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Taking stock of coxibs Probiotics for atopic diseases

Treatnent Notes

Helping children with bedwetting

Ihank you to contributors, addendum

The independent review of medical treatment

Taking stock of coxibs

Highly selective COX-2 inhibitors ('coxibs') were developed in an attempt to minlmise severe gastrointestinal toxicity associated with conventional NSAlDs, without loss of anti-inflammatory efficacy. Five years ago, we concluded that the evidence then available indicated, at most, a small advantage for rofecoxib and celecoxib (the first coxibs to be marketed) over conventional NSAIDs in terms of reduced risk of severe gastrointestinal

complications, such as bleeding or perforation of gastric or duodenal ulcers.l ln September 2004, newly released evidence about cardiovascular risk with rofecoxib led Merck Sharp & Dohme to voluntarily withdraw the drug worldwide.2 This has raised questions about the balance of benefit and risk with coxibs in general.
Here we iscuss the evidence relating to the gastrointestina
Ia

nd ca rd iovascu la r safety of coxibs in patients

with

osteoarthritis (OA) or rheumatoid arthritis (RA).

Background
Conventional (non-selective) NSAIDs inhibit rwo
isoforms ofthe enzyme ryclo-orygenase (CO)0

The coxibs
-COX-1
The withdrawal ofrofecoxib left three orally administered coxibs arailable in the UK for the treamrent ofpatients with OA or RA - celecoxib, Vetoricoxib and Vvaldecoxib. A fourth, lumiracoib, has beeo iicensed but not launched in the UK for the matment of patients with OA.
Coxibs differ from one another in various ways, and cannot be assumed to have identical clinical effects. Celecoxib and valdecoxib are sulfonamides. Etoricoxib and rofecoxib are methylsulfones. Lumiracoxib, a phenylacetic acid derirztive, is structurally diffcrent from the othercoxibs and more closely resembles diclofenac.r'r None of the coxibs

and COX-2.1r COX-1 is expressed continuouslyin most tissues and, in the stomach, catalyses production of prostaglandins that protect the gastric mucosa. COX-2 is

less widely expressed, but is readily induced by pro-

inflammatory stimuli, and catalyses production ofprostaglandins that mediate inflammation.' Inhibition of COX-1 is thought to be the main way in which NSAIDs cause gastrointestina[ damage. ro Anti-infl ammatory effrcacy is believed to result from inhibition of COX-2. At therapeutic doses, coxibs inhibit COX-2 but not COX-1, so it was postulated that they should relieve inflammationwith less gastrointestinal toxiciry than conventional NSAIDs. However, selective iohibition of COX-2 appears more complex than first suggested, as COX-2 has many other functions besides its role in inflammation.r In the vascular endothelium, it mediates production ofprostaglandin

inhibit platelet COX-1 in vivo. However, they differ in

their degee ofselectivity for COX-2 in vitro, celecoxib being least selective and lumiracoxib most."r" They also differ in

their physicochemical properties (e.g. acidiry lipophilicity) and pharmacokinetic characteristics (e.g. rate of absorp-

vasodilator and inhibitor ofboth platelet aggregation and proliferation of vascular smooth muscle cells. Convenely, COX-1 mediates synthesis ofthromboxane A,, a vasoconstrictor and stimulator ofboth platelet aggregation and vascular proliferation.t6 Both isoforms are probably important in vascular homeostasis and rcgulation of platelet function. Both are also expressed in the kidney and are thought to have important roles in health and conditions of renal stress (such as hypovolaemia).r Exa

PGI,

tion and elimination). Lumiracoxib is shortest-acting (elimination half-life around 5 hours), and etoricoxib
longest-acting (half-life 20-26 hours).1')

Clinical efficacy
Published randomised controlled trials of coxibs in patients with OA and RA have, in general, demonstrated anti-inflammatory efficacy similar to that ofcomparator NSAIDs.tt rr We know of only one trial that has shown

perimental evidence suggests that COX-2 may help to protect the myocardium during ischaemia,s and may also be involved in the healing ofgastric ulcers.'

superior efficacy.
12 weeks and

In that

study, which lasted

involved 815 patients with RA, etoricoxib 90mg daily was more effective on all main endpoints than

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Taking stock of coxibs

naproxen 500mg twice daily.rn We know of no convincing evidence that, atoptimal effecdve doses, any one coxib is superior to another in patients with OA or RA.

Rofecoxib

The Vioxx GI Outcomes Research (VIGOR) study

randomised 8,076 patients with RA to rofecoxib 50mg daily (twice the usual RA dose) or naproxen 500mg twice daily (a standard NS{D dose).r Patients taking low-dose aspirin for cardiorascular prophylaxis were excluded from the shrdy. After a median follow-up of9 months (range 0.5-13

Gastrointestinal effects
Dyspeptictype symptoms
Among all patients started on conventional NSAIDs,
around 15-4O26 experience dppepsia, nausea or abdominaJ pain, and up to 1006 change or discontinue treatment as a result.rt Such symptoms often occur without endoscopic evidence ofmucosal damage. In published doubleblind comparative snrdies, dyspeptic symptoms seem to occur at a similar or slightly lower rate with coxibs than with conventional NSAIDs, prompting treatment discontinuation in around 2--6% and 4-8%, respectively II rr'rr'rr'r'q There are few data on gastrointestinal tolerabilit_v ofcoxibs in patients who are unable to tolerate conventional N SAIDs.

months), the rate ofgasroduodenal perforation or obstruction, proven symptomatic ulcer, and upper gastrointestinal bleeding ('PLIBs') - the primary outcome measure - !!?s lower in the rofecoxib group than in the naproxen group (2.7 vs. 4.5 per 100 patient-years, relative risk [RR] 0.5, 95% CI 0.3-0.6).This corresponds to a number needed to treat (NNT) of42. The rate ofconlirmed ulcer complications (perforation, obstmction, severe bleeding) was also lower on rofecoxib (0.6 vs. 1.4 per 100 patient-years, RR 0.4, 950,6 CI 0.2-O.8; NNT 125).

