Therapeutic potential for cytokine antagonists : Thalidomide and pentoxifylline in Hansen ’ s disease

Departments of Medicine and Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia Correspondence and reprints: Dr TC Peterson, Clinical Research Centre, Room C103, Dalhousie University, Halifax, Nova Scotia B3H 4H7. Telephone (902) 494-2571, Fax (902) 494-1624 Received for publication December 21, 1993. Accepted May 13, 1994 TC PETER SON. Thera peu tic po ten tial for cy to kine an tago nists: Tha lido mide and pen toxi fyl line in Han sen’s dis ease. Can J In fect Dis 1995;6(1):3033. Cy to kine an tago nists are a group of drugs de fined by their ac tions on spe cific cy to ki nes. Cy to kine an tago nists can in hibit ac tion of cy to ki nes by act ing di rectly on re cep tors, by af fect ing pro duc tion of cy to ki nes or by bind ing to cy to ki nes and pre vent ing their sub se quent ac tion. Re cent evi dence sug gests that Han sen’s dis ease, which is char ac ter ized by re ac tional states, is as so ci ated with ele vated se rum lev els of tu mour ne cro sis fac tor-α (TNF-α) and interleukin-1β dur ing these re ac tional states. Tha lido mide, a drug used to treat re ac tional states in Han sen’s dis ease, has been re ported to en hance deg ra da tion of TNF-α mRNA. Pen toxi fyl line has also been re ported to al ter TNF-α mRNA lev els by in hib it ing TNF-a tran scrip tion. Com bi na tion of these two drugs as cy to kine an tago nists may prove to be bene fi cial as thera peu tic agents in the treat ment of re ac tional states in Han sen’s dis ease. Pen toxi fyl line may prove to be bene fi cial in the treat ment of re ac tional states in Han sen’s dis ease pa tients who are fe male and of child bear ing age. Cy to kine an tago nists alone or in com bi na tion will likely fill a niche in fu ture thera peu tics.


Potentiel thérapeutique des antagonistes des cytokines : thalidomide et pentoxifylline dans la maladie de Hansen
RÉS UMÉ : Les an tago nistes des cy to ki nes for ment un groupe de médica ments qui se défin is sent par leurs ac tions spéci fiques sur les cy to ki nes.Ils peu vent in hi ber ces der nières en agis sant di recte ment sur leurs ré cep teurs, en af fec tant leur pro duc tion ou en se li ant à elles pour ainsi les neu tral iser.Selon des résul tats ré cents, la mala die de Han sen, caracté risée par des états réac tion nels, est as so ciée à des taux sé ri ques élevés de fac teur-α de né crose tu mo rale (TNF-α) et d'interleukine-1β du rant ces états réac tion nels.La tha lido mide, un médica ment util isé pour traiter de tels états dans la mala die de Han sen a été révé lée apte à fa vo riser la dé gra da tion du TNF-α mRNA.La pen toxi fyl line s'est égale ment révé lée ca pa ble de modi fier les taux de TNF-α mRNA en in hi bant la tran scrip tion du TNF-α.L'as so cia tion de ces deux médica ments comme an tago nistes des cy to ki nes peut se révé ler avan tageuse dans le traite ment des états réac tion nels pro pres à la mala die de Han sen.La pen toxi fyl line peut être un traite ment bé néfique dans le traite ment des états réac tion nels pro pres à la mala die de Han sen chez les femmes en âge de pro créer.Les an tago nistes des cy to kines, seuls ou en as so cia tion, sont sans doute ap pe ler à jouer un rôle thé ra peu tique.
A CCORD ING TO A RE CENT RE PORT, 5 MIL LION PEO PLE SUF FER from Han sen's dis ease world wide (1).Han sen's disease (lep rosy) is char ac ter ized by two re ac tional states (2).Type I re ac tions of Han sen's dis ease in volve mild ery thema and edema while type II re ac tions in volve ery the ma tous lesions last ing from sev eral days to weeks.
