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"'". .&JlA.LUI......,. ing the I ris o AIDs

-Rosie Stather-

The risks posed by NSAIDs on the gastrointestinal tract are well known. However, ways of minimising these risks are less clear. Can an effective prophylactic agent be found? Can new types of NSAIDs be developed that are less harmful to the gut? Where is the damage actually occurring? Answers to these, and other, questions were put forward at a session devoted to the risks and benefits of NSAIDs at the 10th World Congress of Gastroenterology [Los Angeks, USA; October 1994].

NSAID-induced gastric damage can occur in up to 30% of NSAID users, although many patients remain asymptomatic. However, the prcsence of even minimal damage increases the risk of serious complications. And with more than 20 million pre­scriptions for NSAIDs written each year in the UK alone, the problem is enormous.

As there is little in the way of alternative treatment, the search is on for an effective prophylactic agent against this type of gastric damage.

Famotidine prevents NSAID-indlKBl ulcers Researchers from the UK believe that famotidine

may be the answer. The results of a placebo­controlled, randomised study of famotidine suggest that the agent may be suitable for prophylactic use, said Dr N Hudson from Glasgow Royal Infirmary, UK. 1 This is the first time that an H2-antagonist has been shown to inhibit the development of both duodenal and gastric ulcers.

285 patients with osteoarthritis or rheumatoid arthritis, who had been receiving NSAIDs for at least 4 weeks, were recruited and randomised to receive placebo (n = 93), famotidine 20mg bid (95) or famotidine 40mg bid (97). None of the patients had an ulcer at baseline. The primary study endpoint was the development of a gastric or duodenal ulcer at either 1, 3 or 6 months.

Overall, famotidine reduced the incidence of ulceration from 25.8% (control rate) to 14.7% (20mg bid) and 9.3% (40mg bid) [see graph]. Both doses of famotidine were well tolerated.

Prevention of NSAID-related ulcers by lamotidine

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Selective COX-II inhibitors - a step forward? The hunt is on for new NSAIDs that exert bene­

ficial analgesic properties without causing damage to the GI tract. Selective cyclo-oxygenase (COX) II inhibitors have 'the potential to be gut-friendly',

5 Nov 111M INPHARMA-

SC-58125 - a new selective COX-II inhibitor

Searle has developed a selective COX-II inhibitor, SC-58125 [preclinical]. It has ICM! values of> 100 JUTloVL and 0.07 IlmoVL for COX-I and COX-II , respectively.2

Furthermore, SC-58125 has demonstrated analgesic and anli-inflammatory properties in Ihe rat model of carageenan·induced paw oedema. In this model, SC·58125 did not induce GI toxicity.

according to Professor John Wallace from the University of Calgary, Canada.

Two forms of the COX enzyme exist. These are COX-I and COX-II. COX-I is found predominantly in the stomach, intestine, kidney and platelets, while COX-II, a mitogen-inducible isoform of the COX enzyme, is present mainly in inflammatory cells. Thus, the adverse GI effects of NSAIDs probably occur via inhibition of COX-I. Selective inhibition of COX-II may inhibit proinflammatory prosta­glandins only, thereby reducing possible GI adverse effects.

'Sekctive COX-II inhibitors wiU not affect prostaglandin synthesis in the GI tract, and

therefore tll'e not expected to have an adverse effect on this organ, '

Professor John Wallace, University of Calgary, Canada

NSAID + NO donor goes eM)' 00 the nmcosa A new class of NSAIDs is in the development

pipeline: the nitrobutylester NSAID derivatives. These agents have a molecule attached that acts as a nitric oxide donor. The new compounds show the same beneficial effects as unmodified NSAIDs, with­out causing damage to the gut mucosa, Professor Wallace told delegates.

Nitrobutylester NSAID derivatives can deliver nitric oxide to the gut endothelium, which prevents leucocyte adhesion to the endothelium, and maintains blood flow in the gut mucosa. This action appears to offset the damaging effects commonly associated with NSAIDuse.

Studies in rats, examining acute gastric damage associated with flurbiprofen, ketoprofen and their nitrobutylester derivatives, have shown that the new derivatives produce markedly less damage in the short term, compared with either parent drug.

