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POSTGRAD. MIED. J., 37, 76

CORTICOSTEROID TREATMENT OFULCERATIVE COLITIS

S. C. TRUELOVE, M.A., M.D.(CANTAB.), M.R.C.P.Niffield Department of Clinical Medicine, University of Oxford

ULCERATIVE COLITIS is a diffuse inflammatorydisease of a part or the whole of the colon, theatiology of which is at present ill-understood.Medical treatment has, therefore, depended uponthe application of general medical measures tocombat the effects of the disease, together with theuse of agents to diminish the inflammatory process.In the absence of precise atiological knowledge,the search for agents useful in reducing or abolish-ing the inflammatory reaction has necessarily beenon the basis of trial and error. It is, therefore, notsurprising that a multitude of therapeutic agentshas been employed. If we consider the naturalhistory of the disease, it is again not altogethersurprising that a large number of these miscel-laneous agents have been claimed to be highlybeneficial. The disease commonly presents as aseries of attacks of bloody diarrhcea with periodsof complete symptomatic freedom between them.Thus a treatment may be used on two or threepatients who pass into a 'natural' remission andit is then tempting for the physician to claim thatthe treatment was specifically responsible. Inthe history of the disease, therapeutic agents of themost diverse variety have been credited with avaluable action because of their apparent useful-ness in a handful of patients, only to be discreditedin the light of subsequent experience. Fortunately,the controlled therapeutic trial has become anaccepted clinical research method during the pastone or two decades and there is nowadays noexcuse for any useless treatment to remain invogue for very long. Of course, clinical impres-sions are of the utmost value to the physician firsttrying out a new method of treatment. But if hethinks that the results are promising, it is essentialthat he (or other workers) should put the methodto the test of formal trials. This is all the moretrue if the disease being treated is one whichpursues a variable course so that prediction of thecourse of the individual case is impossible.

Paper presented to the Harveian Societv on December14, I 960.

The Idea of Local Treatment in UlcerativeColitisThe idea of using local applications within the

bowel has been in existence for the past 40 years.Hurst (I921) made use of colonic irrigations withsolutions of ' albargin ' or of tannic acid, employingone and a half pints of fluid run into the rectumwith the patient in the knee-elbow position to en-courage the widespread distribution of the treat-ment throughout the colon. Since that time amultiplicity of agents has been used for intra-colonic treatment of the disease, such as acriflavineand other antiseptic agents, silver nitrate and otherastringent solutions, vitamin A, cod-liver oil,adsorbent agents such as Kaolin and aluminiumhydroxide, Pectin, intrarectal oxygen, and anti-biotics of various types (Durand, 1925; Rachetand Busson, 1935; Eyerley and Breuhaus, I937;Best, 1938; Nasio, 1947). None of these measuresseemed to make any substantial difference to theprognosis, and it is certainly true that no crucialtests of their efficiency have been reported. Theprobability is that they are all of negligible value.

Corticosteroids Used Locally in UlcerativeColitisMy own interest in the local treatment of

ulcerative colitis began in earnest in 1955, after alarge-scale controlled therapeutic trial had shownthat cortisone by mouth was a useful addition togeneral medical measures and greatly increasedthe chance of obtaining a remission within sixweeks (Truelove and Witts, 1954, 1955). Ascortisone, but more particularly hydrocortisone,had been found useful when applied topically in anumber of skin diseases, eye-diseases and jointdiseases, it seemed a logical step to try the effect oflocal application in ulcerative colitis. At that time,the available corticosteroids were limited and mostof the preparations were almost insoluble in water.I chose to use hydrocortisone itself, which has alimited solubility in water but which is quitehighly soluble in alcohol. An alcoholic solution ofhydrocortisone was diluted down with normal

LOCAL

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TRUELOVE: Local Corticosteroid Treatment of Ulcerative Colitis

FIG. I.-Method of self-administration of the rectal drip.

saline as the first preparation to be employed. Itwas also necessary to decide on the best method ofapplying the treatment, bearing in mind that thepatients to be treated would be suffering fromdiarrhcea. I decided to use a drip into the rectum,employing a blood-transfusion-giving set slightlymodified to carry a soft rubber catheter for actualinsertion into the rectum (Fig. i). Subsequentexperience has shown that this is quite a satisfac-tory method of application and one which patientscan readily be taught to use at home if they are notso severely ill that hospital treatment is essential.