Type I re ac tions will re spond to non ster oi dal anti-in flamma tory drugs (NSAIDs).Se vere type I re ac tions in volv ing neuro pa thy or neu ri tis, ul cera tion and edema of the hands, face and feet is an in di ca tion for cor ti co s ter oid ther apy (2).Ini tially high dose predni sone 40 to 120 mg daily may be nec es sary, and chronic ther apy is of ten re quired.In the type II re ac tion (ery thema no do sum lep ro sum [ENL]), cell-mediated im mu nity is in creased (3) and cir cu lat ing lev els of C3 break down product C3D are in creased (4).The re duc tion in in ter leukin (IL)-2 pro duc tion ob served in Han sen's dis ease pa tients is re versed dur ing ENL (5).ENL is sub di vided into mild and se vere grades for choice of thera peu tics.In mild ENL NSAIDs pro vide symp tomatic re lief.In se vere ENL, when neu ri tis, se vere sys temic reac tion (high fe ver, etc), iri do cycli tis or skin ul cera tion are pres ent, cor ti co s ter oid or tha lido mide treat ment is used.
Tha lido mide was origi nally used as a seda tive in ENL and was found to im prove symp toms of the re ac tion (6).For men and post meno pausal women, tha lido mide is a drug of choice for ENL (7).The re sponse to tha lido mide ther apy is rapid; within 24 to 48 h there is a de crease in fe ver and in num bers of le sions.ENL rap idly re sponds to tha lido mide ther apy, which may be bet ter than long term ster oid treat ment (8).
On a cau tion ary note a re cent re port by Craw ford (9) in dicates that tha lido mide it self can cause pe riph eral neu ropathies, which can be se vere and ir re versi ble.Re cently tha lido mide has been re ported to cause tha lido mide neu ro pathy (10) when used in other treat ment regi mens (11).It is ob vious that the cur rent treat ment regi mens for re ac tional states in Han sen's dis ease carry with them the po ten tial for se vere side ef fects.
The mecha nism of ac tion of tha lido mide in ENL is not known but re cent re ports sug gest that tha lido mide se lec tively in hib its tu mour ne cro sis fac tor (TNF)-α pro duc tion (12) by enhanc ing deg ra da tion of TNF-α mRNA (13).Cor ti cos ter oids have anti-inflammatory ac tion and can in hibit trans la tion of TNF-α mRNA, ie, they act post-transcriptionally (14); but long term ster oid ther apy car ries with it the pos si bil ity of Cush ingoid syn drome.De lay ing treat ment of the re ac tional states of Han sen's dis ease can re sult in ir re versi ble nerve dam age (15).
The role of cell-mediated im mu nity in lepro ma tous lep rosy, par ticu larly the im por tance of lym phoki nes and cy to ki nes in Han sen's dis ease, is the sub ject of much re search (16).Recent stud ies re port ele vated se rum lev els of TNF-α and IL-1β dur ing lep rosy re ac tional states (17).This is in con trast to an ear lier re port (18) but likely re flects dif fer ences in meth ods of meas ur ing cy to ki nes (ra dio im mu no as say) ver sus cy to kine ac tiv ity (bio as say).Modi fi ca tion of cy to kine pro duc tion eg, IL-1 and TNF-α, can oc cur with cur rently used an ti le pro ma tous drugs, in clud ing cor ti cos ter oids (14) and tha lido mide (12), and this may par tially ex plain their mecha nism of ac tion in Han sen's dis ease.Sev eral re cent re ports sug gest that pen toxi fyl line can inhibit the syn the sis and ac tion of TNF-α (19)(20)(21).Pen toxi fyl line re duces TNF-α mRNA by in hib it ing TNF-α tran scrip tion, thus sup press ing TNF-α gene ex pres sion (22).These ac tions are dis tinct from the ac tions of tha lido mide or cor ti cos ter oids on TNF-α syn the sis, sug gest ing the pos si bil ity of syn er gism when these drugs are used in com bi na tion.Pen toxi fyl line has also been re ported to in hibit IL-1 -mediated func tions (23,24).In hibi tion of phos phodi es terase by pen toxi fyl line would ele vate cAMP (25) and thereby re duce tran scrip tion of TNF-α (26).Due to its ef fects on TNF-α and IL-1, pen toxi fyl line may be an ef fective thera peu tic agent in the treat ment of re ac tional states in Han sen's dis ease alone or when used in com bi na tion with tha lido mide.
In ad di tion to its ef fects on TNF-α and IL-1, pen toxi fyl line inhib its neu tro phil func tion (27,28).Neu tro phils play an im portant role in ENL (29), so this ef fect of pen toxi fyl line may prove to be an added bene fit in Han sen's dis ease, par ticu larly ENL.
