Il meccanismo per cui le diete elementari inducono remissioni in pazienti affetti da morbo di Crohn non è conosciuto, ma si ipotizza che queste ultime possano giocare un ruolo fondamentale contribuendo a migliorare lo stato nutrizionale, o rimuovendo il fattore "intralumiale" che può indurre o estendere l’infiammazione.
Sono stati valutati gli effetti della nutrizione enterale su pazienti affetti morbo di Crohn.
PAZIENTI E METODI
Per effettuare lo studio sono stati presi in esame quindici pazienti, otto maschi e sette femmine, affetti da morbo di Crohn in fase acuta con indice di attività della malattia > di 150 (Modified Crohn Disease Activity Index > 150), di età compresa tra i 12 e i 51 anni.
La patologia è stata diagnosticata da colonsclopia, esami istologici e radiologici.
A tutti i pazienti è stata somministrata una dieta elementare (Peptison, Nutricia), somministrata in continuo tramite sonda nasogastrica (osmolarità della dieta pari a 400 mOsm/l, e apporto energetico di 1Kcal/ml).Dopo 4 settimane è stata gradualmente reintrodotta la normale dieta.
La nutrizione per sonda veniva effettuata a livello ospedaliero ma a tutti i pazienti è stato permesso il ritorno a casa dopo miglioramento del quadro clinico.
Tutti i pazienti hanno ricevuto un trattamento con mesalamine (3-4 g/giorno).
La valutazione dello stato nutrizionale e l’attività della malattia valutati al momento dell’ingresso in ospedale e della dimissione ospedaliera sono stati ripetuti dopo una settimana di dieta elementare e a due, quattro e dodici settimane dopo il trattamento con dieta elementare.

14pazienti hanno completato lo studio, 1 paziente è stato escluso, causa intolleranza della dieta.Un paziente non ha avuto il miglioramento clinico. Dopo 2 settimane di terapia nutrizionale l’MCDAL è migliorato in maniera significativa e questo miglioramento si è mantenuto nei controlli successivi.
Dodici settimane dopo il trattamento nutrizionale, la valutazione dei tredici pazienti evidenziava una completa remissione clinica associata ad uno stato nutrizionale normale.

Il trattamento con dieta elementare nella riacutizzazione della Malattia di Crohn può rappresentare una valida ed efficace alternativa terapeutica.
Potrebbe essere considerato un trattamento di prima scelta nella malattia di Crohn in fase attiva.

TROVATELLO A. - DI FRANCO F. *, ROMANO S. - PASSANESE M. - MALANDRINO S. ** , DIFRANCO S. Azienda Ospedaliera "Umberto I°" - Siracusa - II° Divisione di Chirurgia Generale (Primario: Dr. G. Macca).
* Università di Catania - Dipartimento di chirurgia generale e toracica (Direttore: Prof. S. Latteri).
** Azienda Ospedaliera "Umberto I°" - Siracusa - Divisione di Pediatria (Primario; Dr. L. Nicastro).

In questa pagina sono riportate alcune informazioni sui Probiotici e sul lore impiego nella cura delle IBD.

Background & Aims: Anti-Saccharomyces cerevisiae antibody (ASCA) is a serologic marker associated with Crohn's disease (CD). Although there is still discussion on its clinical value, several companies each promote their own ASCA assay to be used in the gastroenterologist's practice at considerable expense. The aim of this study was to determine whether different ASCA assays agree sufficiently well for the results to be used interchangeably. 
Methods: Blood obtained from a large cohort of IBD patients with inflammatory bowel disease (IBD; 100 with CD, 100 with ulcerative colitis [UC]) and 178 controls (100 healthy blood donors and 78 patients with non-IBD diarrheal illnesses) was studied with 4 different ASCA assays. Sensitivity, specificity, and positive predictive value were compared. Agreement between assays was evaluated. 
Results: Sensitivity of ASCA for CD ranged between 41% and 76%. Sensitivity was inversely related to specificity and positive predictive value. Results correlated well overall (range = 0.54-0.90) and the different ROC curves showed good agreement. When recalculated cutoff points were used, interchangeability increased. However, large differences were seen when absolute values were compared. Conclusions: A large range in sensitivities and specificities of ASCA for CD is seen with different ASCA assays, mainly as a consequence of the cutoff value chosen for each individual assay. Although agreement between and within assays is good, caution is important when absolute values are used. Standardization of ASCA measurements is greatly needed. 

Many patients are not as well-informed about prescription medications as they ought to be. We believe that the more you know about your medications, the better. This leaflet is our attempt to inform you about Lomotil and to emphasize the importance of taking it properly. If any of this information causes you concern or if you desire additional information about Lomotil and its use, check with your doctor or pharmacist.
Lomotil overdosage is especially dangerous in young children. Remember to keep this medication, along with all prescription drugs, beyond the sight and reach of children when not in use. Store Lomotil in its original labeled container; the place of storage should be cool, dry, and dark. Carefully read the instructions on the label before each use.

What is Lomotil?
Introduced in 1960, Lomotil is the most commonly known brand of a potent anti-diarrheal drug called diphenoxylate (dye-fen-OX-i-late). Other brands include Lonox, Low-Quel, Logen, Colonil, Diphenatol, and Lo-Trol. The generic form of diphenoxylate is as safe and effective as the brand-name versions; it is also much less expensive. Each tablet contains 2.5 mg. of diphenoxylate and a trace amount of atropine, a chemical that prevents the use of this medication for illicit drug purposes.

What Lomotil is not.
Lomotil does not act to heal inflammation or fight infection in the bowel; it merely controls symptoms. Although chemically related to narcotics, Lomotil rarely causes dependency or serious side effects when taken as prescribed. It does not cause sexual dysfunction.

How does Lomotil work?
Lomotil delays the passage of waste through the digestive tract by slowing bowel contractions. Such action reduces cramping as well as the frequency and looseness of bowel movements. Taking Lomotil properly
    1. Take the dose as prescribed. Initially, your doctor determines what dose is best for you on the basis of your age, weight, the severity of your diarrhea, and other medical conditions that you may have. In general, adults require one to four tablets of Lomotil per day. However, individuals with severe diarrhea may require higher doses. Your doctor will give you clear instructions about taking Lomotil and will adjust your dosage as needed. The goal, of course, is to control your diarrhea with the lowest possible dose of Lomotil.
Although Lomotil is usually prescribed for the short-term treatment of simple acute diarrhea, it is sometimes prescribed for the long-term treatment of chronic diarrheal conditions like irritable bowel syndrome, ulcerative colitis, and Crohn¹s disease. This should only be done with your doctor's supervision.
    2. Lomotil can be taken on an empty stomach as well as with food or milk. If necessary, the tablets may be chewed or crushed. You do not need to follow any food or beverage restrictions while taking this medication. Alcohol, however, may increase the sedative effects of Lomotil. During an attack of diarrhea, remember to drink extra fluids. The beverage Gatorade® is especially helpful in preventing dehydration at such a time.
    3. It is safe to stop taking Lomotil on your own. In fact, you should discontinue this medication if your symptoms disappear. Taking Lomotil after your diarrhea subsides may lead to severe constipation. Moreover, it is safe to decrease the dosage as your symptoms improve. If you have been taking more than three tablets per day for longer than one month, however, you may need to taper off the medication gradually. Ask your doctor about this.

What are the side effects?
All medicines‹even those purchased without a prescription‹may sometimes produce unwanted side effects. However, serious side effects rarely occur in patients taking this medication. You can help to reduce the risk of side effects by taking Lomotil exactly as prescribed and by promptly reporting any problems to your doctor. It is important that you keep all scheduled appointments so that your doctor can evaluate your response to the medication and check for possible side effects.
These side effects should be reported to your doctor:
    Skin rash, severe itching
    Unexplained fever
    Blurred vision
    Swelling of stomach, vomiting
The following side effects usually do not require medical attention. They often subside as the body becomes used to the medication or when the dosage is decreased. Should these side effects continue or become bothersome, however, check with your doctor:
    Constipation
    Dryness of mouth and throat
    Drowsiness
Side effects not listed above may occasionally occur. If you experience further symptoms, simply check with your doctor, nurse, or pharmacist.

Precautions
Lomotil merely acts to control the symptoms of diarrhea; it does not cure serious disorders or infections of the bowel. For this reason, you should report any persistent change in bowel habits or episodes of blood-stained diarrhea to your physician.
Please tell your doctor if you are pregnant or breast-feeding. Inform your doctor if you have glaucoma severe liver disease, urinary difficulties, or prostate problems. Also inform your doctor if you have recently taken antibiotics or if you are currently taking any prescription medications, particularly sedatives or tranquilizers. Patients using antidepressants known as MAO inhibitors (Nardil, Marplan) should not take Lomotil.
As Lomotil can cause drowsiness, avoid driving and operating machinery until you have learned how this drug affects you. Avoid alcohol while taking Lomotil.

Remember
Lomotil is a powerful drug that can effectively control diarrhea. As with all medications, however, side effects may occur. You can best limit problems with this medication by taking it exactly as prescribed. If you have any questions or concerns, do not hesitate to discuss them with your doctor.

COLAZAL™ (balsalazide disodium), manufactured by Salix Pharmaceuticals, Ltd. is now available in the United States for patients with mildly to moderately active ulcerative colitis. Shipments of this new IBD medication were sent out to drug wholesalers in late December, ready to be ordered by local pharmacies in January.

COLAZAL, a sulfa-free 5-ASA product, is the first entity approved by the FDA for the treatment of ulcerative colitis in seven years. It treats ulcerative colitis by delivering the active anti-inflammatory medication directly to the colon, where it appears to work topically.

A number of drugs that contain 5-ASA are currently used to treat IBD. 5-ASA is the active ingredient of sulfasalazine, which has been a standard IBD medicine for many years. Sulfapyridine, the portion of sulfaslazine that carries 5-ASA to the intestine, is responsible for most of this drug's side effects. To reduce these side effects, several drugs have been developed that deliver the 5-ASA molecule without the use of the sulfapyridine carrier. Examples are olsalazine (Dipentum™) and mesalamine (Asacol™, Pentasa™). COLAZAL, which has been available in Europe for some time, links 5-ASA to a carrier molecule that is less toxic than sulfapyridine.

COLAZAL is approved for up to a 12-week course of therapy. During the course of clinical investigations, the most common side effects were headache and abdominal pain. (COLAZAL was formerly known as Colazide® in the United States prior to approval by the FDA in July 2000).

If you or your physician would like more information, please visit Salix's Web site or call Salix at (888) 802-9956 ext. 4099.