I began by treating 21 patients with mild ormoderate attacks of ulcerative colitis and obtained14 complete remissions within two weeks of start-ing treatment (Truelove, 1956). The strikingfeature was the extreme speed with which thepatients who responded to treatment did so.Although the method was not universally effi-cacious, it nevertheless seemed quite beyond thebounds of chance that as many as two-thirds ofthe patients would respond so rapidly if the treat-ment were inactive. There was, therefore, a primafacie case for concluding that this approach totreatment was worth further study.

All these patients were observed sigmoidoscopi-cally immediately before and after two weeks'treatment and in every case a biopsy specimen ofthe colonic mucosa was taken by means of a specialinstrument developed for the purpose. It wasobserved that a striking sigmoidoscopic improve-ment occurred in all the patients who went intoclinical remission (Fig. 2), but that the histologicalappearances of the biopsy specimens did not show a

markedly favourable response. It appcared pos-sible that the weakly alcoholic solution in which thehydrocortisone was applied might be impeding thehealing of the actual mucosa. Fortunately, at thistime Glaxo Laboratories were able to supply mewith hydrocortisone hemisuccinate sodiutm, whichis highly soluble in water. A second study wasmade employing this agent and it was found that,while the clinical and sigmoidoscopic responseswere similar to those obtained in the earlier study,the histological responses were much more favour-able (Truelove, 1957). Consequently, this ageint,or another water-soluble corticosteroid, pred-nisolone 2 i-phosphate, has been the choice forlocal corticosteroid therapy.

It was then necessarv to submit the method tothe discipline of a formal therapeutic trial inorder to confirm or refute the clinical impressionthat the treatment was valuable. Forty patientswere allotted at random to local treatment eitherwith real hydrocortisone hemisuccinate sodium orwith a dummy preparation. Of the 20 patientsreceiving the dummy treatment only one had aspontaneous remission in the course of one week,whereas i I of the 20 on real treatment wereentirely symptom-free after one wveek. Thisdifference is highly significant in a statistical sense.The sigmoidoscopic and histological responsesalso showed an unequivocal advantage on the sideof the real treatment. The fact that a dummy dripwas employed showed that the treatment wasworking by a pharmacological action and not bvany psychological means (Truelove, I958). Simul-taneously, another ' blind ' controlled trial wascarried out independently by W\atkinson (I958) inLeeds, with closely similar results. He employedthe elegant and efficient method of sequentialanalysis for assessing the results and swN-iftlyobtained an answer favouring the hydrocortisonegroup. As far as clinical responses xN-ere concerned,he found that one out of nine patients on ' dummy '

treatment went into remission in two weeks,whereas nine out of ten patients on real treatmentNvent into remission in the same time.

Optimum Length of Treatment with LocalCorticosteroid TherapyMost of my published work on local cortico-

steroid treatment has dealt with the clinicalresponses obtained with short courses of two orthree weeks. This has been because a principalaim in the last few years has been to find forms oftreatment which bring all attacks of ulcerativecolitis swiftly to a halt. However, as soon ashydrocortisone hemisuccinate sodium becameplentiful, I have made it a rule to continue treat-ment in responsive patients for several wveeks atleast after the cessation of symptoms. I believe

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this to be beneficial in reducing the risk of earlyrelapse although a close analysis of the results hasnot yet been completed.

Long-term Treatment with LocalCorticosteroid Treatment

In general, I do not favour long-term treatmentvN-ith any type of corticosteroid, but there arecertain exceptions. For example, a group ofpregnant women responding favourably to localcorticosteroid therapy has been left on this formof treatment throughout the entire pregnancy.The results have been excellent, the patients beingin good health throughout and deliveries beingnormal.