Celecoxib

Endoscopic u lceration
Gastric or duodenal ulcers can be detected endoscopicallyin around 10-20% ofpeople on regulardoses ofcon-

The Celecoxib Long-term Arthritis Safety Study (CLASS) was originally planned as two separate
randomised controlled trials both involving patients with OA or RA." One study was to compare celecoxib 400mg twice daily (four times the usual dose for OA, twice the maximal dose for RA) with ibuprofen 800mg three times daily, taken for 15 months. The other was to compare celecoxib 400mg twice dailywith diclofenac 75mg twice d?ily for 12 months. Controversially, the findings were published as a single three-arm study involving 8,059 patients, and only included data from the first 6 months extrapolated to a predicted 1-year rate.': This analysis and prcsentation have been heavily criticised,ri not least because, in realiry almost all ulcer complications that occurred after 6 monthswere in patients taking celecoxib.rtl

ventional NSAIDs.'r' An additional 20-400% have mucosal erosions. The incidence of endoscopic ulceration and erosions durin8 treatment with coxibs is much lower (around 5-70,6), comparable to that with placebo,
and does not rise with increasing doses of coxibs.
r'r'rr"rr

rr

Most endoscopically detected ulceration does not

cause

symptoms or complications. However, some authorities consider it a surrogate marker for the risk of a clinical complication, such as bleeding or perforation. Indirect support for this comes from a 6-month double-blind study

which found that co-administration of misoprostol (a

prostaglandin analogue) with an NSAID reduced, by similar proportions, the number of patients who developed endoscopic ulceration and the number who developed a severe ulcer complication.rr However, the usefulness of endoscopic ulcers in assessing either clinical risk or the efficacy of protective strategies is uncertain.":02'

Use

Severe gastrointestina I toxicity ofNSAIDs is associated with around a fourfold increase in the incidence of severe upper gasrointestinal
ulcer complications (e.g. bleeding and perforation) compared with the rate in non-users of NSAIDs.2i Bleeding

or perforation is often the first manifestation of

an

NSAID-induced ulcer and such complications account for an estimated 700 to 2,000 deaths in the UK each year.ru 2t The risk persists throughout treatment,r5 and is
increased by a previous history ofgastroduodenal ulceration; use ofhigher doses of NSAIDs; co-prescription of

daa for the first 6 months, the repon predicted a lower 1-year incidence ofconfirmed syrnptomatic ulcers and ulcer complications with celecoxib than with conventional NSAIDs (2.08 rs. 3.54, p=0.02; NNT 68).rr However, for the designated primary outcome measure ofulcer complications alone, the predicted l-year incidence did not differ significandy between the groups, either for the study population as a whole (0.76% with celecoxib w. 1.45010, p=Q.99; o, for the subgroup ofpatients (around 2S6) who were receiving low-dose aspirin for cardiorascular prophylaxis (2.01026 with celecoxib w. 2.12%, p=0.fi). For patients not taking aspirin, the predicted 1-1ear incidence ofulcer complications was lower in t]re celecoxib group (0.447o rs. 1.27%, RR 0.35, 950,6 CI0.14-0.98; NNT 120).I Howwer, even in this subgroup, subsequendy released actual (rather than prediaed) results at 12 months showed no significant difference.rl
Based on

corticosteroids, anticoagulants or aspirin; and the presence ofother significant diseases.r5 r'The absolute risk is highest in people aged over 65 years. The risk ofsevere gastrointestinal toxicity in people taking coxibs has been investigated in large randomised controlled trials in which serious gastrointestinal events were the primaryoutcome. Fully published studies ofthis kind
are available for rofecoxib, celecoxib and lumiracoxib,

Lumiracoxib
The Therapeutic Arthritis Research and Gastrointestinal Event Tiial (TARGET) randomised a total of18,325 patients with OA to two similar double-blind 'substudies', each lasting 52 weeks.]r In one, patients received randomised treatment with lumiracoxib 400mg daily (two to four times the usual dose for OA) or ibuprofen 800mg thrce times daily.In the other, patients receircd lumiracoxib 400mg daily or naproxen 500mg twice daily. In all,24% ofpatients were receiving low-dose aspirin at trial entryt1 The primary

but

not etoricoxib or valdecoxib.

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outcome measure was the difference in time to definit or probable upper gasftointestinal ulcer complication (clinically significant bleeding, perforation or obsruction). For the overall population, fewer patients on lumaricoxib had a definite or probable ulcer complication (0.32% vs. 0.91% in the combined NSAID groups, hazard ratio [HR] 0.34,95%Cl0.224.52; NNT 169). In patients not taking aspirin, the rate ofulcer complications was also lower with lumiracoxib than with comparator NSAIDs (0.20%

Cardiovascular effects
An important unexpected finding of the trrIGOR study
was a significantly higher incidence ofmyocardial infarc-

tion with rofecoxib than with naproxen (0.4% vs.0.1%, RR 5.0, 95% CI 1.72-14.29). "'The findings sparked debate as to whether they represented a harmful effect of
rofecoxib or a protective (aspirin-like) effect ofnaproxen, or were due to chance. They highlighted concern about the potential for adverse cardior.ascular effects with coxibs in general, and with rofecoxib in particular.