Morbo di Crohn quasi ammansito. La malattia è una infiammazione cronica dell'intestino addebitabile all'impazzimento del sistema difensivo dell'organismo. Normalmente questo sistema è capace di riconoscere tutto quanto è estraneo e che, quindi, potenzialmente potrebbe arrecare danno al soggetto. Nel caso si dovesse affacciare un qualcosa che non è riconosciuto come se stesso da parte di questo meccanismo difensivo, immediatamente si mette in azione la sequela di eventi che portano ad annullare, escludere, rendere inoffensivo, divorare il nuovo venuto secondo una logica che, di volta in volta, viene adattata all'ospite non gradito.
Alcune volte, però, il sistema difensivo impazzisce e scambia i connotati del nemico, dimentica la parola d'ordine e, quindi, spara su chiunque gli sembri estraneo. E tra questi estranei finiscono, purtroppo, anche i tessuti dell'organismo che esso, invece, avrebbe dovuto difendere. Ed è subito malattia grave, è difficile da curare quel sistema colto da improvvisa demenza.
Al Congresso nazionale di aggiornamento in colo-proctologia, organizzato da Universo Sanità (associazione di sanitari per l'informazione corretta ai cittadini, coordinata dal Dott. Lavalle) la scuola del Prof.Francavilla ha presentato la casistica relativa al trattamento della malattia con FK 506.
Questo farmaco è stato studiato e brevettato dal Prof.Francavilla a coronamento dei suoi studi eseguiti a Pittsburg (USA) e Bari. Il farmaco, usato per impedire il rigetto di organi trapiantati, è stato utilizzato in pazienti che non rispondevano ai farmaci classici (cortisonici, ecc.) con buoni risultati e risparmio dell'uso di altri farmaci potenzialmente a rischio quando usati a lungo e in dosi elevate.
La casistica, presentata dal dott.Ierardi, è la più numerosa al mondo ed indica una via percorribile, una possibile svolta nella terapia della malattia. Di rilievo la lettura magistrale del Prof.G.Martino Bonomo sulle malattie benigne del colon-retto.

In questa pagina sono riportate alcune informazioni sull'Infliximab, un farmaco anti-TNFalfa usato per la cura delle M.I.C.I., raccolte dalle varie fonti di informazione quali i siti di associazioni di tutto il mondo per la lotta a queste malattie, o dai siti che trattano in maniera specifica la ricerca medica.

Il frutto-oligosaccaride è una sostanza estratta dalla radice del Cichorium Intybus, appartenente alla categoria dei prebiotici. Dopo l'assunzione il frutto-oligosaccaride attiva la peristalsi intestinale e permette una migliore evacuazione delle feci. Ma l'aspetto più interessante dei prebiotici ed in modo particolare del frutto-oligosaccaride è quello di stimolare in modo specifico la crescita dei bifidobatteri, aumentando pertanto la funzione protettiva e depurativa delle mucose intestinali. Il frutto-oligosaccaride contribuisce inoltre a ridurre l'assorbimento a livello intestinale dei grassi e degli zuccheri.

L’eziologia delle malattie infiammatorie intestinali (IBD) è tuttora poco conosciuta ma si ritiene che il sistema immunitario sia ampiamente coinvolto nella patogenesi sia del morbo di Crohn che della colite ulcerosa. Sulla base di questo presupposto la terapia immunomodulante delle IBD ha trovato largo spazio nel corso del tempo. Attualmente esistono almeno quattro approcci terapeutici basati sia su farmaci di sintesi chimica o estrattivi, sia su proteine ricombinanti. Negli ultimi venti anni la tendenza di intervento terapeutico si è spostata dai farmaci immunosoppressivi non-specifici agli immunomodulatori specifici nell’inibire le funzioni linfocitarie, in particolare la capacità di bloccare la sintesi o la responsività alle citochine è divenuta il punto focale della terapia delle IBD.