Local Compared with Systemic andCombined Corticosteroid Treatment

Both systemic and local corticosteroid treatmenthave been found useful in the medical managementof attacks of ulcerative colitis. It is plainly ofimportance to know which of the two methods isthe better or whether there is any advantage incombining these two methods of administration.Sufficient evidence comes from a comparativestudy of systemic, local and combined cortico-steroid therapy in ulcerative colitis to suggest thatin all but the mildest cases of the disease it is bestto employ combined therapy to bring attacks to arapid halt (Truelove, Ig60a). Once the attack ischecked, the oral corticosteroid can be tailed offbut local treatment can be continued for someweeks longer with negligible risk of side-effects.There is also the strong suggestion that local

hydrocortisone hemisuccinate with oral pred-nisolone is a better combination than prednisolonephosphate locally and prednisolone by mouth. Theexplanation for this difference is uncertain butone possibility is that different corticosteroidsmay have a synergistic action, a possibility which,if proved, would accord with some interestingtheoretical explanations of synergism advancedby Veldstra (1956). It certainly appears truethat the metabolic pathways of hydrocortisone andprednisolone are not identical (Nugent, Eik-Nesand Tyler, I959).

Local Treatment in Severe Attacks of theDisease

It is sometimes supposed that local cortico-steroid treatment is of value only in comparativelymild attacks of ulcerative colitis and especiallywhen only the distal part of the colon is affected.In reality, there is strong presumptive evidencethat this form of treatment can be a valuable partof the medical management of severe attacks. This

(a) (b)FIG. 2.-Corresponding views of part of the barium

enema films of a patient with severe ulcerativecolitis (a) before and (b) after local corticosteroidtreatment.

is not surprising since it is appreciated that liquidsintroduced into the rectum spread extensivelythrough the colon so that there is no prima faciecase for avoiding local treatment merely becausethe disease is widespread.

Certain practical points are of great importancewhen using local corticosteroids in severe attacksof the disease. Firstly, it appears best to use localtreatment at least twice a day in such severe attacksand to emplov systemic corticosteroids in addition.Secondly, if the diarrhlea is very severe, it may benecessary, at first, to employ intravenous proban-thine to paralyse the colon temporarily to allow theevening treatment to act for at least some hours;overdosage with the probanthine must be avoided.Thirdly, the use of corticosteroid treatment doesnot absolve the physician from the duty of applyingcertain general medical measures-blood trans-fusion, control of water and electrolyte balance,and adequate dietary intake without which asevere attack rapidly brings the patient into astate of jeopardy or even to his death.

All these issues have been dealt with in somedetail in a previous article (Truelove, ig6ob) andwill not be enlarged upon here.

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TRUELOVE: Local Corticosteroid Treatment of Ulcerative Colitis

Site ofAction of Corticosteroids Used Locallyin the Colon

It is of some consequence to know whetherlocal corticosteroid treatment acts directly uponthe inflamed colonic mucosa or whether it acts bybeing absorbed and then exerting a systemic action.It would be manifestly absurd to administer anagent by rectal drip if the results were identicalwith those obtained by giving the agent moresimply as a tablet to be swallowed.

Clinically, there is some evidence that localcorticosteroid treatment is not the same as systemictreatment. The clinical response to local cortico-steroid treatment is much more frequentlydramatic than that obtained by systemic cortico-steroids. Moreover, as far as hydrocortisonehemisuccinate is concerned, it is possible to havepatients on daily rectal drips containing ioo mg.of hydrocortisone for several months with noclinical evidence of hypercortisonism. Thisclinical finding is in line with the laboratoryevidence brought forward by Schwartz, Cohn,Bondy, Brodoff, Upton and Spiro (1958) wholabelled hydrocortisone with 14C and found thattopical application of the hemisuccinate to thecolon in quite large quantities produced noappreciable change in the level of circulatinghydrocortisone in the blood. In other words, it isprobable that the main action of topical hydro-cortisone in ulcerative colitis is directly upon theinflamed mucosa. The exact chemical compositionof the particular corticosteroid preparation usedmay be of crucial importance. Thus Nabarro,Moxham, Walker and Slater (I957) found thathydrocortisone itself was readily absorbed fromthe rectum but that hydrocortisone acetate wasnot appreciably absorbed (which might be due toits negligible solubility in water) while only smallamounts of hydrocortisone hemisuccinate sodiumwere absorbed in spite of the high water-solubilityof this compound. This is an aspect of localcorticosteroid treatment which deserves furtherstudy.

