sacral lesion measured 4 x 2 cms. and the ulcer over the lef t th igh 3 x 2 cms. The sur rounding skin was healthy. The daily oral adminis t ra t ion of 5 mgms. of riboflavin was s tar ted on 5-10-40. F r o m 5-10-40 to 5-13-40 one tablet of Brewers yeast was given three t imes a day by er ror but was discontinued on the la t te r date. Dur ing the period of riboflavin adminis t ra t ion, estrone, which had been given for some time, was continued. By 5-17-40 the sacral ulcer was almost ent i rely healed and the th igh ulcer was reduced to a size of 2.5 x 1.3 cms. Seven days la ter (5-24-40) the ulcer of the thigh was completely healed. Riboflavin was reduced to 2 mgms. daily. This pa t ien t was observed unti l discharge on 7-30-40 and the skin in the affected areas remained healthy.

45

46 AMERICAN JOURNAL OF DIGESTIVE DISEASES VOLUME 10 NUMidia 2

Case 6. S. C., white male, aged 15, d i agn os i s - - c on - gestive heart disease with circulatory collapse, pulmo- nary edema followed by pneumonia, interlobar pulmonary effusion and thoracentasis. Admitted 11-21-40. On 12-6-40 an area of gangrene was noted over the sacrum. On 12-11-40 the decubital ulcer measured 5.1 x 3.2 cms. Its central portion had a depth of 2 cms. and the base of the ulcer a t this portion was covered with foul-smelling ne- crotic tissue. The oral administrat ion of 5 mgms. of ribo- flavin was begun on 12-11-40 and continued daily there- after. Six days later this patient was placed on a high vitamin, high calorie diet. In six days the foul center slough had become clean and by 12-19-40 (eight days la ter ) , the ulcer had decreased to 3 x 3.2 cms. in size. On 12-20-40 sulfathiazole 0.5 G. t.i.d, was given for two weeks, and on 1-11-41 a t ransfusion of 250 cc. was also given. By 1-15-40 the ulcer measured 1.25 cms. in diameter and tissue loss was only superficial. Improvement continued, with complete healing of the lesion noted on 2-3-41 (seven weeks la te r ) , but sulfathiazole had been resumed on 2-2-41 in doses of 1 G. Q 4h. and was continued until 2-9-41. The following day he received an additional transfusion of 500 cc. This pat ient remained under observation until dis- charge from the hospital on 3-6-41, at which time the sacral area was healthy.

D I S C U S S I O N

Six cases of decubi ta l u lce ra t ion were t r ea t ed by the da i ly oral a d m i n i s t r a t i o n of 5 mgms. of r iboflavin. F ive of these cases showed complete hea l ing of the ulcers in f rom seven to t h i r t y - f o u r days of r iboflavin the rapy . The s ix th case died a f t e r seven days of t r e a t - m e n t wi th r ibof lavin and at dea th the decubi ta l ulcer- a t ion was reduced in size and showed evidence of heal ing.

Since improvemen t in these six cases was .nQte:d wi th in a few days a f t e r the i n s t i t u t i o n of ribo~a~vin, i t would seem l ikely t h a t the hea l ing of these ulcers was due to the v i t amin t he rapy . The cont inued and p rogress ive development of these lesions up to the day on which r iboflavin was f i rs t g iven should be empha- sized. I t is unl ikely t h a t the improvemen t in the local lesion could have been an express ion of a genera l ized sys temic improvement . On the con t ra ry , the genera l condi t ion of Case 2 g r ew p rogres s ive ly worse and ended in dea th ; Case 5 had an inoperable ca rc inoma of the s igmoid.