La mucosa intestinale rappresenta l’interface tra organismo e mondo esterno ovvero il confine tra la sterilità degli organi e una miriade di agenti microbici potenzialmente patogeni. E’ dunque intuitivo che a questo livello il sistema immunitario sia presente e funzionante per difendere l’ospite senza recare danno. Al sistema immunitario è stato attribuito nel corso degli anni un ruolo sempre più importante nell’insorgenza e nella cronicizzazione delle IBD anche se i meccanismi patogenetici non sono stati ancora chiariti completamente. Sulla base di questa ipotesi si è dato inizio a terapie farmacologiche dirette a modulare le risposte immunitarie in pazienti con IBD che hanno dato risultati clinicamente apprezzabili. Questo elaborato ha lo scopo di riassumere sinteticamente lo stato dell’arte delle terapie immunomodulatorie che trovano impiego nelle IBD. La classificazione dei farmaci immunomodulatori è stata redatta su basi funzionali poiché l’eterogeneità delle classi chimiche di questi farmaci e la complessità delle risposte immunitarie che l’organismo è capace di esprimere rendono estremamente difficile ricondurre ai minimi termini la strategia che sottende l’intervento terapeutico in queste patologie.
-Anti-infiammatori steroidei
-Immunosoppressori citostatici non specifici
-Immunosoppressori specifici dell’attivazione linfocitaria
-Inibitori delle citochine infiammatorie
Questo tipo di classificazione ha lo scopo di avvalorare lo sforzo notevole che è stato compiuto negli ultimi anni, sia a livello conoscitivo che applicativo, per giungere a terapie efficaci e riproducibili per le IBD. L’approccio sperimentale si è andato sempre più perfezionando, passando dalle terapie non-specifiche con farmaci citostatici a terapie basate su proteine endogene che le moderne tecniche di ingegneria genetica rendono disponibili per l’impiego clinico sia come tali che modificate per esaltarne l’effetto farmacologico.
-Anti-infiammatori steroidei
I glucocorticoidi sono farmaci in uso nella terapia delle IBD e di altre malattie ad eziologia autoimmune da lunghissimo tempo. Si tratta di composti steroidei comprendenti il costisolo, il cortisone (che ne rappresenta il derivato stabile) e numerosi loro derivati semisintetici come ad esempio il desametasone. L’impiego di questi farmaci è basato sulla loro attività anti-infiammatoria in larga misura imputabile alla inibizione della fosfolipasi A2, enzima responsabile del rilascio di acido arachidonico dalle membrane fosfolipidiche da cui originano una serie di mediatori flogistici come prostaglandine e leucotrieni. Tale meccanismo di azione non è diretto ma mediato da una lipoproteina indotta dai glucocorticoidi chiamata lipocortina. Per quanto riguarda l’attività immunosoppressiva dei glucocorticoidi negli ultimi anni una serie di dati sperimentali hanno suggerito che questi farmaci, una volta trasportati nel nucleo della cellula, siano capaci di inibire i geni responsabili della sintesi di molte citochine, tra le quali quelle a spiccata attività pro-infiammatoria come IL-1 e TNF. E’ stato inoltre dimostrato che queste citochine siano capaci di potenziare la risposta immunitaria esercitando un effetto adiuvante nella risposta antigene-specifica. Si può ipotizzare che l’inibizione della sintesi di citochine sia alla base dell’effetto immunosoppressivo dei glucocorticoidi e che questo sia il principale meccanismo dell’attività terapeutica di questo gruppo di farmaci.
-Immunosoppressori citostatici non specifici
Questa classe di farmaci è stata inizialmente caratterizzata in base all’effetto antineoplastico, solo in seguito ha trovato largo impiego nella immunomodulazione per la proprietà di inibire la proliferazione di cellule in fase di rapida suddivisione. L’azione di questi farmaci non è specifica verso le cellule coinvolte direttamente nella risposta immune pertanto il principale effetto collaterale associato a questi immuosoppressori non specifici è l’inibizione della crescita di cellule emopoietiche staminali, precursori della serie bianca e rossa. Questi farmaci possono essere classificati in base al loro meccanismo di inibizione della replicazione degli acidi nucleici in agenti alchilanti ed antimetaboliti.
-Agenti alchilanti: Ciclofosfamide.
Gli agenti alchilanti si legano ai gruppi nucleofili presenti nelle molecole biologiche alchilando in modo non selettivo DNA , RNA nucleare e citoplasmatico, enzimi e proteine strutturali. I farmaci che presentano due centri alchilanti possono causare cross-linking di catene di DNA, DNA-RNA, DNA-proteine, etc. La ciclofosfamide è certamente l’agente alchilante più usato come immunosoppressivo. Questo farmaco diviene attivo solo dopo biotrasformazione da parte di enzimi microsomiali, a livello epatico in particolare, con formazione di idrossiciclofosfamide che si trasforma in aldofosfamide, successivamente catabolizzata a fosforamide mostarda, il principio attivo, e acroleina. La ciclofosfamide possiede alta reattività e bassa specificità per cui è difficile identificarne con precisione il meccanismo di azione. E’ stato dimostrato che la maggioranza delle alchilazioni avvenga a carico dell’azoto in posizione 7 della guanina rendendo questo aminoacido simile all’adenina e causando quindi errori nell’accoppiamento delle basi. L’introduzione del gruppo alchilico può inoltre causare indebolimento del legame con la porzione glucidica e causarne il distacco. La ciclofosfamide presenta una certa selettività nell’inibire la proliferazione dei linfociti attivati e il danno midollare sulla linea mieloide sembra modesto.
-Agenti antimetaboliti: Azatioprina, 6-Mercaptopurina e Metotrexate.
Gli agenti antimetaboliti sono un gruppo di farmaci di origine sintetica o estrattiva che presentano forti analogie strutturali con precursori degli acidi nucleici e che possono pertanto interferire con la loro sintesi. Gli antimetaboliti più usati sono analoghi di purine e pirimidine, antagonisti dell’acido folico. L’azatioprina è stata per lungo tempo il farmaco immunodepressore più utilizzato in clinica assieme agli steroidi. Si tratta di un derivato nitroimidazolico della 6-mercaptopurina, uno dei primi farmaci antineoplastici. Queste molecole sono analoghi strutturali di adenina e ipoxantina ed hanno la capacità di inibire fortemente la risposta immunitaria sia umorale che cellulare. L’azatioprina è stata sintetizzata come "pro-drug" per ridurre gli effetti tossici della 6-MP, ciò nonostante è stato appurato che queste due molecole posseggono differenti attività e che non tutti gli effetti della azatioprina possono essere ricondotti al rilascio in vivo di 6-MP. Entrambi questi farmaci posseggono un metabolismo molto complesso i cui metaboliti possono ritrovarsi nel DNA, nell’RNA ma anche legati a proteine strutturali. Il principale sito di azione sembra essere a livello della conversione dell’acido inosinico in adenilsuccinico, precursore dell’acido adenilico e xantilico. Il metotrexate è un acido dicarbossilico derivato dall’acido L-glutammico. Questa molecola presenza forti analogie con l’acido folico e si comporta da antagonista nel legame con la deidrofolato reduttasi. In presenza di metotrexate viene inibita la conversione dell’acido diidrofolico in tetraidrofolico. L’effetto del metotrexate è completamente reversibile mediante somministrazione di forti dosi di acido folico o folinico tanto che si applica una terapia detta di recupero che prevede la somministrazione di alte dosi di metotrexate ed in successione di acido folico.
-Immunosoppressori specifici dell’attivazione linfocitaria
Una nuova era nel campo dei farmaci immunosoppressivi ebbe origine nel 1972 quando Borel dimostrò l’attività di una nuova molecola estratta dai miceti e denominata Ciclosporina A la quale non presentava alcun effetto collaterale sull’emopoiesi. Con la ciclosporina A e con altri farmaci di questa classe si è potuto disporre di molecole con azione più specifica che interferiscono selettivamente sull’attivazione, la trasduzione del segnale e la differenziazione dei linfociti.
-Ciclosporina A e Tacrolimus (FK506)
E’ un endecapeptide ciclico neutro provvisto di numerosi aminoacidi N-metilati e contenente un aminoacido non naturale. Per la ricchezza in residui idrofobici la molecola è fortemente lipofila e questa caratteristica rappresenta il primo evento del suo meccanismo di azione per la capacità di diffondere passivamente attraverso la membrana cellulare e formare un complesso macromolecolare con la sua proteina di legame, la ciclofilina. Questo legame altera la configurazione della ciclosporina A e dà origine ad un complesso attivo che si lega alla calcineurina inibendo la sua attività di serino-treonino fosfatasi. La calcineurina ha la proprietà di attivare e consentire la traslocazione al nucleo del fattore nucleare di trascrizione NF-AT nel processo di trasduzione del segnale del recettore delle cellule T attivate. La calcineurina agisce come regolatore della trascrizione dei geni delle citochine ed in particolare di IL-2.
Sebbene chimicamente diverso dalla ciclosporina A, la molecola FK 506 agisce con meccanismo di azione molto simile legando fortemente una binding protein denominata immunofilina e determinando blocco della produzione di citochine, in particolare di IL-2. I vantaggi nell’uso del FK506 rispetto alla ciclosporina A non sono stati ancora completamente chiariti. Gli effetti collaterali di entrambe le molecole, soprattutto nel caso di somministrazioni prolungate, vanno dalla nefrotossicità all’osteoporosi.
-Sirolimus (rapamicina)
Strutturalmente molto simile a FK506, la rapamicina appartiene alla stessa famiglia di molecole macrocicliche ad attività immunosoppressiva di ciclosporina A e tacrolimus, rispetto ai quali agisce però in fase più avanzata nel meccanismo di attivazione dei linfociti. Anche la rapamicina lega FK-binding protein ma il complesso formato non interagisce con la calcineurina, legando invece una classe diversa di proteine non chiaramente identificate. La formazione di questo complesso blocca l’attività delle cicline necessarie alla regolazione della suddivisione cellulare. Contrariamente ad altri composti appartenenti alla stessa famiglia la rapamicina ha mostrato scarsa incidenza di effetti tossici anche a livello renale, inoltre la sua azione sinergica con la ciclosporina A consentirà la riduzione del dosaggio di quest’ultima in terapie multifarmaco.
-Gusperimus (deossispergualina)
Questo composto, una volta penetrato nella cellula, lega proteine della famiglia delle heat-shock proteins (in particolare HSP 70), le quali sono coinvolte nel trasporto del fattore di trascrizione NFXB all’interno del nucleo, causando in questo modo una ridotta espressione del gene relativo al recettore IL-2. Inoltre si osserva una ridotta espressione del recettore IL-2 da parte dei monociti. Il vantaggio di questo farmaco è quello di presentare scarsa tossicità.
-Leflunomide
Il meccanismo di azione di questa molecola non è stato del tutto chiarito. Si presume che esso interferisca con eventi legati alla trasduzione del segnale. Forse l’effetto immunosoppressivo è dovuto all’inibizione di una tirosina chinasi essenziale nel meccanismo di trasduzione del segnale a carico dell’interazione IL-2-recettore nella fase G1 del ciclo cellulare. Altri studi ipotizzano che leflunomide inibisca la sintesi de novo delle pirimidine. Nonostante sia un potente immunosoppressore rivelatosi molto efficace nella prevenzione dei fenomeni di rigetto nel trapianto d’organo lo sviluppo di questa molecola nel trattamento delle IBD è dubbio, principalmente a causa del suo tempo di emivita eccessivamente lungo (6-40 giorni).
-Micofenolato mofetile
Questa molecola, rapidamente metabolizzata in vivo ad acido micofenolico, è un potente inibitore dell’enzima inosina-monofosfato deidrogenasi (IMPDH). Questo enzima è coinvolto nella generazione di GDP, GTP, dGTP ma non è essenziale nella via alternativa di sintesi delle purine. L’acido micofenolico inibisce quindi la sintesi del nucleotide guaninico, impedendo la sintesi del DNA ma risulta in qualche modo specifico per i linfociti poichè queste cellule non sono in grado di utilizzare la via di sintesi alternativa.
-Inibitori delle citochine infiammatorie
Questo gruppo di farmaci è alla base di un nuovo approccio terapeutico alle IBD che si stà affermando negli ultimi anni il quale si basa sul presupposto che l’inibizione delle citochine infiammatorie possa risultare in un beneficio per l’ospite. Questo tipo di approccio potrebbe essere definito sintomatologico poichè la produzione di citochine infiammatorie, di cui IL-1 rappresenta il prototipo, non dovrebbe ridurre i meccanismi auto-immuntari antigene-specifici che si presume possano essere alla base delle IBD. Altresì è vero che IL-1 è un forte induttore di IL-2, una citochina di estrema importanza nell’espansione di linfociti T antigene- specifici, si può pertanto ipotizzare che l’inibizione delle citochine infiammatorie come IL-1 possa da un lato contribuire a bloccare direttamente la sintomatologia infiammatoria causa della esacerbazione della malattia e nello stesso tempo limitare i fenomeni antigene-specifici che sono alla base del mantenimento dell’autoimmunità. In questo senso la terapia anti-citochine infiammatorie come IL-1 e TNF può trovare impiego sia tramite farmaci sintetici convenzionali che tramite proteine ricombinanti.
-Cytokine-suppressive anti-inflammatory drugs (CSAIDs)
Questo gruppo di farmaci costituisce una classe molto eterogenea di molecole di sintesi capaci di inibire la produzione o l’attività di citochine pro-infiammatorie. Fino ad oggi sono state identificate numerose molecole in grado di esercitare un effetto di modulazione sull’attività di IL-1 e che potrebbero in futuro dare origine a farmaci per forme di infiammazione cronica con uno spettro di azione distinto rispetto agli attuali anti-infiammatori. Il meccanismo di azione per quasi tutte le classi coinvolge l’inibizione della biosintesi o del rilascio di IL-1 ed in molti casi rimane allo stato di ipotesi. Particolarmente interessante risulta una classe di composti con struttura di tipo piridinil-imidazolica. Studi recenti hanno evidenziato che alla base dell’attività biologica di questi composti è la proprietà di inibire una chinasi (CSBP cytokine-suppressive binding protein) che sembrerebbe pertanto svolgere un ruolo determinante nella sintesi di IL-1 e TNF.
-Anticorpi monoclonali anti-TNF
Alla fase iniziale di grande ottimismo riposto in questa terapia biotecnologica ha fatto seguito un fase negativa e di scetticismo. Il fallimento nell’ottenere la controparte umana degli anticorpi monoclonali murini è stato il principale motivo della mancata crescita di questo approccio in clinica. Solo di recente i dati incoraggianti ottenuti con un anticorpo monoclonale chimerico anti-TNF stanno rilanciandone l’uso. Si tratta di un anticorpo composto dalle regioni costanti dell’immunoglobulina umana G1k accoppiate alla regione variabile di un anticorpo murino neutralizzante ad alta affinità contro TNF. Questo anticorpo monoclonale chimerico è stato denominato cA2. L’utilizzo clinico di cA2 nel morbo di Crohn stà dando risultati incoraggianti. Analogamente un secondo anticorpo monoclonale umano elaborato mediante ingegneria genetica definito con la sigla CDP751 è entrato nella sperimentazione clinica per IBD a seguito dei risultati incoraggianti ottenuti nei primati.
-Interleuchina 10
Questa citochina a prevalente attività anti-infiammatoria e immunosoppressiva inibisce la sintesi sia di citochine infiammatorie come IL-1, IL-6 e TNF che di citochine immunopotenzianti come IL-2. L’IL-10 è una proteina di 178 aminoacidi che, sulla base della sua sequenza primaria, si ipotizza possa possedere una struttura con quattro alfa eliche tenute insieme da connessioni random. Questa molecola è stata recentemente clonata e sono iniziati studi farmacologici in modelli animali. E’ stato osservato che topi knock-out per il gene IL-10 sviluppano con alta incidenza coliti ulcerose. Sulla base di queste evidenze sperimentali si sono proseguiti studi sull’uomo ed i primi dati clinici ottenuti su pazienti affetti da morbo di Crohn resistente agli steroidi sono incoraggianti.
-Antagonista recettoriale di IL-1 (IL-1ra)
La famiglia IL-1 è composta, oltre che da due molecole fortemente pro-infiammatorie e immunostimolanti quali IL-1 alfa e IL-1 beta, anche da un terzo membro definito come antagonista recettoriale di IL-1. Questa molecola è presente in molti distretti anatomici e compete con IL-1 per il legame al recettore inibendo l’attività biologica di IL-1. Dal punto di vista molecolare IL-1ra è una proteina di 152 aminoacidi che si organizzano in un barile beta formato da 12 foglietti beta tenuti insieme da connessioni random. Mediante tecniche di ingegneria genetica si è potuto clonare ed esprimere IL-1ra per utilizzarlo come farmaco in modelli animali di IBD. In questi sistemi si è potuto dimostrare l’efficacia di IL-1ra ricombinante e studi sono in corso per caratterizzare mutanti di IL-1ra con proprietà terapeutica superiore a quelle della molecola parentale.