Favourable Experiences of OtherPhysiciansAmong the first to use local corticosteroid treat-

ment in ulcerative colitis were the Italian workers,Allodi and Muratori (1956). They introducedhydrocortisone into the bowel through a sig-moidoscope, daily or every other day, duringattacks of ulcerative colitis and claimed excellentresponses in seven of the nine patients treated.However, this is a method of application whichcan hardly be regarded as ideal. In the UnitedStates, Patterson and McGivney (I959) have usedlocal hydrocortisone with a considerable measure

of success and so also have Schwartz, Bardoff,Cohn and Spiro (I 959). Among English physicians,reference has already been made to the work ofWatkinson (1958).More recently, Matts (I960) has employed

prednisolone phosphate already prepared insolution in disposable plastic enema bags. Thisappears to be a convenient method of administer-ing local treatment to the colon, although my ownexperience of the method is small. Matts' initialresults were most encouraging and in his lateststudy, which deals with ioo patients treated bythis method, he reports improvement in 88 (Matts,I96I). Of course, relapse is liable to occur inpatients who have responded well to treatmentbut comparatively few break down quickly and75% of the patients who showed improvementwith their first course of treatment were still freefrom relapse nine months later. Furthermore,most patients who relapsed responded well to afurther course of treatment.

A Discordant NoteBy contrast with the favourable experiences just

mentioned, one group of physicians has foundlocal corticosteroid treatment to be disappointing.Lennard-Jones, Longmore, Newell, Wilson andJones (I960) report their experiences of a trial ofdifferent forms of therapy in the management ofoutpatients with ulcerative colitis, one type oftherapy being a daily rectal drip of hydrocortisonehemisuccinate sodium. Their results with thisform of treatment were so poor that one is im-mediately forced to wonder why they should be sodifferent from those obtained by other workers.Perhaps a clue is provided in the authors' ownremark that' The technique used was cumbersomeand complicated, suitable more for hospital thanoutpatient use'. This does not accord with myown experience in treating more than 200 out-patients by the method. My own clinic is organizedso that the giving apparatus is ready at hand topresent to the patient who is also given a shorttalk on exactly what to do. Originally this talk wasalways given by me but, more recently, owing tothe pressure of numbers, by an experiencedtechnician who assists in the clinic. The numberof patients who have had the slightest difficulty incarrying out the treatment has been trivial. Thereare only two dons (one from Cambridge!) amongmy patients, so there is no reason to suspect anunduly high level of intelligence among theOxford patients. Nevertheless, the need for someorganization and instruction is apparent and it ispossible that the disposable enema bag pioneeredby Matts will supplant the use of a rectal drip foroutpatient use.

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Possible Dangers of Local CorticosteroidTreatmentThe rate of absorption from the colon is so

low, at any rate as far as hydrocortisone hemi-succinate is concerned, that systemic side-effectsof therapy do not arise. On theoretical groundsone might fear that local corticosteroid treatmentwould lead tp an increase of pyogenic complicationsaround the rectum, such as ischio-rectal abscess,fistula-in-ano and recto-vaginal fistula. Practicalexperience has shown that this fear is groundless.Brooke (1956) has described thinning and excessivefriability of the colon as a complication of corti-costeroid treatment, including its local use, butsuch changes in the colon were encountered beforethe introduction of corticosteroid treatment. Themain risk of corticosteroid therapy, including itsuse as a local application, is that an unwaryphysician may persist blindly with medical treat-ment in the minority of patients who show nofavourable response. If the patient is very ill,such persistence may result in some dangerouscomplication of the disease, such as perforation ofthe colon, or may so delay recourse to surgery thatthe risks of emergency operation are greatlyincreased. In brief, corticosteroid treatment needsto be handled with skill when one is dealing withthe more savage attacks of the disease. However,it is no new situation in medicine to find that potentremedies can be dangerous unless employed withskill. William Withering (1785) himself remarkedin connection with the unguarded way in whichmost other physicians of his day employeddigitalis, ' shall we wonder then that patientsrefuse to repeat such a medicine, and that prac-titioners tremble to prescribe it?' Yet digitalis wasone of the few therapeutic agents of any value tobe discovered before the 20th century and is oneof the even smaller number which survive asessential drugs today.