vs.0.92%, HR 0.2, 95% CI 0.12-0.37;

NNT 139). In

those on aspirin, the rate did not differ significantlv between the groups (0.69% vs. 0.88%). "

There are seyeral ways in which matment with a COX-2 selective inhibitor might, in theory increase cardiovascular

More patients on lumiracoxib than on the comparator

NSAIDs had a greater than threefold increase in the level of
li!,er transarninases, which resohcd on cessation

risk in susceptible patients, compared with conventional NSA-IDs or no treatrne nt.i6 Inhibition ofCOX-2 could leave
patients exposed to unopposed pro-thrombotic effects of COX- 1-mediated production ofttrromboxane Ar. A coxib might block potentially prctective effects ofCOX-2 on ischaemic mrocardium or on atherogenesis. Also, coxibs'eF fects on blood pressure and renal function could tum out to be more detrimental than those ofconventional NSAIDs.

ofmatrnent
1

(2.57% rs. 0.63%). The liver abnormalities were considered severe in 5 patients on lumiracoxib and 3 on other NSfDs. I

Other data Individual efficary studies with coxibs have generally been
too small to detect or exclude significant treatment effects on the rate ofseverc ulcer complications. However, several pooled anallses ofsuch nials have suggested a lower rate of these events with coxibs than with various NSAIDs.ri " Such anall,ses often have crucial limitations. They tend to

Besides the

Evidence of harm with rofecoxib \rlGOR study, a number ofclinical and epi-

demiological studies have signalled possible harmflrl cardiovascular effects with rofecoxib. Some have found more
marked increases in blood pressure than with comparable doses ofcelecoxib or naproxen.t''2 AJso, a retrospective study in elderly patients found that hospital admission for congestive cardiac failure rvas significantly more likely in those treated with rofecoxib than with celecoxib (RR 1.8, 95% CI 1.4-2.4)." Three epidemiological studies have suggested an increased risk ofacute cardiac events in patients given rofecoxib in high doses (above 25mg daily).''r'rt In one, the incidence of acute myocardial infarction or cardiac death in new users ofthe drug at such doses was almost twice that in non-users of anti-inflammatory drugs (24 vs. 13 events per 1,000 patient-years, RR 1.93,95% CI 1.09-3.43).| A second study suggested an increased riskofacute myocardial infarction in patients aged over 65 years during the first 90 davs ofrofecoxib therapy (most marked with doses over 25mg daily) compared with celecoxib or no NSAID.6A recent case-control study, commissioned by the US Food and Drug Administration, found that current use ofrofecoib in doses above 25mg daily was associated with a threefold increase in the risk of an acute cardiac event, compared with the rate in people who last used anyNSAJD more than 60 days previously (odds ra-

group togethcr trials of different design, in which

gasffointestinal events are generally a secondary outcome. They may also include unpublished trials, the data from which are not independendyvcrifiable. Furthermore, some analyses pool uncomplicated or endoscopically detected ulcers with proven and unproven gastrointestind bleeding
and perforations,which precludes differentiation of severc complications from less clinically important outcomes.r

Two retrospective studies, using very large population databases in Canada and the UK, respectively, have also
suggested a lower risk for upper gasuointestinal haemor-

rhage among patients prescibed coxibs compared with the risk in patients given cqnventional NSAIDs.ri}The Canadian study found a fourfold higher rate ofhospital admission for such events in pcople aged over 65 years newly prescribed a conventional NSAID, compared with those prescribed celecoxib, despite a higher prevalence of risk factors in those given celecoxib.r3 However, such studies are prone to a number ofconfounding factors and potential biases, so provide less robust evidence than do large prospecrive srudies. Furrhermore, a recent retrospective analysis using the same Canadian database, found ttrat the use ofanti-inflammatory drugs among elderlypeople had risen by 41% since the introduction of coxibs (the
increase being entirely amibutable to this drug group) and hospital admissions for upper gasrointestinal bleeding had risen by 10%.*) This suggests that prescribing precautions for such high-risk groups may be being disregarded too readily in the beliefthat coxibs are 'safe'.

tio [OR] 3.15,95% CI 1.14-8.75) or compared with current use ofcelecoxib (OR 3.69, 95% CI 1.30-10.45).r5

In September 2004, Merck Sharp &Dohme announced

voluntary worldwide withdrawal of rofecoxib. This followed the release of data from an unpublished 3-year randomised placebo-controllcd trial that involved 2,500 patients and investigated the use ofthe dmg to prevent recurrence of colotectal polyps.'?The srudy found an increased risk of confirmed thrombotic events, including myocardial infarction and stroke, in patients on rofecoxib

The summaries ofproduct characteristics (SPCs) for all

marketed coxibs advise caution with treatment ofpatients most at risk ofdeveloping a gastrointestinal complication

with NSAIDs.
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Taking stock ot coxibs

25mg daily (1 extra event per 133 patient-years oftreat-

The SPCs for all coxibs currently marketed in the UK

patientswith a history of ischaemic heart left ventricular dysfunction or cardiac failure. They advise that coibs should be stopped, and appropriate measurcs taken, if there is any clinical evidence of deterioration in these conditions. Cardiovascu.lar prophylaxis with antiplatelet therapy (such as lowdose aspirin) should not be discontinued, and should be considered for patients at risk, or with a history ofcardiovascular or other thrombotic events.
advise caution in disease, hypertension,

ment), the increase first becoming apparent after

18 months of treatment.16

The authors of a recent cumulative meta-analJsis of all randomised controlled trials comparing rofecoxib with

NSAID or placebo in patients with chronic musculoskeletal disorders (18 trials, a total of 20,742 patients)
concluded that clear evidence for an increased riskof myocardia.l infarction with rofecoxib was present by the end of 2000.rr According to this anahsis, the relative risk (2.30, 950,6 C\ 1-224.33) appeared uninlluenced by trial duration or whether patients in control groups received placebo, naproxen or a non-naproxen NSAJD.{i

So what options for gastroprotection?