Bibliografia.
Allegretti M, Tagliabue A - Immunomodulatori. Sillabus International Meeting on IBD, Capri 19-21 Settembre 1996.
Spreafico F, Tagliabue A, Vecchi A. Chemical immunodepressants In: Immunopharmacology. P. Sirois and M. Rola-Pleszcynsky (Eds.), Elsevier North-Holland, Amsterdam, 1982; pp. 315-348
Mantovani A, Tagliabue A. Modulation of mononuclear phagocytes by cancer chemotherapeutic agents In: The Reticuloendothelial System. A Comprehensive Treatise. 5, Cancer. R.B. Herberman and H. Friedman (EDS.), Plenum Press, New York, 1983; pp. 253-278
Boraschi D, Bossù P, Ruggiero P, Tagliabue A, Bertini R, Macchia G, Gasbarro Cet al. Mapping of receptors binding sites on IL-1 beta by recontruction of IL.-1ra-like domains. J. Immunol., 1995; 55; 4719-4725
Fantuzzi G, Ghezzi P. Glucocorticoids as cytokine inhibitors: role in neuroendocrine control and therapy of inflammatory diseases. Mediators in Inflammation, 1993; 2: 263-270.
Kunz J, Hall MN. Cyclosporine, FK 506 and Rapamycin more than just immunosoppression. Trends Biochem. Sci., 1993; 18: 334-338.
Liu J. FK 506 and cyclosporin molecular probes for studying intracellular signal transduction. Immunol. Today, 1993; 14: 290-295.
Maggon KK. Immunosuppressive gold rush and drug development. DN&P, 1994; 7: 389-401.
Lee CJ, Laydon JT, McDonnel PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumental MJ et al. A protein kinase involved in the regulation of inflammatory cytokine biosyntesis. Nature 1994; 372: 73-746.
Van Dullemen HM, Van Deventer SJH, Hommes DW, Bijl HA, Jansen J, Tytgat GNJ, Woody J. Treatmen of Crohn’s disease with antitumor necrosis factor chimeric monoclonal antibody. Gastroenterology 1995; 109: 129-135.
Chernoff AE, Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB, Kennedy JS, Rabson Ar, Wolff SM, Dinarello C. Randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol. 1995; 154: 5492-5499.
Dinarello C. Biological basis for Interleukin-1 in disease; Blood 1996; 87: 2095-2147.
Cominelli F, Nast CC, Duchini A, Lee M. Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis.
Blood 1996; 87: 2095-2147.

This is a list of companies who are investigating therapies to diagnose or treat IBD. This information is taken from the companies' online pipelines, from news releases, or from findings presented at medical meetings. The Pipeline will be updated monthly. Any information we have on ongoing clinical trials is available in the IBD Clinical Trials Registry. For more information on this research, and current press releases, please check with these companies' Web sites, as indicated.
 
 

COMPANYPhase I	PRODUCT	INDICATION	STATUS
Alizyme plc www.alizyme.co.uk	ATL-2502 (approved steroid using COLAL™, delivery system to colon)	IBD	Completed Phase I
The Ares-Serono Group www.serono.com	Human interferon beta-1a	IBD	Phase II
AstraZeneca www.astrazeneca.com	Entocort® (budesonide, a glucocorticosteroid)	IBD	Launched in Europe for ulcerative colitis
Axys Pharmaceuticals, Inc. www.axyspharm.com	APC-2059 (tryptase inhibitor)	Ulcerative colitis	Phase II (see Registry Index)
Cantab Pharmaceuticals www.cantab.co.uk	OX40 fusion protein to block interaction between Ox40 and ligand	IBD	Discovery
Celgene Corp. Www.celgene.com	Thalidomid® CC-1088 (SelCID™, Selective Cytokine Inhibitory Drug)	Crohn's disease	Phase II (see Registry Index)
Celltech Therapeutics Ltd www.celltech.com	Humicade™ (CDP 571, humanized anti-TNF [alpha] antibody)	Crohn's disease	Phase II complete; fast track designation from FDA for steroid-dependent Crohn's
Centaur www.centpharm.com	™NRTs (nitrone related therapeutics)	IBD	Preclinical
Centocor Inc. www.centocor.com	Remicade™ (infliximab, anti-TNF-alpha antibodies)	Crohn's disease	Approved by FDA in 1998; long-term studies (ACCENT Trials) underway
Elan Corp., PLC www.elancorp.com	Antegren® (humanized monoclonal antibody)	IBD	Phase II
Enzo Biochem www.enzo.com	Immune modulation therapy	IBD	Preclinical
Fujisawa Healthcare Inc. www.fujisawausa.com	FK506 (tacrolimus, an immunosuppressant)	Severe Crohn's disease	Phase II study funded by CCFA Clinical Alliance (see Registry Index)
Genetics Institute www.genetics.com	Neumega® (oprelvekin, rhIL-11)	Crohn's disease	Phase III
Human Genome Sciences, Inc. www.hgsi.com	Repifermin (KGF-2, keratinocyte growth factor-2)	IBD	Filed New Drug Application with FDA; plans to initiate phase II trial in ulcerative colitis
ICAgen, Inc. www.icagen.com	Ion channel modulating therapeutics	IBD	Discovery
ICOS www.icos.com	Alpha D Modulator, ICM3 (ICAM-3)	IBD	Preclinical
Immunex Corp. www.immunex.com	Enbrel® (etanercept, humanized anti-TNF-alpha antibody)	Crohn's disease	Approved for rheumatoid arthritis; phase II for Crohn's disease
Immunomedics www.immunomedics.com	LeukoScan® (sulesomab, anti-neutrophil antibody) Diagnosing and assessing	IBD	Phase II
Incara www.incara.com	OP2000 (ogliosaccharide product derived from heparin)	IBD	Phase I
Inflazyme www.inflazyme.com	IPL423,088 (inhibits inflammatory enzymes)	IBD	Preclinical
InKine Pharmaceuticals www.inkine.com	CBP-1011 (progesterone, progesterone analogs)	IBD	Phase II
Isis Pharmaceuticals www.isip.com	ISIS 2302 (ICAM-1 inhibitor)	Ulcerative colitis	Phase II, Europe
Millennium www.mlnm.com	LDP-02 (humanized monoclonal antibody targeting alpha4beta7 integrin)	IBD	Phase II, Canada (see Registry Index)
NicOx SA www.nicox.com	NCX 1015 (nitric oxide-releasing derivative of the steroid prednisolone); NCX 456 (nitric oxide-releasing mesalamine derivative)	IBD	Preclinical
Ophidian Pharm. Inc. www.ophidian.com (Web site not up yet)	OPHD-002 (oral avian antibodies)	IBD	Preclinical
Otsuka America Pharmaceuticals, Inc. www.otsuka.com	Gliotoxin (fungal metabolite)	Ulcerative colitis	Preclinical
Oxis Therapeutics, Inc. www.oxis.com	BXT-51072 (blocks activity of free radicals)	IBD	Phase IIa complete
Palatin Technologies, Inc. www.palatin.com	LeuTech™ (imaging monoclonal antibody)	Ulcerative colitis	Late stage development
Pharmos www.pharmoscorp.com	Dexanabinol™ (HU-211, optic isomer)	Ulcerative colitis	Preclinical
ProtoMed, Inc.	Bowman-Birk protease inhibitor concentrate (BBIC)	Ulcerative colitis	Phase II (see Registry Index)
Resolution Pharmaceuticals Inc. www.respharm.com	RP128 (peptide combined with Tc-99m, for imaging inflammation)	Diagnosis and assessment of Crohn's disease	Phase II clinical trials completed
Salix Pharmaceuticals, Inc.	Colazide® (balsalazide disodium)	Ulcerative colitis	Received second approvable letter from FDA, 3/27/2000
SangStat Medical www.sangstat.com	RDP58 (small molecule that inhibits TNF-alpha synthesis at the translational level)	IBD	Preclinical; plans to file with FDA for trials in ulcerative colitis
Santarus, Inc. www.santarus.com	Delayed-release formulation of enteric-coated azathioprine	Crohn's disease	Phase I complete
Schering Plough www.schering-plough.com	Tenovil® (IL-10)	IBD	In various phases of clinical trials for IBD
Shire Pharmaceuticals Group plc www.shire.com	Tazofelone (antioxidant & free radical scavenger)	IBD	Enema formulation for ulcerative colitis in phase II trials

La Isis Pharmaceuticals Inc. ha annunciato che i risultati della sua recente sperimentazione clinica dell' ISIS 2302 non dimostrano che questo farmaco sia efficace ed esso non riceverà l'approvazione della FDA (Food and Drug Administration).

Questo farmaco usa una "antisense technology" (in cui le istruzioni genetiche che codificano certe proteine vengono cambiate) per inibire le "molecole di adesione(?)", le quali attirano le cellule immunitarie nell'intestino. "I risultati qui presentati rappresentano una analisi iniziale dei dati" commenta l'Isis in una conferenza stampa. "Questi dati possono cambiare da uno studio all'altro."
L'ISIS 2302 ha mostrato una percentuale di efficacia del 20 per cento in quest'ultima sperimentazione. Questo risultato negativo era inatteso, secondo la casa farmaceutica. Alla fine del 1998 l'analisi dei primi 150 pazienti arruolati nello studio indicò risultati positivi. Il farmaco indusse una completa remissione clinica, senza bisogno di steroidi, nel 29 per cento dei pazienti, rispetto al 14 per cento dei pazienti che prendevano un placebo. Nel gruppo-placebo il 34 per cento dei pazienti interruppe il trattamento prematuramente a causa della mancanza di risultati, rispetto al 16 per cento dei pazienti trattati con l' ISIS 2302.
Nella seconda metà della sperimentazione i risultati sono stati significativamente diversi. Solo il 20 per cento dei pazienti che prendeva l' ISIS 2302 ha raggiunto la remissione senza bisogno di steroidi. Il 6 per cento dei pazienti che prendevano il placebo ha interrotto il trattamento per mancanza di risultati, rispetto al 20 per cento nel gruppo trattato col farmaco. I risultati sulla sicurezza non sono ancora stati analizzati a fondo; comunque, il farmaco è stato ben tollerato.
"La compagnia continuerà a indagare sul perchè la seconda metà dello studio è stata così differente dalla prima" dice la nota dell'ISIS Pharmaceuticals Inc. "Diverse variabili sono in gioco per spiegare i risultati finali. La compagnia prenderà una decisione definitiva riguardo lo sviluppo dell' ISIS 2302 per il morbo di Crohn dopo una indagine completa su questi fattori.
Nel frattempo, l'Isis sta conducendo uno studio in "fase IIa" su una formulazione dell' ISIS 2302 in clisteri, contro la colite ulcerosa. Questo studio coinvolgerà 40 pazienti in Francia, Belgio e Paesi Bassi. Vi terremo aggiornati sugli esiti di questo farmaco nella cura delle IBD.