Local Corticosteroid Treatment Used inCombination with Other Forms of MedicalTreatmentThe combined use of local and systemic

corticosteroid treatment has already been men-tioned. Apart from corticosteroid therapy, thereis only one pharmacological agent which appearsto be of major benefit in ulcerative colitis, if weexclude those general medical measures which areessential to preserve life and strength during anacute attack of the disease. This is salacylazo-sulphapyridine, which is more commonly knownas ' salazopyrine ' or ' asulfidine '. This compoundwas introduced in 1940 by the Swedish physician,Dr. Nanna Svartz, who has used it extensively(Svartz, 1954, 1956). Although it has not been putto such crucial tests of efficiency as has cortico-

steroid treatment, there is ample evidence that it isbeneficial in a considerable proportion of patients.The salient facts of its pharmacology and use havebeen given in a previous article in this journal(Truelove, I959) and will not be reiterated.

At present it is a moot point whether salazo-pyrine is as good as combined corticosteroidtreatment in checking an attack of ulcerative colitisbut a formal trial to settle this point is in fullprogress. However, in the present context, it issufficient to remark that, in patients who resisteither salazopyrine or corticosteroid treatmentused separately, it is possible to combine thesetreatments and the combination often appears tobe successful.

Local Corticosteroid Treatment Combinedwith Conservative SurgeryThe accepted surgical approach today is colec-

tomy either with permanent ileostomy or withileo-rectal anastomosis. However, there are somecircumstances when a physician can only regardthis major procedure as unfortunate. With theactive collaboration of a surgical colleague, Mr.Harold Ellis, a group of patients has been treatedwith temporary double-barrelled ileostomy tofacilitate local treatment of the colon. In a sense,this is attempting to put the clock back, becauseby I92I Hurst was advocating appendicostomy topermit irrigation of the colon with fluid agents,although it is unlikely that the agents at hisdisposal were of any benefit. Ellis (I96I) hasgiven the indications for the combined surgicaland medical treatment which we have beenemploying. In essence, we have used it on theone hand when a savage attack has appeared to beresisting medical treatment and, on the other,when pararectal complications, such as recto-vaginal fistula, have required diversion of thefecal stream to permit of their satisfactory surgicalrepair after treatment of the colitis. It is too earlyto state dogmatically that this approach to treat-ment is a good one, but the results so far are notdiscouraging.

Assessment of the Present SituationLocal corticosteroid treatment is not a cure for

ulcerative colitis. The liability to relapse persists,although it is unusual for immediate relapse tooccur after a course of treatment which has beensuccessful in checking an attack. All that we cansay is that local corticosteroid treatment is one ofthe ways in which attacks of ulcerative colitis canbe checked or aborted and that, when it is success-ful, it commonly works with great speed. There isa distinct possibility that, if first attacks of thedisease are promptly diagnosed and treated by

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February 196I TRUELOVE: Local Corticosteroid Treatment of Ulcerative Colitis' 8i

PERCENTAGE CASE-FATALITY RATEOF INPATIENTS

Radcliffe Infirmary & ChurchillHospital, Oxford.

Introduction of1 7 systemic corticosteroid

.16 therapy

14 -Introduction of1local corticosteroid

12 - therapy

Fatality -- 'R^atea-

4

2

1938- 1944-1949 50- 52- 54-'56-59'51 *53 '55

FIG. 3.-Showing the marked decline in the proportionof patients dying in hospital from an attack ofulcerative colitis since the introduction of modemmedical treatment.

some method such as local corticosteroids whichreduces the inflammatory reaction and thusminimizes the damage to the colon, the long-termcourse of the disease is improved. In any event, ifpatients with ulcerative colitis are kept unfdermedical supervision and attacks of the disease aretreated without delay as soon as they arise, there isevery indication that the prognosis of the diseaseis greatly improved.