A 2-week study in rats, which looked at the use of diclofenac and its nitrobutylester derivative, nitrofenac, supported these results. In sharp contrast to diclofenac administration, which caused death due

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DRUG REACTIONS

to small bowel perforation in all rats by day 7, admin­istration of nitrofenac caused no mortality and no small bowel injury.

o

Nitrofenac

All derivatives studied so far in animals are equi­potent to their parent NSAID, and their pharmaco­kinetic properties are very similar. Thus, linking a nitric oxide donating group onto an NSAID does not appear to interfere with its desirable actions, but does appear to negate the effects of COX-I inhibition, consequently reducing the risk of mucosal injury, Professor Wallace concluded.

Where is the damage happening? Are we being misled by focusing un the sromach

and duodenum, when we are considering NSAID­induced gastric damage? Dr Ingvan Bjarnason from King's College, London, UK, believes we are. He asserts that the small intestine is the main site of both NSAID-related damage and clinically relevant complications.

'You have been led to believe that the stomach is the main site of damage from

NSAIDs, but this is not true. NSAIDs have a damaging effect on the whole

of the intestine.' Dr Ingvan Bjarnason. King s College.

London. UK

In the stomach, erosions are seen in 20-40% of patients taking NSAIDs. This figure is very similar for the rate of erosions in the small intestine. However, in NSAID users, the incidence of ulcers in the stomach is only 10-20%, compared with an incidence of 35~0% in the small intestine.

Erosions and ulcers indicate damage, but blood loss is more important from a clinical standpoint. Bleeding from erosions and ulcers in the stomach is very rare, with < 0.2% experiencing significant bleeding.

In contrast, 60% of patients taking NSAIDs experience bleeding in the small intestine, losing an average of 2-10ml of blood per day. This is clinically significant, since it contributes to iron-deficiency anaemia. Iron deficiency is evident in 50-70% of patients with rheumatoid arthritis who have anaemia of chronic disease.

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Strategies to minimise damage Dr Chris Hawkey from University Hospital,

Nottingham, UK, advocates the use of an evidence­based strategy for minimising the risk of NSAID­induced gastric damage. By analysing the available data he has identified 5 risk factors. These are:

• age ~ 60 years • past history of GI damage • high-dose NSAID regimen • use of a more toxic NSAID • concomitant use of steroids.

Patients that have one or more of these risk factors should be treated with agents associated with a low risk for GI damage. In numerous studies, ibuprofen has been shown to have a low risk compared with other NSAIDs. So, could all patients in need of NSAID treatment use ibuprofen? Dr Hawkey believes that many, but not all, patients could be switched.

How about using paracetamol? In osteoarthritis, studies have shown that paracetamol, an analgesic that causes no GI damage, is better than placebo for pain relief. However, it is not as good as comparator NSAIDs in efficacy studies. 'Widespread switching to paracetamol may be possible, but at the moment we do not have the evidence to support this view', Dr Hawkey stated.

When asked whether he believed that enteric coating reduces the risk of GI complications, Dr Hawkey referred to data indicating that short-term use of enteric-coated aspirin 'is magic in terms of reducing injury '. However, he cautioned that avail­able data for NSAIDs do not clearly show whether entcric coating reduces the risk of GI damage associated with the use of these agents.

What are the costs? Using available clinical knowledge, it should be

possible to have a significant impact on both the use of resources for NSAID treatment, and the incidence of adverse drug reactions (ADRs) seen with NSAID use, stated Dr Alan Maynard, Director of York University Centre of Health Economics, UK.

In general, there is evidence to suggest that some NSAID prescribing is inappropriate, and overall levels of NSAID prescribing could be reduced.

However, opinion and behaviour are very slow to change, even in the light of new data, said Dr Maynard. He added that, regrettably, 'clinical behaviour in the field of NSAID use continues to be inappropriate and damaging to patients '. 1. Hudson]\;. et al. Prevention of ]\;SAID-related gastric and duodenal ulcers by

famotidine. A placebo-controlled double-blind srudy. 10th World Congress of

Gastroenterology: abstr. 183. 1994 2. Morgan OW. Recent advances in

eicosanoid biosynthesis inbibitors of prostaglandin endoperoxide synthase.

phospholipase A2 and arachidonic acid release. Expert Opinion on InvcslIgational Drugs 3: 1063-1065. Oct 1994

INPHARMA" 5 Nov 1994

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