Recent weeks have seen reports of exciting efforts to improve the treatment of Crohn's disease and ulcerative colitis. The following preliminary studies were presented at Digestive Disease Week 2000 (DDW), in the medical literature, and by the pharmaceutical/biotech industry. Here is a roundup of these findings. Any information that we have on clinical trials is posted in the IBD Clinical Trials Registry.

Methotrexate for Maintaining Remission
Brian G. Feagan, MD, and the North American Crohn's Study Group Investigators (comprising colleagues from medical centers in the United States and Canada) reported on a multicenter study of methotrexate versus placebo at a Distinguished Abstract Plenary Session during DDW 2000. Their results also were published in the June 1 issue of The New England Journal of Medicine.

The study involved 76 people with active Crohn's who had entered remission after treatment with 25 mg of methotrexate given once weekly as an intramuscular injection. Patients were randomly assigned to receive 15-mg methotrexate or placebo (an inactive substance) once weekly for 40 weeks. Patients took no other medications for IBD. The effectiveness of treatments was compared using the Crohn's Disease Activity Index (CDAI). The CDAI score ranges from 0 to 600, and measures disease activity as reflected by the number of soft stools, abdominal pain, or general well-being.

At week 40, significantly more patients taking methotrexate were in remission -- 26 of the 40 people (65 percent), compared with 14 (39 percent) in the group on placebo. Eleven people taking methotrexate required prednisone for relapse (28 percent) compared with 21 people (58 percent) in the placebo group. One patient withdrew from nausea; otherwise there were no adverse events in people taking methotrexate.

"This particular study clearly demonstrates that a reduced dose of methotrexate at 15mg once weekly is effective at maintaining remission," comments Charles Sninsky, MD, of Vanderbilt University, Nashville, and Chairperson of CCFA's Patient Education Committee. "Clinicians may consider reducing the dose of methotrexate to 15mg in their patients already on higher doses of methotrexate."

R. Balfour Sartor, MD, of the University of North Carolina, Chapel Hill, adds in an accompanying editorial, "Approximately twice as many patients in the placebo group required prednisone therapy for relapses. This is an important clinical observation, since patients with Crohn's disease who are dependent on corticosteroids and who have no response to mercaptopurine or azathioprine or who cannot tolerate these drugs need an effective alternative for long-term therapy."

However, Dr. Sartor cautions that as Dr. Feagan enrolled people who had entered remission due to methotrexate, the results may not apply to people who enter remission on corticosteroids, infliximab, or immunosuppressants, such as azathioprine or 6-MP. He also recounts an earlier study of treatment with methotrexate to induce remission, in which 17 percent of patients withdrew because of side effects.

"The potential hepatic [liver] toxicity and teratogenicity [potential to cause birth defects] of methotrexate and its unknown long-term efficacy and adverse effects suggest that treatment of patients with corticosteroid-dependent Crohn's disease and of patients with no response to corticosteroids should begin with mercaptopurine or azathioprine," concludes Dr. Sartor, commenting that methotrexate should be reserved for those who cannot tolerate these other medications. In people who respond to methotrexate, continued use is justified, with doctors using blood tests to check for adverse liver effects every four to eight weeks.

CDP 571 for Crohn's
Dr. Feagan (London Clinical Trials Group, London, Ontario, et al.) and William Sandborn, MD, (Mayo Clinic, et al.) reported further results from multicenter trials of CDP 571 (Humicade™, Celltech Therapeutics, Ltd.) a humanized anti-TNF antibody for the treatment of Crohn's disease, at DDW 2000. The initial reports of these studies were reported in November 1999.

Dr. Sandborn reported that significantly more patients treated with 10mg/kg of CDP 571 improved -- 29 of 54 people (54 percent), compared with 15 of 26 patients treated with placebo (27 percent). The difference between CDP 571 and placebo in inducing remission was not significant. Fistulas closed in 12 of 24 (50 percent) people treated with CDP 571, compared with two of 13 people taking placebo (15 percent). The frequency of side effects was similar among patients taking the study drug and placebo; no cases of lymphoma or lupus were reported. Dr. Sandborn concluded that the drug is effective in inducing a clinical response at two weeks in people with severe Crohn's, but that it is too soon to draw comparisons with other anti-TNF agents.

Dr. Feagan reported on a study to determine the safety and effectiveness of CDP 571 in maintaining remission and enable patients to withdraw from steroids. In 71 people with steroid-dependent Crohn's, prednisone was decreased gradually over 40 weeks. Seventeen of 39 people who received CDP 571 (43 percent) remained free of a flare-up at the study's end, compared with seven of 32 (21.9 percent) taking placebo. The drug was tolerated well, with no severe infusion reactions, lymphomas, or lupus reported.

In a May 25 press release, the company commented, "Humicade™ has FDA Fast Track Designation for the treatment of steroid-dependent Crohn's disease patients, and a further confirmatory Phase III study will be carried out in steroid-dependent patients, which will begin in the near future. The results from this study will be included, together with the Phase IIb findings, in a US Biologics License Application which Celltech expects to submit during the first half of 2001."

Infliximab in Children with Crohn's
Eric A. Vasiliauskas, MD, and colleagues (Cedars-Sinai Medical Center, et al.) reported on a study of 23 children with Crohn's disease at DDW 2000. They treated the patients with one to three 5-mg/kg doses of infliximab (Remicade™, Centocor, Inc.); 75 percent of those with active disease responded at four weeks, and 65 percent were in remission. One-third relapsed by two months, and one-half by three months. All eight children with fistulas experienced reductions by four weeks, and fistulas closed in four patients. Steroids were discontinued in nine of the steroid-dependent patients (75 percent). Weight and height improved in eight patients with growth delay. "Response to initial dosing is short-lived in many," note the authors. "The median time to relapse is two months...optimal dosing and dosing regimens need to be clarified."

Subra Kugathasan, MD, and colleagues (Medical College of Wisconsin and Marshfield Clinic, Marshfield, WI) presented findings on 15 children with Crohn's who had not responded to other therapies. Fourteen of 15 kids (93 percent) improved after one infusion of 5 mg/kg, and 11 (74 percent) achieved remission by 10 weeks. At follow-up at one year, four patients maintained the response to infliximab: These children all had early Crohn's (i.e., Crohn's for less than two years). The authors conclude that "There is a remarkably prolonged duration of response following infliximab therapy in children with early compared to late Crohn's disease."

Infliximab in Adults
In adults with severe Crohn's, Elena Ricart, MD, and colleagues (Mayo Clinic, Rochester, MN) reported on the first 100 patients to receive infliximab, noting in particular that steroid withdrawal was possible in 29 of 40 patients (74 percent). In a similar effort from Richard J. Farrell, MD, and colleagues (Beth Israel Deaconess Medical Center, Boston, Brown University, Providence, RI), noted that of 26 people with active disease who did not respond to a first infusion, 3 responded to a second infusion, and none to a third infusion. The authors conclude that, "Patients with active disease who fail to respond to two infusions should not receive further infusions."
 

Thalidomide for Ulcerative Colitis
Lori Kam, MD, and colleagues at the Cedars-Sinai Medical Center, Los Angeles, reported on a study of thalidomide (Thalidomid®, Celgene Corp.) in ulcerative colitis. Seven adult male patients with moderately active ulcerative colitis, who had not responded to treatment with aminosalicylates, steroids, or immunosuppressants, received either 50mg or 100mg of the drug.

At week four, three patients had responded to therapy, based on the Truelove and Witts criteria (an index for measuring disease activity in ulcerative colitis). Patients also reported improvements in quality of life, based on the IBDQ (a questionnaire). Those who did not respond by week 4 discontinued therapy, and one patient stopped taking the study drug at week 8 due to decreased libido. Adverse events were "mild and transient," noted the authors, citing sedation, numbness, and dry skin.

Celgene reports that, based on these and other study results, they will continue to study thalidomide in ulcerative colitis. The company also presented findings on SelCIDs™ (Selective Cytokine Inhibitory Drugs, forms of thalidomide which inhibit an enzyme that spurs on production of TNF). John Prehn, PhD, and colleagues from Cedars-Sinai found that these compounds to be more potent inhibitors of inflammation than thalidomide in tissue taken from resected colons. These compounds have not caused birth defects in animal models (a concern of the use of thalidomide) and were well-tolerated by people in phase I trials (which involve healthy people). "Efficacy can now be clinically tested in conditions like Crohn's disease and rheumatoid arthritis," note the authors.

Celgene Corporation has received FDA approval for thalidomide for the treatment of a complication of leprosy. The drug has orphan drug status for Crohn's disease, meaning that it is intended for use in a condition that affects fewer than 200,000 people in the United States; the company estimates that the population of people with moderate to severe Crohn's disease comprises such a population. Once the manufacturer files for and receives FDA approval, orphan drug status grants exclusive marketing rights for seven years.

Etanercept for Crohn's
Geert D'Haens, MD, and colleagues (University Hospitals Gasthuisberg, Leuven, Belgium) reported on a study of etanercept (Enbrel®, Immunex) at DDW 2000. This protein inactivates TNF-alpha, and is approved for use in patients with rheumatoid arthritis.

Ten people with active Crohn's disease were treated with 25 mg of etanercept twice a week for 12 weeks. Aminosalicylates, steroids, and immunosuppressants were kept stable during the trial. At week 2, six patients had responded to treatment, five at week 4, 6 at week 8, and 7 at week 12. Remission was achieved in 3 at week 2, 2 at week 4, 3 at week 8, and 4 at week 12. There was no significant healing of tissues, however, as demonstrated by endoscopy and laboratory findings. The author commented that it would be too soon to adapt these results to clinical practice; the effectiveness of this drug would need to be evaluated in a controlled trial.

Growth Hormone Therapy for Crohn's
Alfred E. Slonim, MD, and colleagues (North Shore University hospital, Manhasset, New York University School of Medicine) evaluated the use of the growth hormone somatropin and a high-protein diet in people with moderate-to-severe Crohn's. Their report appears in the June 1 issue of The New England Journal of Medicine.

Nineteen patients received self-administered, 5-mg injections of somatropin daily for one week, and 1.5-mg doses daily until four months thereafter. Eighteen received placebo. All patients were instructed to increase protein intake to at least 2 kg/kg daily. All medications for IBD were continued.

At four months, 74 percent of the growth hormone group experienced reductions in CDAI scores of more than 90 points (traditionally considered an improvement), and all seven who were taking prednisone discontinued or decreased dosage. In the placebo group, CDAI reductions were significantly lower, and prednisone was not reduced in 6 patients who were on the drug; it was initiated in two more.