I t is not to be i n f e r r e d f rom these observa t ions tha t decubi ta l u lce ra t ion is a cl inical m a n i f e s t a t i o n of ar ibof lavinosis , nor a re these resu l t s to be i n t e r p r e t e d as evidence t h a t r ibof lavin is a specific in the t r e a t - ment of bed sores. I t is i n t e r e s t i n g to recall t ha t ea r ly in our cl inical expe r imen t s wi th r iboflavin many ob- se rvers believed t h a t che i l i t i s was a cl inical s t a t e cha rac t e r i s t i c of r ibof lavin d e f i c i e n c y . Subsequent s tudies have been r epo r t ed in which the admin i s - t r a t i on of py r idox ine in cases of chei l i t i s has been followed by the d i s appea rance of these l e s i o n s . F u r t h e r m o r e , cases of che i l i t i s which have been re- s i s ten t to r ibof lavin t h e r a p y have shown complete hea l ing when py r idox ine was given (5) .

I t is ex t r eme ly l ikely t ha t o the r member s of the B complex as well as r ibof lavin m a y exer t a f avorab le effect upon decubi ta l u lcera t ion . Quite p robab ly the add i t ion of the en t i r e B complex to the r iboflavin ad- min i s t e r ed migh t have resu l ted in a more r ap id im- p rovement in the local lesions of these six cases. Such cl inical poss ib i l i t i es a re in keeping wi th our increas- ing knowledge of v i t amin the rapy .

Bed sores a r e genera l ly s l o w - h e a l i n g , indolent lesions and t h e i r r ap id response to r iboflavin t h e r a p y

gives r i se to specula t ion as to the mechan i sm involved. Riboflavin is an essent ia l f ac to r in n u t r i t i o n and is of g r e a t impor tance to the oxida t ion enzymes of the body. I t is believed to be a basic cons t i tuen t of the xan th ine oxidase and thus es tab l i shes a closer l ink between v i t amins and t i s sue enzymes (1) .

The lesions of the skin and subcutaneous t i s sue in chei l i t i s have a para l le l in m i n i a t u r e to the t i s sue changes seen at t imes in decubi ta l u lcera t ion, and the cl inical response in both of these lesions to the ad- m i n i s t r a t i o n of r ibof lavin serves to emphas ize th i s para l le l i sm. F u r t h e r specula t ion seems to re la te the va r ious members o~ the B complex to t i s sues of o r ig ina l ec todermal o r ig in ; t h i a m i n to nerve t i ssue , n icot in ic acid to skin and mucous membrane , r ibof lavin and p robab ly pyr idox ine to skin and subcu taneous t issue. Now tha t inositol and pan to then ic acid a r e avai lab le i t seems logical to con jec ture w h e the r these two newer member s of the B complex a re not also possessed of an influence on ep i the l ium or s im i l a r t i ssues .

A l though inosi tol was f irst i sola ted in 1850 (19) , i t was not bel ieved to have an essent ia l role in nu t r i t i on unt i l Woolley in 1940 ident if ied i t as the mouse an t i - a lopecia f ac to r (13). The a lopecia produced in mice by a deficient diet was not influenced by b io t in or p-aminobenzoic acid. This d ie t conta ined adequa te pan to then ic acid, in add i t i on to o the r me mber s of the B complex. However , when inosi tol or some of i ts de- r iva t ives were added to the d ie t the a lopecia d isap- pea red (12) .

P u r e inosi tol was made avai lab le to us fo r s tudy and i t seemed logical to explore i ts poss ib le value in dis- eases of the skin and ha i r . On the bas is of p re sen t concepts the da i ly adu l t r e q u i r e m e n t of the human be ing is about one gram. Severa l vo lun teers were asked to t ake th is amoun t da i ly and no un toward effects were observed.

In a recent communica t ion , s tud ies on an ima l s sug- ges ted t ha t inosi tol appea r s to s t imu la t e in t e s t ina l pe r i s t a l s i s (6) . This ques t ion has been followed cl ini- cally in t w e n t y pa t i en t s t a k i n g f rom one to two g r a m s of inosi tol dai ly. In not one of these cases was any change in the normal bowel hab i t s noted, even though many of them had mild to mode ra t e cons t ipa t ion .