Four years ago, the National Institute for Clinical Excel lence (NICE) advised that, for the treatmentofOA or RA, coxibs (and the COX-2-preferential drugs, meloxicam and etodolac) should be used only in patients at high risk of developing serious gas&ointestinal adverse effects, and then only after careful consideration ofthe risks.']o NICE also concluded that coxibs should not generally be used in preference to NSAIDs in patients with cardiovascular disease, and that the available evidence did notjustiS their use in patients receiving low-dose aspirin. Subsequent data seem to support these restrictions. Indeed, on the balance ofbenefit and risk, the case for prescribing a coxib appears even more marginal than when we last reviewed these drugs.r

What about other coxibs? A crucial question is whether the

apparent treatmentassociated increase in cardiovascular events is unique to rofecoxib or applies to other COX-2 selective drugs, and whether it applies to all patients or only to a subset, such as those with known risk factors for vascular disease.

In CLASS, the

celecoxib group and the combined

ibuprofen-/diclofenac groups did not differ in the incidence

ofcardiorascular events (0.90,6 with celecoxib vs. 1.0026) or myocardial infarction (0.3% vs.0.3%) in the study population as a whole.rr Nor were there any differences in the
aspirin and non-aspirin zubgroups. The incidence ofhypertension was lower in the celecoxib group than in the com-

bined NSAJD group (1.7% vs.2.3%, p<0.05), and fewer patients on celecoxib had an increase in plasma creatinine (O.7% w. 1.2%, p<0.05).r') Funhermore, epidemiological studies have not suggested an increased risk ofmyocardial infarction in patients receiving celecoxib.'""5

The most important element in gastroprotection is to ensure that patients at high risk, and those with noninflammatory disorders, are not exposed unnecessarily to NSAIDs, including coxibs. Paracetamol, given in hrll dosage, should be tried first, and if an NSAID is needed it should be given in the lowest dose and for the shortest time necessaryr

In TARGRI, there was no significant difference between

the lumiracoxib group and the ibuprofen or naproxen groups

(separately or combined) in the incidence of the prospectively defined composite endpoint ofnon-fatal or silent myocardial infarction, stroke or cardiovasc,ular death.J, Nor was there any significant difference in the incidence ofmyocardial infarction in patients receiving lumincoxib or ibuprofen, for the groups
groups.
as a

Various gastroprotective dlugs are commonly coprescribed with NSAIDs to help prevent severe gastrointestinal complications. The most widely used are
proton pump inhibitors, such as omeprazole. Proton pump inhibitors reduce endoscopically diagnosed mucosal damage and are effective for healing NSAID-induced ulcers. However, no prospective outcome studies have demonstrated that co-prescription ofthese drugs with NSAIDs reduces the riskofsevere gastrointestinal complications.r'

whole or for the aspirin/non-aspirin sub-

More myocardial infarctions occurred in patients on lumiracoxib (18 wents,0.38% ofpatients) than in those on naproxen (10 events,0.21%). This apparent excess risk was not significant, either in the group as a whole (HR 1.77,
950/6

CI 0.82-3.84), or in the aspirin

subgroup

(HR

1.36,

950.6 CI0.47-3.93)or non-aspirin subgroup (HR 2.37,95% CI 0.7,{-7.55).'s Mean systolic blood pressure rose less on

lumiracoib than on comparator NSAIDs,

recent meta-analysis of strategies for the prevcntion of NSAID-associated gastrointestinal toxicity concluded that only misoprostol had definitely been shown to reduce the likelihood of severe gastrointestinal complications." In a 6-month double-blind randomised trial involving 8,843 patients with RA, co-prescription ofmisoprostol with conventional NSAID reduced the risk of severe complications

It

is important to note that neither CLASS nor TARGET was powered to identifr an effect of celecoxib or

by 40% compared with NSAID alone (25 events

vs.

lumiracoxib, respectively, on cardiovascular endpoints. Furthermore, neither study lasted as long as 18 months the point at which the adverse cardiovascular outcomes became apparent in the rofecoxib study in patients with
colorectal polyps, that ultimately led to its worldwide withdrawal. Fully published long-term data on cardiovascular safety are lacking for valdecoxib or etoricoxib in patients

42 events, OR 0.60, 95% CI 0.3H.98).r' Disadvantages ofmisoprostol include that it has to be taken two to four times daily and commonly causes troublesome diarrhoea.

Conclusion
Unqualified assertions that COX-2 selective inhibitors
(coxibs) are, as a class, 'safer' NSAIDs are untenable on current evidence. Coxibs seem possibly less likely than con-

withOAorRA.

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Taking stock of coxibs

ventional NSAIDs to cause dyspeptic-type s,.rnptoms and are associated with fewer endoscopically visible gastroduodenal ulcers or erosions. Epidemiological data also suggest a lower likelihood of upper gastrointestinal bleeding with celecoxib than with conventional NSAIDs. However, long-term outcome studies have not demonstrated a significant reduction in major ulcer complications (such as bleeding or perforation) wittr celecoxib compared with commonly uscd NSAIDs, and there are currently no firlly published trials of this kind for Vetoricoxib or Yvaldecoxib. When given for up to 1 year, lumiracoxib (which has not yetbeen launched in the UK) causes fewer ulcer complications than ibuprofen or naproxen. However, the number needed to treat is high, and even this advantage is lost in patients who take low-dose aspirin for cardiovascular
prophylaxis. Also,
as

possible increase in the risk ofserious cardiolascular events.