Dr. Sninsky advises interpreting this study with caution. "There are a limited number of patients in each group," he says. "The CDAI scores at the beginning of the study were significantly higher in the growth hormone group, so this group was more likely to decrease."

Dr. Sartor adds in the accompanying editorial, that although the drop in CDAI compares favorably with responses induced by infliximab, findings raise many clinical questions. "Although the most frequent adverse effects in this trial were transient edema [swelling] and headaches, it is not known whether intestinal fibrosis and strictures [thickening and narrowing of the intestinal tract] could occur with long-term treatment," he writes. Growth hormone spurs on the production of insulin-like growth factor I, a protein that is increased in animal models with fibrosis and in people with strictures.

"This study provides the impetus to do a well-designed, multicenter trial," concludes Dr. Sninsky. "However, it's premature to use growth hormone in patients with Crohn's."

LDP-02 in Ulcerative Colitis
Dr. Feagan and colleagues (London Clinical Trials Research Group, et al.) reported results on the use of LDP-02 (Millennium Pharmaceuticals) in ulcerative colitis. LDP-02 is an antibody to alpha4beta7, a molecule that has been shown to contribute to inflammation in IBD.

Twenty-eight patients were divided into five treatment groups, each receiving one dose of LDP-02 (.15 mg/kg given in subcutaneous injection [under the skin], or .15 mg/kg, .5 mg/kg, or 2.0 mg/kg given via intravenous infusion, or placebo). Five of 20 people taking LDP-02 responded to the drug, compared with two of eight taking placebo. Forty percent of those taking .5 mg/kg achieved remission.

Based on these results, the company reported on May 24 that it is planning to file an Investigational New Drug Application with the FDA to initiate phase II trials in ulcerative colitis, which may begin later this year. A trial in Crohn's is ongoing in Canada, and is listed in the IBD Clinical Trials Registry.

We will keep you posted on these medications as they progress, and will bring you further news from DDW.

By Dr.Alan Meager FRACS, Department of Colorectal Surgery, St.Vincent's Hospital,Sydney.
Thalidomide is perhaps the most notorious medication ever introduced. Used as a sedative and to decrease nausea, particularly in pregnant women, it was later found to cause severe birth defects - and was withdrawn from worldwide use. The current international experimental use of this drug in Crohn's disease following its initial use in Australia clearly requires some explanation, and may be of interest.
St.Vincent's Hospital, Sydney has a large AIDS unit, with many drugs being investigated to treat its complications. In the mid-1990'' Thalidomide was being evaluated for the treatment of very debilitating, multiple, deep ("aphthous") ulcers, which often affected the mouth and esophagus of patients with AIDS. Similar, but much larger ulcers often affected the anus in AIDS patients and I was considering trailing Thalidomide in a small group of these patients. However, just at that time remarkably successful combination anti-viral medications for AIDS were introduced, and these conditions effectively disappeared. Nonetheless, by that time the gastroenterology registrar, Dr.Antony Wettstein, had helped use Thalidomide in a number of HIV patients with oral-esophageal aphthous ulcers, with success.
In early 1997 a 55 year old woman weighing 39kg with a 32 year history of Crohn's disease requiring multiple small bowel and colonic resections for fistulae, abscesses and strictures resulting in short bowel syndrome, presented with rectal bleeding and severe anemia. Colonscopy showed multiple actively bleeding aphthous ulcers throughout the remaining colon and terminal small bowel above the ileo-colic anastmosis. After transfusion, high does steroids were begun and sulfasalazine was changed to mesalazine. During the next six months bleeding continued, requiring 12 hospital re-admissions. All known treatments for Crohn's disease at that time, including azthioprine, intravenous steroids, bowel rest and total parenteral nutrition, metronidazole and cyclosporin were tried without success. Three further colonoscopies showed no change in the ulcers. Intravenous access was becoming difficult, with the need for subclavian catheters for transfusions. I was particularly keen not to operate as bowel resection would, very likely, be unsuccessful with the aphthous ulcers being so widespread.
After a lot of thought and discussions, and after informed consent was obtained, we started Thalidomide. Visible bleeding diminished over three weeks, and has not recurred. "Whereas 39 units of blood were required in the six months from presentation with bleeding to introduction of Thalidomide, no transfusions have been required since then, with no recurrence of anemia. On colonoscopic examination the aphthous ulcers have resolved. This was the first time Thalidomide had been used in Crohn's disease and we reported it as a research letter in the Lancet in 1997 (1). Understandably this inititated a lot of interst and Thalidomide now has been used in many European and American centers.
We were very keen to continue to study the role of Thalidomide and Dr. Carolyn Bariol, who took over as gastroenterology registrar, undertook the onerous task of setting up and running a clinical trial in patients with inflammatory bowel disease resistant to the usual medications. Approval from our Ethics committee was obtained and we were given $20,000 for the trial form St.Vincent's Clinic Foundation. So fare we have analyzed the first eleven patients who completed the trial, which involves taking Thalidomide for three months and undergoing regular evaluation by clinical examination, blood tests and colonscopy including biopsies. Nerve conduction studies are also performed, as Thalidomide very uncommonly can cause permanent peripheral nerve damage. Two patients withdrew from the study; one due to sedation, which was the commonest side effect seen, and the other due to anxiety. Of the remaining nine patients two showed no signs of improvement while seven improved on clinical, biochemical, colonoscopic and histologic (biopsy) criteria. Overall, there was a statistically significant improvement in many of these criteria. Dr.Bariol presented these results at Digestive Diseases week in America last year, and three other groups presented similar results. While we will publish our results soon (2) two American groups have already published their results (3,4).
In one study, of 12 males with active refractory Crohn's disease, all patients completed the 12-week trial (3). All patients were able to reduce their steroid dose by more than 50%, while 44% of patients stopped steroids completely. At the end of the trial 70% of patients achieved a clinical response while 20% had achieved remission. Another study included 21 patients with refractory Crohn's disease, of whom 14 completed the 12-week trial (4). Of these 14 patients, 12 had a clinical response and 9 achieved clinical remission. It was concluded that Thalidomide is efficacious in some patients with refractory Crohn's disease.
At this year's Digestive Diseases week there will also be an American paper presented on Thalidomide in ulcerative colitis, with promising early results. We have only studied a few patients with ulcerative colitis: in some patients it seems t have been helpful.
In our trial women of childbearing age have been excluded, because of the risk of birth defects. However, in another study women with childbearing potential were included if they used two concomitant forms of birth control (one hormonal and one barrier method) (4). Clearly, there is no simple "correct" ethical answer with regard to using thalidomide in women of childbearing age. At present we remain very reluctant to use it in these patients, although in some extenuating circumstances it might have to be considered - where the patient's health is at great risk, where all other treatments have failed, and all steps to avid pregnancy can reliably be undertaken. Even when used by patients without childbearing potential great care must be taken to avoid mistaken ingestion by other individuals.
At present there is a greater volume of proof that the new drug Infliximab is efficacious in Crohn's disease than Thalidomide, and probably should be considered in most resistant patients before Thalidomide is used. (Interestingly both may act by similar mechanisms - inhibiting Tumour Necrosis Factor activity.) While we very strongly suspect that Thalidomide is successful in some patients with Crohn's disease, its use must still be seen as experimental until placebo controlled trials (rather than in open-label trials performed so far) are completed. Nonetheless, in some patients with difficult to control disease, a trial of Thalidomide seems warranted at present and ongoing research into its use is important. Understandably, obtaining government approval for use of Thalidomide in Crohn's disease is difficult - but patients with very resistant disease interested in its potential role should discuss this further with their gastroenterologist.

References:
1. Wettstein AR,Meagher AP. Thalidomide in Crohn's disease. Lancet 199;350:1445-6.
2. Bariol C.Meagher AP, Vickers C, Hing M, Byrnes D, Edwards P, Wettstein AR. Thalidomide in resistant inflammatory bowel disease. Presented at Digestive Diseases week in USA 1999. (Drs Chris Vickers,Michael Hing, /David Byrnes and Paul Edwards are gastroenterologists who entered some of the patients in the initial trial and are part of the ongoing research, along with others).
3. Vasiliauskas EA, Kan LY, Abreu-Martin MT, etal. An oper-label pilot study of low-dose Thalidomide in chronically active, steroid dependent Crohn's disease. Gastroenterology 1999;1117:1278-87.
4. Ehrenpreis Ed, Kane SV, Cohen LB, Cohen RD, Hanauer SB. Thalidomide therapy for patients with refractory Crohn's disease: an open-label trial. Gastroenterology 1999;117:1271-7.

"Nel corso degli ultimi 20 anni c'è stato un grosso lavoro di ricerca sperimentale volto a conoscere i meccanismi dell'infiammazione delle MICI. Oggi noi conosciamo che l'infiammazione è un processo multipotente, è un processo che una volta innescatosi da luogo alla liberazione di un enorme numero di mediatori chimici (mediatori dell'infiammazione) che amplificano a cascata il processo dell'infiammazione. Se qualcuno di essi possa giocare un ruolo fondamentale non è chiaro.
Quello finora ritenuto più importante è la citochina denominata TNF (Tumor Necrosis Factor), probabilmente è una citochina chiave: se essa è liberata da luogo alla liberazione di molti altri mediatori. Allora se si pensa di inibirla, forse si può bloccare il processo infiammatorio. Questo è quello che alcuni studi hanno cercato di fare negli ultimi 2-3 anni.
Tramite la biologia molecolare si sono 'costruiti' anticorpi chimerici (in parte umanizzati e in parte no) specifici contro il TNF che utilizzati in pazienti affetti da malattia di Crohn hanno determinato una risposta di grande portata, poichè in un periodo di tempo ragionevolmente breve hanno permesso di modificare in maniera sostanziale le lesioni tipiche rilevabili endoscopicamente in questa malattia.
Dapprima studi preleminari, poi studi su più larga scala ne hanno evidenziato una certa efficacia terapeutica sopratutto nei pazienti che non rispondevano alle terapie tradizionali. Su questa spinta il farmaco è stato registrato negli Stati Uniti e presto sarà utilizzato in Italia (a Bologna), nell'ambito di uno studio multicentrico internazionale e poi più avanti per il cosidetto 'uso compassionevole' in alcuni malati...
... In questo momento la prudenza è d'obbligo, anche perchè abbiamo tra le mani un farmaco molto potente e come tale andranno valutati molto attentamente sia i benefici che gli effetti collaterali. ...Ciò che si può affermare è che oggi è difficile dire se esso manterrà tutte le sue promesse.
Non dobbiamo tuttavia dimenticare che nei due decenni trascorsi vi è stata anche una notevole mole di studi clinici sulla malattia di Crohn, la quale è servita a posizionare meglio i farmaci a disposizione, come i cortisonici, che rimangono la prima scelta nella riacutizzazione, talvolta integrati dai nuovi cortisonici ad assorbimento limitato e minori effetti collaterali, come l'acido 5-aminosalicilico (5 ASA) che ha qualche efficacia nella terapia di mantenimento sopratutto nei pazienti già sottoposti a intervento chirurgico, come gli immunosoppressori rappresentati dall'aziotioprina che se usati bene possono ridurre il numero delle ricadute e favorire lo spegnimento della malattia laddove essa tende a resistere alle altre terapie, gli antibiotici, la nutrizione parenterale, i supporti nutrizionali (a esempio gli omega-3) e in determinate situazione il ricorso alla chirurgia."