Gavin and M c H e nry found a s i m i l a r i t y be tween the ac t ion of inosi tol and l ipocaic in p r e ven t i ng the "b io t in" type of f a t t y l iver (3) . W i t h th is in mind inosi tol was a dmin i s t e r e d to a 58 year -o ld female d ia - bet ic wi th a blood cholesterol of 398 mgms. This pa t i en t also had a b i l a t e ra l s y m m e t r i c a l th ickened e rup t ion of the lower e x t r e m i t i e s and back. A f t e r the p a t i e n t had received 2 g r a m s of inosi tol da i ly for th ree weeks t he e rup t ion had cleared. The cholesterol was 313 mgms. severa l days a f t e r d i scon t inu ing the inosi- tol. F u r t h e r s tudies a re in p rog re s s and will be re- por ted .

Cases of a lopecia have been selected for s tudy and da i ly doses of f rom one to two g r a m s of inosi tol have been a d m i n i s t e r e d to these pa t i en t s for severa l weeks and in some ins tances for over two months . Defini te conclusions a re not poss ible a t th is t ime, bu t on the bas is of our ea r ly observa t ions the re a re not sufficient changes to indica te tha t inosi tol is the human an t i - a lopecia fac tor .

W i t h the a id of our assoc ia tes in the field of de rma- to logy a sys t ema t i c su rvey is a t p r e sen t be ing made of

Joum D. D. FEBRUARY, 1943

VORHAUS, GOMPERTZ AND FEDER--CLINICAL EXPERIMENTS WITH RIBOFLAVIN 47

the possible value of inositol in a var ie ty of skin dis- eases hi therto res is tant to t rea tment . These detailed studies will be reported later, but our pre l iminary observations seem to indicate tha t inositol may have a value in some skin diseases. Two examples of such a response are described in detail.

An 84 year-old female suffering from an extensive generalized prur i t i c eruption with thickening and desquamation was t reated by a dermatologist for four months. The eruption failed to respond to a var ie ty of local medication, X-ray and Vitamin A orally. She volunteered for inositol therapy. Af te r all other t rea t - ment had been stopped for three weeks and no change in the eruption had occurred, she was given 0.5 gram tablets of inositol orally, twice a day. In ten days there was a lessening of the prur i tus , in two weeks a modification of the eruption, and at the end of five weeks the eruption had almost entirely disappeared.

A 51 year-old male diabetic had a prur i t ic thick scaly symmetrical eruption involving both ankles and the inner aspect of both feet. Smears and cultures for fungi were negative, and t rea tment for two years by various dermatologists had not modified the eruption. He volunteered for inositol and was placed on one gram daily by mouth. Within two weeks there was a reduction in the amount of the eruption and at the end of nine weeks the eruption had almost entirely disappeared. Medication was then discontinued in order to evaluate clearly the effect of the inositol upon the eruption. Within two weeks the eruption again was manifest and at the end of two months had de- veloped to its original extent and severity. Inositol has been resumed recently with its original beneficial effect.

Since the chemical identification of pantothenic acid and its synthesis two years ago (9, 11, 10), it has been confirmed over and over again tha t pantothenic acid is one of the factors pr imar i ly responsible for the prevention of nutr i t ional achromotrichia in animals (8, 2, 4).

Recent studies in animal experimentat ion indicate that inositol and calcium pantothenate exert a definite influence on tissues of ectodermal origin. Woolley has emphasized the relationship between inositol and pan- tothenic acid, since the quant i ty of pantothenic acid fed influenced his animal cases of alopecia (14, 15). In some instances, with inclusion of large amounts of calcium pantothenate in the diet, no alopecia de- veloped, even though there was a marked absence of inositol in the rat ions fed. The explanation for th~s tends to emphasize more emphatically the inter-re- lat ionship of vi tamins of the B complex. I t has recently been reported that mice are able to synthesize inositol, if sufficiently high levels of pantothenic acid are fed, by means of intestinal micro-organisms (17). These reports are so very recent that they are mentioned here only to show the trend in animal ex- perimentation. Thus far, no human clinical research in this direction has been reported. Woolley has shown that mice fed on a low pantothenic acid diet developed signs of inositol deficiency. When these animals are given fu r the r supplements of inositol by mouth thei r signs of inositol deficiency continue unabated. Woolley raises the question as to whether there is interference of inositol absorption or destruction of the ingested inositol. In this connection Mart in has varied these experiments in an a t tempt to answer this question. When his mice on a low pantothenic acid diet de-

veloped signs of inositol deficiency he injected inositol intramuscular ly and observed the disappearance of the signs of inositol deprivat ion (18).