This risk has not been adequately evaluated for any currentlylicensed coxib at therapeutic doses.

We can see few, if any, situations in which a coxib is unequivocally indicated. All NSAIDs, including coxibs, should be avoided, wherever possible, in patients at high risk of
gastrointestinal complications. We see potential hazards in prescribing a coxib to a patient who is at risk from cardiorascular disease, and no advantage for patients taking low-dose aspirin for cardic*asc,trlar prophylaxis. Anti-inflammatory dmgs, including coxibs, should be prescribed at tle lowest effective dose and in accordance with the plecautions set out in the summary ofproduct characteristics current at the time. The patient should be carcfirlly monitored and rwiewed regulady to aroid unnecessary rqrcat prescriptions. Any suspected advene reactions with coiba should be reponed to the Comminee on Safety of Medicines on a Yellow Card.

experience

with the recendy witlldrawn

rofecoxib has demonstrated, there maybe a'trade-off'between befter gastrointestinal tolerability with coxibs and a
[M--meta-analysis; R=randomised controlled trial]

Are rclecoxib and celecorib satrr ltSAlDs?

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Matsurnoto A( et al. A randomized, co0trclled. clinicaltrialol etoncoxib in

bneling86TTbl_0,4-stats.doc.

attlifis.

J Rheumatol2002:29:

32.

Silve6tein Ft et al. Gastrointestmalloxicity

l4 December 20041. uth celecoxib vs nonsteroidal

The

17. 18.

Brun i. lones R. llonsteroilal aflti-inilammab.y drug-associated the $ale ol McKenna

anti-idammatory drugs l0r osteoarthdis and deumatoad adhdtis.

CI.ASS study,

fie

pmblem. ,4/,./ ned 200

t; I l0

(suppt

lA | 12,3S.

a randomized

ontolled tiat. JAMA200U zpAt tZ47 -55.

et al. Upper Saslrcintestinal tolerability ol celecoxib compared

33.

HrachovecJB, Mora M. Reportog ol6-m0ntt vs

l2-modl

data in a clinical

ltiti
19.

diclolenac in the treatment of osteoarthdtis and rteumatoid artiritis.

tral ol

celecoxib. /,4rrl 2001, 286: 2398

Ain Ap Rheumatol2O02t 20, 35-43.

Watson DJ etal. Gastrointesttnaltolerability ol lhe selective cycloorygelase-

34. laniP

el al. Arr selective CoX 2 inhibiors supenor to traditonal non

steroidal anti,iiflammatory dru8s? Adequate analysis o,

tB

CL-ASS

trial

2 (C0X-2) inhibrtor rofecoxib compared with nonselectiye CoX-l and C0X,2 inhibilors in osteoarhritis.,4rc, hlten Med 20OO: 160: 2998-3003
M

indicates thal this may not be the case. 8n./ 2002; 324, t Z87-8.

35.

LanSrnan

llij

et al. Adverse upper gastr0intestiial eflects of rolecorib

20.

Nalronal lnsttute lor

0inr.ilE .f/]erte.200l.

AJida\ce or

tp

use

ol

clth-

compared with N!,AlDs. ./,4rr,4 1999; 282, 1929 33

DTB

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43

No

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Taking stock of coxibs

36. 37.

Goldstein Jl. et al.

Huced

risk ol upper gastrointestinal ulcer comdications

elderly Datients, a Do00laton-based cohort sbdy. larcel2004; 363,

l75l-6.

Irith celecoxib, a novel C0)(-2 M

inliblfi.

An J kstr@ntealz\ooi 95, 168l -90.

ga

44. 45.

RayWA et al. C0X-2 selective non- steroidal ant'inflammatory drugs afld dsk ol sedous coronary heart disease. laacel2002; 360, Graham Dl et al, 2004.

Goldstein rL et al. Reduced incidence ol u pper

strointestina I u lcer

l07l-3.

complications with the C0X-2 selectve inhibitor, laldecorib. ,4limert

iisl

ol acute nyocardial infarction and sudden

Phamacol lhetz(n4: 20, 521 -38.

cardiac deak in patienls treated

na

vik C0l-2

selectve and non-sehcbve

38.

Mamdani M et al. obse ationalstudy of u pper gastointEstr

l haemo flhage in

/Vr4/Ds [online] Available: http://wwulda.gov/cder/drug/intopage/viord

eldert patienb given seHfue clclo-orxenas 2 inhititors or conveitirnal non-s'teroidala i-i,fiammatory drugs. 0W 2tfi2;325,624-7
.

vao[graham pdl [kcessed 14 December 2004].

46.

Medicines and Healthcare products Regulatory Agency,2004. Advbe fot

39.

MacDooald ll\,t et al. Channelling blas and the incidence of gastrointestinal haemofihage in users ol meloxicam, coxibs, and older, non-specific non-

patbnts follouiqg the vitldnwal ol a videly uted Nin tilbthntiinflanmatoty

- Vio

lonline). Available, http,//www.mhra.gov.!k/news/

steoidalanti idlammatorydruSs. 6u12003; 52, 1265-70.

vion.htm {Accessed 14 December2004l.

M

40. 41.

Mamdani M el al. Gastrointestinal bleeding after the introducton of CoX 2

47. llniP etal.