Trato da: Copyright * 1998 Nidus Information Services, Inc. Well-Connected Report: Inflammatory Bowel Disease. September 1998. (Online) www.well-connected.com

Drugs cannot cure inflammatory bowel disease, but they are effective in reducing the inflammation and accompanying symptoms in up to 80% of patients. Many such drugs are available, including corticosteroids, aspirin-like medications, and drugs that suppress the immune system. The primary goal of drug therapy is to reduce inflammation in the intestine. The success of therapy is determined by its ability to induce and maintain remissions without incurring significant side effects. The patient's condition is generally considered in remission when the intestinal lining has healed and symptoms, such as diarrhea, abdominal cramps and tenesmus, are normal or close to normal. It is more difficult to define remission in Crohn's disease than in ulcerative colitis, because diagnostic test results do not always correlate with a patient's symptoms or complications outside the intestine.
Mesalamine (5-Aminosalicylic Acid) and Its Preparations
Mesalamine is the common name of the compound 5-aminosalicylic acid or 5-ASA, which inhibits substances in the immune system, particularly leukotrienes, that cause inflammation. Mesalamine seems to benefit women more than men. The 5-ASA compound itself is very effective and has few side effects, but it is absorbed so quickly in the upper gastrointestinal tract that it usually fails to reach the colon. Other substances are added to 5-ASA or it is formulated so that it can reach the lower intestine before it is absorbed. The 5-ASA preparations and formulations are generally useful for mild to moderate ulcerative colitis and Crohn's disease and for preventing relapse of ulcerative colitis. They are less useful in maintaining remission of Crohn's disease. The degree of effectiveness for each condition varies depending on the particular drug preparation. Mesalamine has a chemical structure similar to aspirin. People allergic to aspirin, therefore, should not take any of the 5-ASA drugs or preparations, including sulfasalazine -- the standard combined preparation. All 5-ASA preparations, including sulfasalazine, appear to be safe for children and for women who are pregnant or nursing. Side effects vary depending on whether the drug is used alone or in combination with other components.
Sulfasalazine
Sulfasalazine (Azulfidine) has been the standard mesalamine, or 5-ASA, preparation for years. Sulfasalazine combines mesalamine with sulfapyridine, a sulfa antibiotic that prevents mesalamine from being absorbed until it reaches the colon. There, intestinal bacteria break sulfasalazine into its two components: mesalamine, the active component, blocks the inflammatory process; the other component, sulfapyridine plays no role in treating the disease.
In ulcerative colitis, sulfasalazine is useful for treating mild to moderate attacks and for maintaining remission. It is helpful for some Crohn's disease patients whose active condition occurs in the colon, but it is not effective in the small intestine and does not prevent recurrence. One study has found, however, that long-term therapy is protective against colon and rectal cancers in patients with ulcerative colitis.
The sulfa component of sulfasalazine is responsible for most of its adverse side effects and allergic reactions, which are experienced by up to 30% of patients taking this drug. Some common side effects include heartburn, headache, loss of appetite, abdominal discomfort, dizziness, anemia, fever, and rashes. The drug may temporarily lower sperm count in men and can turn urine a bright orange-yellow color. Rare but serious side effects include a lupus-like disorder, pancreatitis, liver damage, and blood disorders. Some of these blood disorders can become life threatening (although very rarely), so blood counts should be performed regularly, particularly during the first few weeks of treatment. Sulfasalazine can also cause folic acid deficiency, and patients should take supplements of this important B vitamin. As with most major drugs for IBD, withdrawal of sulfasalazine when the disease is still active can trigger a severe relapse.
Formulations Using Mesalamine Alone
Formulations have been developed that allow mesalamine alone to reach the lower intestine without the need for the sulfa component. Unfortunately these ASA-5 formulations are more expensive than sulfasalazine.
A rectal form, Rowasa, can be administered using enemas or suppositories. Mesalamine enemas have been reported to help 80% to 90% of patients with ulcerative colitis of the lower colon. Rowasa relieves mild to moderately active UC and prevents relapse. It is not usually given to patients with Crohn's disease, although some with disease of the left colon may benefit. The enemas are administered at night with the patient lying on the left side and are instilled for about 8 hours. The treatment continues every night for 4 to 8 weeks or until the lining has healed.
A number of oral forms of mesalamine use coatings or time-released formulations to prevent absorption in the upper intestine. Different brands affect different regions in the intestine. Asacol, for example, is effective in the last section of the ileum and the colon; Pentasa is useful in the stomach and colon; Claversal, Mesasal, and Salafalk affect the ileum and colon; and Balsalazide benefits the colon. A combination of oral and rectal forms may be particularly effective for some people. In one study patients with severe ulcerative colitis who took 5-ASA orally daily and as an enema twice a week had significantly fewer relapses than those taking only an oral form.
Mesalamine used alone does not adversely affect sperm count fertility, as sulfasalazine does. About 5% or less of patients taking oral mesalamine experience diarrhea. Oral mesalamine, particularly Asacol, may slightly increase the risk for kidney damage, although this is a very rare event. Other less severe side effects of all oral forms of mesalamine are skin disorders, nausea, cramps, itchiness, anxiety attacks, and inflammation of other organs, although one study reported that mesalamine caused no more side effects than placebos (inactive substances used for comparisons in drug studies).
Olsalazine
Olsalazine (Dipentum) is similar to sulfasalazine, in that the drug stays intact until it reaches the intestine and is then broken down by intestinal bacteria into two components, one of which is mesalamine. Unlike sulfasalazine, however, the other component is a harmless molecule that is similar to mesalamine and does not have sulfapyridine's adverse side effects. Olsalazine does, however, cause diarrhea in 15% of those taking the drug, which may be minimized by starting out with lower doses and taking the medication with meals.
Corticosteroids
Corticosteroids (also called steroids) are powerful anti-inflammatory drugs. Prednisone, prednisolone, hydrocortisone, and methylprednisolone are the most common steroids. They are used only for active ulcerative colitis and Crohn's disease. Because they have serious long-term effects, they are not useful for maintenance therapy. Corticosteroids are sometimes combined with other drugs to produce more rapid symptom relief and to allow quicker withdrawal, although such combinations do not improve remission time. Some physicians favor corticotropin (ACTH), which stimulates natural production of steroids, but it is effective only in certain patients and is not in common use. Newer steroids, such as budesonide, beclomethasone, and tixocortol, are being developed so that they affect only local areas in the intestine and do not circulate throughout the body. If they prove to be effective, such drugs may avoid the widespread side effects that are serious problem with long-term treatment using the older steroids. A slow-release oral form of budesonide, for example, is proving to be more effective and safer for mild to moderate Crohn's disease in the ileum and cecum regions than either older steroids or mesalamine. In one study, after eight weeks, 69% of those taking budesonide once a day experienced remission compared to only 45% of those taking mesalamine twice a day. Neither budesonide nor mesalamine were very effective, however, for patients with severe conditions. Budesonide appears to have less severe side effects than either mesalamine or older steroids.
Steroids can be taken orally, intravenously, by injection, or rectally as a suppository, enema, or foam. In general, oral preparations are used for moderate to severe ulcerative colitis and Crohn's disease. Enemas, suppositories, and, in limited cases, foam preparations may be used for mild to moderate ulcerative colitis located in the left section of the colon, the rectum, and anus. If the patient requires hospitalization, intravenous steroid therapy, with or without rectal steroids, are administered initially. (If these drugs are not effective after a week of intravenous therapy, they are not likely to work.) Once bowel movements are normal and the patient can eat, oral doses replace intravenous and rectal forms, and then they are tapered gradually. Patients who are malnourished are less likely to respond to steroids and those who had an initial inadequate response to steroids are also less likely to do well with repeat therapy.
Side Effects
Standard steroids can have distressing and sometimes serious long-term side effects, including susceptibility to infection, weight gain (particularly increased fatty tissue on the face and upper trunk and back), acne, excess hair growth, hypertension, accelerated osteoporosis, cataracts, glaucoma, diabetes, wasting of the muscles, and menstrual irregularities. Personality changes can occur, including irritability, insomnia, psychosis, and depression; such emotional changes are sometimes severe enough to produce suicidal thoughts. Growth may be retarded in children. Treatments are available for steroid-induced diabetes, swelling, and hypertension. Vaccines are available to help prevent influenza and pneumonia. Any infection should be treated promptly. Supplemental calcium and vitamin D are important to help to preserve bone mass against osteoporosis. The newer oral steroids, such as budesonide, have far fewer and less severe side effects.
Once the intestinal inflammation has subsided, steroids must be withdrawn very gradually in order to give the body time to recover its own ability to produce natural steroids. Withdrawal symptoms, including fever, malaise, and joint pain may also occur if the dosage is lowered too rapidly. If this happens, the dosage is increased slightly and maintained until symptoms are gone. More gradual withdrawal is then resumed.
Immunosuppressive Drugs
For very active inflammatory bowel disease that does not respond to standard treatments, immunosuppressant drugs are now being used for long-term therapy. Such drugs suppress actions of the immune system and therefore its inflammatory response, which causes ulcerative colitis and Crohn's disease. The two most commonly used immunosuppressants for IBD are azathioprine (Imuran) and mercaptopurine (Purinethol). An immunosuppressant may be combined with a corticosteroid during active attacks; lower doses of the steroid are then needed, resulting in fewer side effects. Corticosteroids may also be withdrawn more quickly. Immunosuppressants, then, are sometimes referred to as steroid-sparing drugs. They cannot replace steroids for an initial attack, because it takes azathioprine or mercaptopurine three to six months to become effective (although they work more rapidly for subsequent attacks). Administering azathioprine intravenously (called a loading dose) may speed up the initial response. Immunosuppressants can, in any case, prevent relapse when used alone, and in some studies have proved to be effective for maintaining remissions in ulcerative colitis that have lasted at least two years. They also appear to help maintain remission in Crohn's disease, and appear to heal fistulas and intestinal ulcers caused by this disease.