Calcium pantothenate was made available for study. One hundred mgms. of pantothenic acid were given twice a week by int ramuscular injections to three volunteers for six weeks. No effect upon the g ray ha i r present was noted. In one case of alopecia totalis (a 54 year-old white male) one gram of inositol was given daily by mouth and 100 mgms. of calcium panto- thenate were injected in t ramuscular ly twice a week for six weeks. At the end of this test period no change was noted and the experiment was discontinued.

A 45 year-old white male with alopecia a rea ta for three years volunteered for t reatment . Before t rea t - ment white hair had regrown in some of the areas of alopecia. 655 mgms. of calcium pantothenate were given by int ramuscular injection during ten weeks in varying amounts, and at the end of this t ime there was an unmistakable new growth of black ha i r in a central white streak. In the next two months 950 mgms. more of calcium pantothenate were given. At the end of tha t t ime no new growth was noted, al- though the previous old black hair was about one inch long. The t rea tment was stopped for two months and at the end of that t ime there was no change in the hair. In the next two months 42 grams of inositol were given in divided doses by mouth, and no change was noted. Then calcium pantothenate was again given by injection in doses of 500 mgms. intramuscu- larly twice a week. Twelve injections (a total of 6000 mgms.) were given and a slight new growth of black hair was observed. During all this t ime no pig- mentation was noted in the areas of white hair present in this patient. F u r t h e r studies are in progress and will be reported.

DISCUSSION

Although inositol has been known for many years and used extensively in animal experiments by Woolley in the past two years, no reports of its use in humans have appeared. Since we have reason to believe tha t this is the first t ime pure inositol has been given to human subjects, observations were made on doses of inositol that approached physiologic amounts. F rom analyses of the human diet it is assumed that the daily requirement of inositol is about one gram. All our observations were made in cases receiving one or two grams daily and the inositol was given in the form of 0.5 G. tablets in divided doses, irrespective of meals.

Our pre l iminary observations indicate that in these doses there is no apparent harmful effect of inositol in healthy subjects. Fur thermore , the bowel habi ts of our pat ients were not modified by this amount of inositol and therefore in these doses there is no clinical confirmation of the previous report that inosi- tol s t imulates intest inal peristalsis.

The results of animal experiments with inosito! present two outstanding fac ts - - f i rs t ly , tha t the signs of inositol deficiency in animals seem to be mainly changes in the skin and ha i r : and, secondly, tha t inositol is used by animals to make more complex t issue substances. One such substance has been identi- fied as phosphatide, found in the brain and nerve t issue; it appears to be a combination in some complex

4 8 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 10 NUMBER 2

form of inositol and phosphates (16). This combi- na t ion is lipid soluble in cont rad is t inc t ion to the wa te r soluble compound in muscle which is made up of inositol and other as yet unidentif ied substances (18).

Af te r we were convinced tha t inositol has no ha rmfu l effect in our doses we admin is te red this vi ta- min to a n u m b e r of pa t i en t s with alopecia both total and regional, and to a n u m b e r of pa t ients with chronic bi la teral skin e rupt ions of unknown etiology h i ther to res i s tan t to all forms of therapy. In the cases of alopecia we did not observe any regrowth of hair . In the cases with var ious skin diseases we have noted both negat ive and posit ive results. Several examples of rapid improvement in chronic erupt ions following the admin i s t r a t i on of inositol are detailed. Our ex- perience is still too recent to pe rmi t definite state- ments tha t inositol is or is not of benefit to any par- t icular skin disease. However, it offers a new approach to the problems of dermatology and it is hoped tha t cont inued and extensive clinical t r ia ls will be made by the workers in this field.