In principle, it is easy to see how we shouldtreat ulcerative colitis if we had the necessaryknowledge. With the first attack, the essential aimwould be to stop the attack promptly to removeimmediate danger and discomfort. This done, weshould then identify and remove or correct what-ever factor was found to be responsible for thechronic liability to develop attacks of this illness.The first of these two steps can nowadays beaccomplished successfully in the great majority ofinstances by medical management and I believethat local corticosteroid treatment is a useful part of

this management. The second step-that ofidentifying and eliminating the responsible chronicfactor-is usually impossible for us. Some workers,among whom Andresen (1942) was the pioneer,have regarded allergy to certain foods as an im-portant cause of ulcerative colitis, and I havepersonally made some observations which suggestthat specific foods may be of great importance insome of the subjects (Truelove, I96I); There arealso some patients in whom psychological difficul-ties are apparent and improvement in the clinicalcourse may result from successful handling of thesedifficulties. Indeed, there are some physicians whoregard the illness as psychosomatic and conse-quently regard psychotherapy as the mainstay oflong-term treatment (Paulley, 1956; Groen andBastiaans, 1951; Grace, Pinsky and Wolff, 'I954).But most of us find ourselves unable to give anysatisfactory explanation in the majority of ourpatients to account for the liability to relapse. It isevident that further work on atiology is urgentlyneeded. Observations by Broberger and Perlman(1959) suggest that auto-immune reactions com-monly occur in the disease but the importance ofthese in causation or in perpetuation of the disorderremains uncertain.

In brief, the cardinal problem in the medicalmanagement of ulcerative colitis today is how toprevent relapses occurring after a patient has oncebeen rendered symptom-free. To this we have nosatisfactory answer at present. However, it maybe remarked that this problem has been thrown upinto sharp relief chiefly because the dangers ofthe individual attacks have been su'bstantiallyreduced in recent years. Among the measureswhich have been responsible for this improve-ment, local corticosteroid therapy has played auseful part.

AcknowledgmentsFigs. i and 3 are reproduced by permission

of the Honorary Editors of the Proceedings of theRoyal Society of Medicine and of the Editor of theBritish Medical Journal respectively.

REFERENCESALLODI, A., and MURATORI, F. (1956): A Propos du Traitement Associ6 Antibiotiques-cortisone dans la Colite

Ulc6reuse Aspecifique plus Particulierement en ce qui Concerne l'Administration par Voie Rectale de l'Hydro-cortisone, Gatroenterologia (Basel), 86, 697.

ANDRESEN, A. F. R. (1942): Ulcerative Colitis-an Allergic Phenomenon, Amer. J. dig. Dis., 9, 9I.BEST, R. R. (1938): Cod Liver Oil per Rectum as an Adjunct in the Treatment of Ulcerative Colitis, Ibid., 5, 426.BROBERGER, 0., and PERLMAN, P. (1959): Autoantibodies in Human Ulcerative Colitis, J7. exp. Med., 11O, 657.BROOKE, B. N. (1956): Cortisone and Ulcerative Colitis: An Adverse Effect, Lancet, ii, II75.DURAND, G. (1925): L'acriflavine dans la Traitement Local des Colites Ulcereuses Chroniques, Arch. Mal. Appar.

dig., zI, 3I6o.ELLIS, H. L. (I96I): In a panel discussion on the treatment of ulcerative colitis, Proc. Internat. Congr. Gastroenterology,

Leiden, I960. In Press.EymuEIy, J. B., and BRENHAus, H. C. (1937): Treatment of Ulcerative Colitis with Aluminium Hydroxide, and Kaolin,

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GRACE, W. J., PINSKY, R. H., and WOLFF, H. G. (I954): The Treatment of Ulcerative Colitis, Gastroenterology, 26, 462.GROEN, J., and BASTIAANS, J. (I95I): Psychotherapy of Ulcerative Colitis, Ibid., 17, 344.HURST, A. F. (1921): Ulcerative Colitis, Guy's Hosp. Rep., 71, 26.LENNARD-JONES, J. E., LONGMORE, A. J., NEWELL, A. C., WILSON, C. W. E., and JONES, F. A. (I960): An Assessment

of Prednisone, Salazopyrine and Topical Hydrocortisone Hemisuccinate used as Outpatient Treatment forUlcerative Colitis, Gut, I, 217.