Other immunosuppressants being investigated for IBD and showing promise include cyclosporine (Sandimmune) and methotrexate (Folex). Methotrexate is being used increasingly by patients with Crohn's disease who have failed other treatments and cannot tolerate mercaptopurine. Cyclosporine may be useful for Crohn's disease accompanied by fistulas, but it does not seem to be beneficial for long-term maintenance. Initial treatment with intravenous cyclosporin followed by oral administration is reported to be the first therapy in recent years to have a major impact for patients with acute severe ulcerative colitis. Studies indicate that up to half of patients can avoid surgery for over four years. Serious complications, some life-threatening, can occur, however, in patients with ulcerative colitis who have an unfavorable response to both cyclosporine and corticosteroids. Experts recommend that cyclosporine be used only by ulcerative colitis patients who have previously responded favorably to steroids and who can be closely monitored by knowledgeable specialists.
Side Effects
Although experts have been concerned about dangerous side effects based on experience with immunosuppressants used in transplant operations, the lower doses of the drugs required for IBD and other inflammatory disorders may make them safer in the long run than steroids, and they are being increasingly used for maintaining remission. One study of Crohn's disease patients, for example, reported that mercaptopurine was safe for long-term use. The most frequent side effects of immunosuppressants are not serious and include stomach and intestinal distress, rash, numbness or tingling in the hands and feet, mouth sores, and hair loss (or excessive hair growth with cyclosporine). It should be noted, however, that the actions of immunosuppressant damage certain rapidly-growing immune system cells, including those that produce antibodies, causing an increased risk for infection. Oversuppression of the immune system can result in low blood cell counts as well and other serious side effects. These include anemia, herpes zoster (shingles), hepatitis, bladder toxicity, and menstrual irregularity with possible sterility. (Administering pulsed doses at the time of menstruation may avert infertility in women.) Some increase in blood cancers has been associated with the use of azathioprine for other disorders, but no clear evidence exists that this risk is increased in patients taking the drug for IBD. Between 3% and 15% of patients taking immunosuppressants develop pancreatitis; in such cases immunosuppressants should never be used again. Symptoms of pancreatitis usually occur within the first few weeks and include nausea, vomiting, and upper abdominal pain that may radiate to the back.
Antibiotics
The antibiotics ciprofloxacin (Cipro) and metronidazole (Flagyl), used in combination or alone are useful for people with Crohn's disease whose condition is accompanied by bacterial overgrowth, abdominal abscesses, and infections around the anus and genital areas. These antibiotics are used for infections caused by anaerobic bacteria, which are organisms that can exist without oxygen and often cause abscesses and abdominal and gynecologic infections. Ciprofloxacin is becoming the antibiotic of choice. In one study metronidazole helped prevent IBD recurrence after surgery, but side effects were severe. Other antibiotics used for Crohn's disease include trimethoprim/sulfamethoxazole (Bactrim, Cotrim, Septra) and tetracycline. Withdrawal brings on relapse, so long-term therapy is required, carrying a risk for side effects, including numbness and tingling in the hands and feet. Antibiotic therapy does not seem to offer many benefits for patients with ulcerative colitis other than helping prevent complications after surgery.
Drugs that Block Anti-Tumor Necrosis Factor
Infliximab (Remicade) is the first genetically-engineered drug to be approved for Crohn's disease. The drug is made from a specially developed antibody (termed a monoclonal antibody) called cA2, which acts against tumor necrosis factor (TNF), a major player in the inflammatory process that causes IBD. Recent trials of the drug indicate that it may help patients with moderate to severe Crohn's disease that has not responded to other treatments. Infliximab might even heal fistulas in many of these patients. Side effects are usually temporary and related to the intravenous administration of the drug; they include chills, low blood pressure, and chest pain. Of concern are reports of four cases of lymphomas in people taking the cA2 antibody, but the cancers may have been due to their underlying diseases, not the drug. Thalidomide is another anti-TNF drug under investigation for IBD.
Experimental Therapies
4-Aminosalicylic Acid
A variant of mesalamine, 4-aminosalicylic acid, is being studied for IBD.
Fatty Acids
Patients with ulcerative colitis appear to have low concentrations in their feces of certain essential fatty acids. One known as butyrate has been tested in enema preparations with some success.
Nicotine
Some patients with ulcerative colitis have reported that their disorder began after they quit smoking, and many studies have reinforced the association between smoking and protection against ulcerative colitis. Studies are showing that the nicotine patch helps to induce remission and reduce symptoms in almost 40% of patients who use it for four weeks. Another study found, however, that patches are not useful for maintaining remission. Side effects, particularly in nonsmokers, include nausea, lightheadedness, and headache. (No one should smoke for relief of ulcerative colitis symptoms; the risks from cigarettes far outweigh the potential benefits of their nicotine.)
It should be noted that smoking has the opposite effect for Crohn's disease; in one study, when smokers with the disease quit, the incidence of relapse was reduced by 40% over a year.
Anti-ICAM1 Therapy
ICAM1 is a protein that plays an important role in the production of immune factors that cause the inflammatory response in IBD. A molecular treatment known as antisense therapy is being developed to block the genetic expression of ICAM. This experimental therapy has recently been shown to be effective in a small trial.
Treatments for Symptoms and Complications
Diarrhea and Constipation
Mild to moderate diarrhea may be reduced by taking one teaspoon of psyllium hydrophilic colloid (Metamucil) twice a day in a glass of water. Opiates or drugs used to relax muscle spasms may help relieve mild to moderate diarrhea and abdominal cramps, but they should be used for very short periods and not for severe cases. In very ill patients, large doses of certain antidiarrheal drugs can trigger the onset of toxic megacolon. Bulk-type laxatives can help constipation.
Treatment of Anemia
Iron supplements may be required for anemia. The hormone erythropoietin, which acts in the bone marrow to increase the production of red blood cells, is being tested for severe anemia that does not respond to iron alone. It is effective but very expensive.
Antidepressants
Antidepressants may help relieve emotional problems. It should be stressed, however, that inflammatory bowel disease is not a psychologic disorder, and such drugs will not affect the basic illness.
Pain-Relievers
Acetaminophen, sold as Tylenol and other common brands, is the drug of choice for mild pain. Acetaminophen is not one of the nonsteroidal anti-inflammatory drugs (NSAIDs), which include, among dozens of others, aspirin, ibuprofen (Advil, Motrin, Rufen), naproxen (Anaprox, Naprosyn, Aleve). NSAIDs are often used against other inflammatory disorders, but they have been implicated in triggering inflammatory bowel disease; one study found that they doubled the risk for emergency treatment of gastrointestinal symptoms in patients with colitis. NSAIDs, therefore, should be avoided for IBD.
Diet
Foods
Children with inflammatory bowel disease may suffer from malnutrition -- probably the major factor in growth retardation. Some experts recommend that children with IBD increase their calorie and protein intake by 150% of the daily recommended allowance for their specific ages and heights. Studies indicate that nutritional support in children is as important as medications for achieving remission.
Although no evidence exists that any specific foods reduce inflammation, certain foods have been associated with a lower or higher risk for IBD or its symptoms. The foods linked to a lower risk were fruits (for both IBD disorders) and vegetables (for Crohn's disease). One study found that large doses of fish oil, which is rich in omega-3 fatty acids, improved Crohn's disease. Patients, however, disliked the fishy breath and side effects, including flatulence, heartburn, belching, and diarrhea. Recently, a coated preparation of fish oil was tested and was found to prevent relapse for at least a year in 60% of patients. Omega-3 fatty acids may also be useful for ulcerative colitis.
Foods most often blamed for aggravating existing symptoms are milk and milk products, spicy foods, fats, and sugars. When symptoms erupt, physicians recommend a bland, low-fiber diet. Surgery for IBD may increase the risk for absorption of oxalate, a substance that reacts with calcium to form kidney stones. Surgical patients should avoid foods high in oxalates, including spinach, rhubarb, beets, coffee, tea, diet sodas, and chocolate. Patients should drink plenty of fluids.
Vitamin and Mineral Supplements
Crohn's disease and surgical procedures that remove parts of the small intestine can inhibit absorption of vitamins, fats, calcium, and magnesium. Iron supplements and monthly injections of vitamin B-12 may be necessary in such cases. Folic acid supplements may be important for patients who must restrict fresh fruits and vegetables and for patients taking sulfasalazine. In general, vitamin supplements may be recommended for everyone with IBD, particularly for children to avoid growth retardation; taking large doses of certain vitamins, however, may be harmful.
Elemental Diets
Elemental diets comprise liquids that are fully nutritional. They are sometimes helpful in improving symptoms, reducing relapses, and improving nutrition in Crohn's disease patients. Included in the nutritional solution is a large amount of glutamine, an amino acid that provides energy for the lining of the small intestine. The solution has an unpleasant metallic taste, and some health professionals recommend adding flavored toppings or instant coffee and drinking the liquid cold to improve its taste. Over-the-counter and less expensive liquid diets, such as Ensure, Sustacal, and others that meet full nutritional needs and are absorbed in the upper intestine may also be beneficial, but no studies have determined this.
Parenteral Nutrition
Patients with very severe Crohn's disease who cannot tolerate any nutrition by mouth may need total parenteral nutrition (TPN), or hyperalimentation, which is the intravenous administration of nutrients through an indwelling catheter (tube). The procedure carries a risk for infection. Patients with ulcerative colitis may also need TPN if they are malnourished, require surgery, or have very severe symptoms.

Well-Connected Board of Editors
Harvey Simon, M.D., Editor-in-Chief
Massachusetts Institute of Technology; Physician, Massachusetts General Hospital
Masha J. Etkin, M.D., Gynecology
Harvard Medical School; Physician, Massachusetts General Hospital
John E. Godine, M.D., Ph.D., Metabolism
Harvard Medical School; Associate Physician, Massachusetts General Hospital
Daniel Heller, M.D., Pediatrics
Harvard Medical School; Associate Pediatrician, Massachusetts General Hospital; Active Staff, Children's Hospital
Irene Kuter, M.D., D. Phil., Oncology
Harvard Medical School; Assistant Physician, Massachusetts General Hospital
Paul C. Shellito, M.D., Surgery
Harvard Medical School; Associate Visiting Surgeon, Massachusetts General Hospital
Theodore A. Stern, M.D., Psychiatry
Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital
Carol Peckham, Editorial Director
Cynthia Chevins, Publisher

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