There has been much comment as to the value of calcium pan to thena te as an an t i - g r ay ha i r factor. In our hands this has not been the case. Even though we used huge doses, f rom 100 to 500 mgms. per in- jection, we have only rare ly noted any response in the hair . When response was appa ren t it occurred as a new growth of p igmented ha i r bu t no change in the exis t ing g ray ha i r was seen.

CONCLUSIONS

Riboflavin appears to be of value in the t r ea tmen t of decubital ulcerat ion. Fol lowing its admin i s t r a t i on the bed sores show rapid healing. The combined use of r iboflavin and the en t i re B complex may be of even g rea te r value in decubitus.

Inositol in doses of f rom one to two grams by mouth has no apparen t ha rmfu l effect. In alopecia no bene- ficial resul ts were noted. Rapid response in a va r ie ty of skin diseases following inositol admin i s t r a t i on were observed. I t is hoped tha t the dermatologis ts will s tudy this v i t amin and c lar i fy its field of usefulness.

Calcium pan to thena te seems to have li t t le value as a human an t i -g ray ha i r factor.

We wish to thank Dr. A. J. Beller, Dr. Milton Boden- heimer, Dr. Morris Dinnerstein, Dr. A. A. Epstein and Dr. S. Jahss for permission to use their cases.

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J. Dig. Dis., 8:290-295, 1941. 7. Sebrell, W. H. and Butler, R. E . : Pub. Health Reports, 53:2282-

2284, 1938. 8. Unna, K., Richards, G. V. and Sampson, W. L . : J. Nutrit . ,

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DISCUSSION DR. HARRY SHAY (Philadelphia): Mr. President,

Ladies and Gentlemen: I think this contribution of Dr. Vorhaus extremely important. We are beginning to recog- nize the importance of some of the newer members of the B group, in animal and in human metabolism: We have had some experience with inositol in the human being, not in relation to skin changes, but were tempted to t ry inositol for its effect on fat metabolism based on the work of Mc- Henry and his group at Toronto.

McHenry was able to produce cholesterol fat ty changes in the liver in Vitamin B deficient animals given Biotin. He was able to prevent and cure these fat ty livers with lipocaic and subsequently was able to do the same thing with inositol.

On the basis of these observations, we were prompted to study the effect of inositol in the diabetic, particularly in the diabetic with enlarged liver. Not knowing the re- quired dose for the human being, we calculated our dosage on the basis of McHenry's results. He was able to pro- duce beneficial results in his rats with a 5-milligram dose, and, considering the average rat as a half pound, we de- cided upon the use of 1.2 grams a day for the average patient.

We administered 1.2 grams per day to humans for a considerable period, without any ill effects, but, unfortu- nately, without being able to produce changes in the blood cholesterol levels or in the size of the liver.

The Oral Use of the Amino-Acids of Hydrolyzed Casein (Amigen) in Surgical Patients

By

ROBERT ELMAN, M.D. ST. LOUIS, MISSOURI

F ROM t ime to t ime "predigested" pro te in has been fed to a var ie ty of pa t ien ts and, indeed, prepa-

ra t ions have been described which were admin is te red per rectum. These a t t empts to spare prote in digest ion, aroused very li t t le in te res t probably because very li t t le was known of prote in and amino-acid metabolism. Tha t prote ins are normal ly absorbed f rom the intes-

*From Washington Univers i ty Depar tment of Surgery and Barnes Hospital, St. Louis, Missouri.

Read at the Annual Meeting of the American Gastro-Enterological Association at Atlantic City, N. J. , June 8-9, 1940.

t ine as amino-acids, is now general ly agreed. The problem of saving the body the need for pro te in di- gest ion reduces i tself to the admin i s t r a t i on of an ap- p ropr ia te m i x t u r e of amino-acids, pa r t i cu la r ly those which are now known as essential . Inasmuch as mix tu res of these bu i ld ing s t o n e s of pro te in in the pure form are at present prohibi t ive ly expensive, i t is necessary to obta in them by the appropr ia te hydro- lysis of complete proteins. Such a p repara t ion has been available for several years and we have used it