LIDDLE, G. W. (1956): Al, ga-fluorohydrocortisone; a New Investigative Tool in Adrenal Physiology, J. clin. Endocr.,6, 557.

MArrs, S. G. F. (I960): Local Treatment of Ulcerative Colitis with Prednisolone-2i-phosphate Enemata, Lancet,i, 517.(I96I): Intrarectal Treatment of ioo Cases of Ulcerative Colitis with Prednisolone-2i-phosphate Enemata,

Brit. med. J7., i, I65.NABARRO, J. D. N., MOXHAM, A., WALKER, G., and SLATER, J. D. H. (1957): Rectal Hydrocortisone, Ibid., ii, 272.NASIO, J. (1947): Local Sulphanilaminotherapy in Chronic Thrombo-ulcerative Colitis by Means of Single or Double

Colonic Tube, Rev. Gastroent., 34, 253.NUGENT, C. A., EIK-NES, K., and TYLER, F. H. (1959): A Comparative Study of the Metabolism of Hydrocortisone

and Prednisolone, Y. clin. Endocr., 19, 526.PATTERSON, M., and MCGIVNEY, J. (1959): Topical Steroids in Diseases of the Colon, Sth. med. J. (Bgham, Ala.),

52, 423.PAULLEY, J. W. (I956): Psychotherapy in Ulcerative Colitis, Lancet, ii, 215.RACHET, J., and BUSSON, A. (1935): Le Traitement des Recto-c6lites Ulcereuses par la Vitamine 'A', Arch. Mal.

Appar. dig., 25, 743.SCHWARTZ, R. D., COHN, G. L., BONDY, P. K., BRODOFF, M., UPTON, G. V., and SPIRO, H. (1958): Absorption of

Cortisol from the Colon in Ulcerative Colitis, Proc. Soc. exp. Biol. (N. Y.), 97, 648., BARDOFF, M., COHN, G. L., and SPIRO, H. M. (1959): Rectal Cortisol in the Therapy of Ulcerative ColitisArch. intern. Med., IO4, 260.

SVARTZ, N. (1954): The Treatment of Ulcerative Colitis, Gastroenterology, 26, 26.(1956): The Treatment of Ulcerative Colitis, Gastroenterologia (Basel), 86, 683.

TRUELOVE, S. C. (I956): Treatment of Ulcerative Colitis with Local Hydrocortisone, Brit. med. J., ii, 1267.(1957): Treatment of Ulcerative Colitis with Local Hydrocortisone Hemisuccinate Sodium, Ibid., i, 1437.(I958): Treatment of Ulcerative Colitis with Local Hydrocortisone Hemisuccinate Sodium: A Report on a

Controlled Therapeutic Trial, Ibid., Ha, 1072.(I959): Medical Treatment of Ulcerative Colitis, Postgrad. med. Y., 35, 62.(Ig60a): Systemic and Local Corticosteroid Therapy in Ulcerative Colitis, Brit. med. .7., i, 464.(Ig6ob): Local Corticosteroid Treatment in Severe Attacks'of Ulcerative Colitis, Ibid., ii, 102.

- (I961): Ulcerative Colitis Provoked by Milk, Ibid., i, I54.- and WITTS, L. J. (1954): Cortisone in Ulcerative Colitis: Preliminary Report on a Therapeutic Trial, Ibid.,

ii, 375.(1955): Cortisone in Ulcerative Colitis: Final Report on a Therapeutic Trial, Ibid., ii, 1041.

VELDSTRA, H. (1956): Synergism and Potentiation with Special Reference to the Combination of Structural Analogues,Pharmacol. Rev., 8, 339.

WATKINSON, G. (1958): Treatment of Ulcerative Colitis with Topical Hydrocortisone Hemisuccinate Sodium: AControlled Trial Employing Restricted Sequential Analysis, Brit. med. 3., ii, 1077.

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