Risk o, cardiovascular eveits and rolec0xib: cumulatve meta

inhibitors, ecological strdy. 8,1r2004; 328, 14l5-6. whelton A etal. Etfecls ofcelecoxib and rolecoxib on blood pressule and
edema in patients >65 years 0t age with systemic hypertension afld

analysis. tal,.e|2004; 364: 2021 -9. R

48.

Farkouh ME et al. Compadson ol lumiracoxib with naproxen and ibuprolen

in

lheTherapeulic Arthritis Research and Gastroifiestinal tvenl Tnal

osleoatlhtdis. An J Catdid200?: 90, 959-63.

(TARCEI), cardiovascular outcones: randomised controlled ttial.

lrrcet

42. 43.

Solomon DH et al. Relationship between C0)(-2 specific inhibitors and

2004,364,675-84
M

h,Jwrlension. Hlwtensionz0u; {,4, 140 5. MamdaniM etal. Cyclo-oxygenase-2 inhibitors versus non-selective nonstemidal anli-inllammatory dru8s and congestive heart tailure outcomes in

49.

Hoopr l- et

al

The effectiveness ol

live strategies for

lie

prevention 0l

gastroantestioalloxicity induced by non-steroidalanti-inllammatory

systematic review. BrLl 2004; 329: 948'52

dr!8s:

Probiotics for atopic diseases

One suggestion for why some people develop atopic diseases, such as allergic rhinitis, asthma and atopic eczema, is that there are alterations in their intestinal microflora not seen in those without such conditions.r This idea underlies the proposal that probiotics (ora lly admin istered m icro-organ isms) containing, for example,

Lactobacillus and Bifidobacterium species, might help to prevent and treat atopic disorders by altering intestinal microflora.l We have recently reviewed the use of probiotics for gastrointestina I disorders.2 Here, we look at whether they have a place in the prevention and treatment of atopic diseases.

Preventing atopic disease

Background
The so-called'hlgiene hypothesis' suggests that a lack ofexposure to infections in early life predisposes people to atopic diseases.lt One postulated ocplaration is that a lack ofstimulation by infectious agents oflhelper 1 cell-mediated (T1pe 1) immune response in early life leads to an inability to counterT-helper 2 cell-mediated (Type 2) allergic response.oAnother suggestion is that a lack ofexposure to infection in early life may contribute to the differences in intestinal flora seen benveen people with and without atopic diseases; people with atopic disease have been found to have more Clostidium species and fewer Bitldobacterium species in their stools.o

In one trial

assessing primary prevention ofatopic disease in children, 159 pregnant women with a family history of atopy (eczema, rhinitis or asthma; the only inclusion criterion) were randomised to two capsules ofeither Lactobacillus rhannosus GG (1 x 10t0 colony-forming units lcful daily) or placebo, for 2-4 weela before expected deliveryrl

For 6 months after delivery breast-feeding mothers could

In-vitro and in-vivo research has found that some probiotics may stimulate anti-inflammatory and anti-allergic responses,r'i
3

suggesting

possible role for probiotics in people

continue to rake their allocated treatment or it was given direcdy to the infants (capsule contents mixed with water). The rationale for this approach was based on previous research suggesting that giving breast-feeding infants probiotics containin g L. rhamoosus GG direcdy, or giving it to their mothers, resulted in similar amounts of tlis organism in infant faeces.")The exact mechanism for this is unknown.In all,62 of the mothers who breast-fed continued to take either the probiotic (30) or placebo (32)."The
mean time ofexclusive and tota.l time ofbreast-feeding were similar inboth groups. Children were examined during the neonatal period and at3,6,12,1'8 and24 months old.

with atopic diseases. One theory is that these effects may be due to the ability ofprobiotic organisms to restore to
normal the altered intestinal permeability and flora, characteristically found in chi.l&en with atopic eczema and food allergy.r's'r" Other suggestions include that Probiotics enhance digestive tract-specific IgA responses, Promote the digestive tract's defence barrier mechanisms, and reduce cytokines associated with allergic inflammation.'

At 24 months, the ftequency ofatopic

eczema (the

primary

outcome measure) in the 132 infantswho completed the study was lower in the probiotic group (23% rt. 46% in the placebo group, relative risk [RR] 0.51, 95% CI 0.32-0.84).11 Abo, fewer breast-feeding infants in the probiotic group had developed atopic ecztma at 24 months (15% rs. 47% in the placebo group, RR
0

Clinical efficacy
Several published

.32,95ok Cl0.124.85).t'|

double-blind randomised controlled nials have investigated whether probiotics can help to prevent or treat atopic diseases.lE'o

Of the 132 children who completed the

of64
(83026)

study, a total of53 in the probiotic group and 54 of68 (796) in the

DTB

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43

No

.lanuary 2005

Probiotics for atopic diseases

placebo group were assessed again 2 yea$ later.rs By this time,

atopic eczema had been diagnosed in fewer chil&en in the probiotic group than in the placebo group (26% rs. 46%, RR 0.57, 95% CI 0.33-{.97). However, it is not clear from the trial report whether or to what extent any ofthe children had taken probiotics during the intervening period.

though 56% ofthc parients taking the probiotic believed their symptoms had improved compared with 15% of
those on placebo (p=0.001).