Pen toxi fyl line ap pears to be a very safe drug when used in chronic treat ment of other dis or ders (30).Chronic use of pentoxi fyl line for up to one year car ries a low in stance of side effects, which in clude gas tro intestinal dis tur bances in 2.6% of pa tients treated, while fewer than 0.25% of pa tients treated ex pe ri ence car dio vas cu lar, psy cho logi cal, neu ro logi cal, hepatic or der ma to logi cal ef fects (31).
In re ac tional states of Han sen's dis ease, pen toxi fyl line may prove to be an ef fec tive thera peu tic agent, with par ticu lar in di ca tion in women of child bear ing age where tha lido mide use is con tra in di cated.In the sub group of Han sen's dis ease pa tients in whom tha lido mide is cur rently used, the com bi nation of tha lido mide with pen toxi fyl line will likely pro vide ad ditional thera peu tic bene fit.Both drugs af fect TNF-α tran scrip tion, but at dif fer ent sites, thus pro vid ing the pos si bility of syn er gis tic ac tiv ity.It is un der stood, how ever, that a certain level of cy to kine pro duc tion (eg, TNF-α) can be bene fi cial (32), so care ful ti tra tion of cy to kine in hi bi tion will likely be neces sary to achieve op ti mum re sults.
The role of cy to kine an tago nism by pen toxi fyl line in the treat ment of other cytokine-mediated dis eases, dis or ders and in jury is be com ing in creas ingly evi dent in the lit era ture.Pentoxi fyl line has been shown to pro long sur vival in ani mal models of peri to ni tis (33) and bac teremia (34), po ten tially through a mecha nism whereby pent oxifylline in hib its TNF-α-induced polymor pho nu clear leu ko cyte ac ti va tion in clud ing poly mor pho nuclear leuko cyte ad her ence, de granu la tion and su per ox ide pro duc tion (35).Pen toxi fyl line im proves the he mo dy namic and his to logi cal changes, as well as a de crease in neu tro phil ad he sive ness, in a pig fe cal peri to ni tis model (36).
Re ports in the lit era ture sug gest that pen toxi fyl line also reduces both sep tic-and TNF-α-induced acute lung in jury and mul ti ple or gan dam age in the guinea pig (37)(38)(39).They also sug gest that pen toxi fyl line at tenu ates edema for ma tion in pro te olytic enzyme-induced lung in jury (40).
Hoff man and co-workers (41) re port that pen toxi fyl line attenu ates Escheri chia coli-i nduced acute lung in jury in guinea CAN J INFECT DIS VOL 6 NO 1 JANU ARY/FEB RU ARY 1995 pigs.Fur ther re ports by Gib son et al (42) in di cated that group B strep to coc cus in duces TNF-α in neo na tal pig lets and that pen toxi fyl line treat ment both at tenu ates group B streptococcus-induced TNF-α pro duc tion and pro vides some im prove ment in pul mo nary he mo dy nam ics and hy poxe mia in the pig let model.Noel et al (43) re port that pen toxi fyl line in hibited lipo polysaccharide-induced se rum TNF-α and pro tected the ani mals from the le thal ef fects of an in tra ve nous chal lenge with lipo poly sac cha ride.
TNF has been im pli cated in the patho gene sis of sep sis, cancer cachexia (44), the cachexia of chronic heart fail ure (45), IL-2 tox ic ity (46), ische mia/reper fu sion in jury (47,48), cere bral ma laria (49), pul mo nary fi bro sis (50) and acid aspirationinduced lung in jury (51).The block ade of TNF-α ac tion with neu tral iz ing anti-TNF anti bodies has im proved some of these con di tions, in cluding sep tic shock and IL-2 tox ic ity.This suggests that there may be an im por tant role for cy to kine an tagonists in these and other con di tions in which TNF ap pears to have a dele te ri ous ef fect.It has clearly been shown that pen toxi fyl line blocks TNF-α at the mRNA level (52) and can be used suc cess fully in vivo for the treat ment of dis eases with high en doge nous TNF-α lev els (39,43,(53)(54)(55)(56).
The re lease and/or ac tion of other cy to ki nes has re cently been re ported to be in hib ited by pen toxi fyl line treat ment (57)(58)(59)(60), thus pro vid ing fur ther roles for pent oxifylline as a cy to kine an tago nist in dis eases and dis or ders in volv ing other cy to kines (61,62).
The fu ture ap pli ca tion of pen toxi fyl line and tha lido mide, alone or in com bi na tion, as well as other cy to kine in hibi tors has wide im pli ca tions in thera peu tics.