Treating perennial allergic rhinitis

38 teenagers and young adults who were allergic to birch pollen comparcd the effects of L. rhamnosus GG (two capsules containhg at least 5 x 10' cfu twice daily) with placebo on respiratory and eye symptoms ofallergy.ri

A srudy involving

Treating atopic eczema

assessed the effects of L. rhamnosus GG in 31 children (aged2.5-15.7 months)with atopic eczema and

One trial

cow's milk allergy.ro

Cowt milk

was eliminated from their

diet and the infants were given an exensivelv hy&ollsed whey-based formula milk that either did or did not contain L. rhamnosus GC (5 x 10s cfir,/g), for 1 month. In all, 13
infants in the probiotic group and 14 in the control group completed the snrdy and were included in the analysis. The severity of atopic eczema was assessed clinically using the ralidated SCORAD (SCORing Atopic Dermatitis) index
established by the European Task Force on Atopic Dermatitis.r'There was no significant difference in mean SCORAD
scores at baseline

Patients were treated for 5.5 months: 2.5 months before the pollcn season, 1 month during the season (May) and 2 months after. They were instructed to keep a symptomand- medication diary during the week{ong run-in period, the bi-rch-pollen sezrson and for 3 weeks afterwards. Patients evaluated their slnptoms on a 0-10 scale, recording eye, nasal and lung s1'rnptoms separately. The symptom
scores for each ofthese were orpressed as weeldy sums (scale

0-70 for each). Compared with placebo, the active treatmentdid not affect symptoms during the birch-pollen season or during the subsequent 2 months.

in the two groups. At 1 month, the scores

tillen significandy in infants in the probiotic group (from 26 to 15, p=0.008) but not in those in the control group (from 21 to 19, P=0.89). However, the difference between the groups with regard to change in scores was not reported and, at 2 months, the SCORAD scores in the two groups were similar (16 with the probiotic and 14 with the control).
had

A second trial compared the effects of fermented milk cortiring Lactobacillus paracasei-33 (2 x 10, cfu,/bottle) with milk containing no probiotic (both given for 30 days) on the qualiry oflife of80 children with perennial allergic rhinitis.l6 The mean age of participalts was 16
years in the probiotic group and 14 years in the control group.In all,60 were given thc probiotic-containing milk

In another study, 27 breast-fed infants (mean age 4.6 months) atopic cczema werc weaned on to a hydrolysed whey formula with or without one of two probiotic strains, L. rhamnosus GG (3 x 10' cfi-r/g) or Bifdobacteium lactis Bb-12 (1 x 10' cfir/g), for 6 months.rr The primaw outcome measures were the cytent, severity and subjective symptoms (pruritus and sleep loss) ofatopic eczema (assessed using the SCORAD index). After 2 months, the SCORAD scores had fallen more in both probiotic groups compared to the control group (p=0.002). The score was 16 before the study began, and fell in the B. /acas Bb-12 group to 0 and in the L. rhamnosusGG group to 1, compared to 13.4 in the control group. However, at 6 months, the SCORAD scores were similar in all groups.

witl

and 20 were given the control milk. A modified questionnaire on paediatric rhinoconjunctivitis and quality of lift (the primarv outcome measure) was given to all the children or theirparents at each clinical visit. At 30 days, scores for overall quality oflife had improved more in the probiotic group, both in terms offrequency of symptoms
(p=0.037) and level ofbother they caused (p=0.022).

Unwanted effects
In one trial, unwanted gastrointestinal effects were seen with heat-inactirated I. rlramnosus GG,lrwhile another trial re-

ported that there were no severe adverse effects with

L. paracaser:33.r6 None ofthe other published trials reponed on unwanted effects.ru'2 r'r5 Generally speaking probiotics appear to be well tolerated. Howwer, there have been a few cases of serious infections arising from probiotic use,r particularly in debilitated or immunocompromised patients.r,'ar

A third smdv compared the effects of

lysed whey formula plus

or heat-inactivated I. rlamnosusGG, or formula alone in 35 infants (mean age 5.5 months) with atopic eczema and allergy to cow's milkrr Recruitment was prematurely stopped after complaints from children's parents concerning advirse gastrointestinal symptoms (e.g. diarrhoea),which occurred only among the group given heat-inactivate d L. rhamnosus GG. Why this group developed these symptoms is unclear. SCORAD scores fell significantly but similarly in all tfuee groups during the 2-month study period.

l.

extensively hydrorhamnosus GG (1 x 10, cfir/g)

Preparations and dose

Supplements and foods containing probiotics are avail-

A fourth trial, involving 58 children (mean age 5.2 years) wirh atopic eczema and lasting 6 weeks. evaluared rhe

clinical effecrs of rwo Lactobacillus strains (lyophilised L. rhamnosus 19070-2 and Lactobacillus rciteri DSM 722460,101" cfu of each strain twice daily) compared with number of micro-organisms rhat a probiotic product placebo.r'At 6 weeks, the SCORAD siore (the primary should contain.r or the most appropriate ,egi-en ro p.e_ outcome measure) had not changed in either group, al_ vent or treat atopic disorders. DTB
Vol

able from supermarkets, pharmacies and health food shops. In the UK, probioric preparations are classified as foods or food supplements so, unlike for medicines, there is no statutory regulation ofthe quality of commercially available probiotic preparations. This is reflected in disl crepancies between the claims made by some manufac_ rurers and rhe findings ofinvestigators as ro the amount ofviable bacreria preseni in certain products..-r, ,and rype We know o[ no pubtished guidance on the optimum

43

No

January 2005

Probiotics for atopic diseases

Conclusion
Evidence from one trial suggests that the probiotic l,aaobaclus rhamnosus GG, when taken by a women during preg nancy and then eitler continued during breast-feeding or
lM=meta-analysis; R:ra0domised controlled triall

given to the baby, may help to prevent atopic eczema in children with a family history ofatopy This needs con6.rmation. Thcrr is no corvincing evidence that probiotic trcatrnent helps chjldren with established atopic eczema, or prerrcnts the development of, or helps to control, allergic rhinitis or asthmaR 14.
Rosenleldt v et al. Etfect oi gtobioic Lactobacillus stains in children with

l.
2. 3.

lGlliomdki M. lsolaun E. Role of intestinalflora in the development of

allery. Cun 1pi,

Stachan

AIW

Clin

Innuol\(fr3t

15-20.

alopic demalit,s. I Alerg Clin i/r/rurol 2003; I I l, 389-95. R 15. flelin I etal.l{0 ellect ol oraltreatmlrt wth an intesti[albactenalstrain. Lactobacillus kannosus\AICC 53103), on birch-pollen allerBlr a placebocontrolled double blind study. Allerg2002: 51 : 243-6.

ftobiotics for gastrointestinal disorders.

DP Hay tuver,

,I8

2004; 42, 85-8.

hygene, and housetold size.

Br,

1989; 299, 1259-60.

4
5.

Wills-&0

M etal. The gemless lheory olallerglc disease: revisiting the

R 16. R 17.

WanS

Mf et al. Treatmenl of perennialallergic rhinitis with lactic acid

hygiene hypofiesis. llrture nev

hnunol200l: l:69-15.
he
lrygiene hypothesis.

bacletia. Pediatr AlhW ln nunol 2004; 15, 152-8.

Rautava S et al. Probiotics during pregnancy and br4slleeding migit conrer irrmunonodulatory prctection againstatopic disoase in the iniant.

Yazdanba*hsh M et al. Allelsr, pamsites, and

,t lerce

2002: 296, 490-4.

6. 7.

lsola0riE. Ditary modification of atopic disease, use ol probiotics

prevenlion of atopic dematfi s. Cur CraneJ. Pro and

i[tie

) Allerg Clin

lnnuool2tfi2:109: ll9-21.

AleW Asthna

Rep

20M. 4, 270-5.

I8.

lGlliomeliM etal. Probiotics and prevention of atopic disease:4-year

f0llovr'up ofa andomised placebo-controlled

antirlie

brotics ol allerSrc disease. Ihuax2002t51

tial.

tarcef20031 361,

(supplll), ll40-6.

1869-r.

R 8.
R

Kirjavainen PV et al. Abemnt composition 0f gul microbiota ol allergir

19.

Seyenty scoring ol atopic dermatitis, the SCoRAo index. Consensus reoort ol

infants: a targeto{ bifidobacteial therap! atweaning? drt2002; 51, 5l-5.

tD

Eumpean

lasl force

0n Alopic

Dematilis- &rrMtolo&r 1993; 186, 23-31.

RosedeldtV et al. Etlect 0l probiotics on gastrointestinal symptoms and small antestinal pemeability in children 2004; 145:612 6.

20. 21.

Marteau 3 Seksik P Tolerance o, probiotics and prebiotics../ C/i,

wili

atopic dematitis.,/

ftdlatr

&slruenterol2004; 38 (suppl 2), 567'9.

Cesaro S el al. Sa.craronyces

cwisiael$genia i'
Care

a neubopenic patient

R 10. lilaiamaa R

H,

lsola! t.
J

Probiotics, a novel approach in

lie

management ol

tealed wlil Saccharcnyces fuulardii. Supwt

Ancer7\Nt

8, 504-5.

lood allery.

Allerg Clil lnnu\ol 1997r 99, 179-85.

22- Fainalelal.
wrth ulcerative

Laclobacillus caieisubsp.

/rrlrrosrs

sepsis in a patient

ll.

NalliomekiM etal. Probiotics in primary preve0tion ol atopic disease, a

randomised placebo-controlled trial.

colitis../C/1,6astoe erol2O0l 33, 251-2. Srccrrrorrlcrs spe.ies

in a patirnt treated

lrrcea200l; 357, 1076-9.

23. 24.

Niautt M et al. Fungemia due to

R 12. lsolauri R 13.

et al. Probiotjcs in Ure management of atopiceczena. Clin E\p

wih

entetal Sacchannyces bouladii. Clir lnfed As 1999; 28, 930.

,U/ergl 200{; 30, 1604-10. Nirjavainen Fryetal. Probiotc bactelia

in

Hamilton-Maller JM et al. "Probiotic" remedaes are not

that hey

seem. 8rl./

the management 0l atopic

t996:312, 55-6.

disease: undersconng the imm/,.a$ce ol viabilu. J

hdiat eastuentenl

25.

Hamilton MillerJM, Shah S. Deliciencies in microbiological quality and

labelling ot probiotic supplemet'ls.

ut200l

36, 223-7

lntl

Food

Mictobiol200L 1L 175 6.

Treatmenf lVofes - Helping children with bedwetting

Helping children with bedwetting, the latest in the Treatment Notes series, is now available. UK users can see the whole series at www.nelh.nhs.uk/treatmentnotes. For more information or for an order form to purchase Papet coPies, go to www.dtb.org.uk/dtb/tnotes, email dtb@which.co.uk or call0845 9830082.

Thank you to contributors: addendum

Last month's issue of DTBincluded a list of people whom we wished to thank for their major contribution to articles 2004 (DTB 2004; 42: 96).The list should have included Dr D wood, London and Dr T Khong, published we apologise to them for these omissions. London, and

it

*..tidu, Shi tltt Ptan.l,se ttst ffimns. l5s{.id. tditols, Helen Bamt 8ft rr, s.. t ct, ,lr8'L4 Sosfl Can 8&. #$.

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DTB

Vol

43

No

January 2005