Thus, inhibition of prostagiandin biosynthesis may be implicated as one of the
mechanisms involved in both the anti-inflammatory actions and gastrointestinal
inhibit prostagiandin production at the site of inflammation and not in the gastrointestinal tract.
mucosa and a reduction of prostagiandin concentrations in inflammatory exudates
collected from the same animals (Figure 3) (Whittle, Higgs, Eakins, Moncada &
Vane, 1980). The inhibition of gastric cyclo-oxygenase correlates closely with the
ulcerogenicity of these drugs. In contrast, sodium salicylate and BW755C, which
selectively reduce the generation of inflammatory prostaglandins without inhibiting
gastric mucosal cyclo-oxygenase, do have anti-inflammatory activity, yet are not
ulcerogenic. Thus, the development of anti-inflamrnatory compounds wh ich lack
topical irritancy and fail to inhibit prostagiandin production in the gastrointestinal
tract appears to be a feasible proposition. It is also possible that the gastrointestinal
side effects ofchronic corticosteroid administration are due to their interference with
arachidonic acid metabolism, although this area is less clearly defined than with the
Dual inhibitors ofarachidonic acid peroxidation are likely to have significant clinical
advantages over selective cyclo-oxygenase inhibitors, by avoiding the potentiation of
leucocyte migration and by having a greater effect on leucocyte-mediated responses
steroid treatment. Furthermore, the demonstration that prostagiandin synthesis can
be selectively inhibited in different tissues indicates that well-tolerated non-steroid
anti-inflarnmatory drugs can be produced.
The potential therapeutic importance of dual inhibitors is also indicated in the
BW755C does not have this effect (Adcock, Garland, Moncada &Salmon, 1978). It is
possible that the development of a drug wh ich is equi-active in inhibiting both
enzymes may be the next step in the evolution of non-steroid drugs for the treatment
ofchronic inflammation and bronchoconstriction.
Austen, K. (1978). Homeostasis of etTector systems which can also be recruited for immunologic
reactions. J. Immunol., 121, 793-805.
ANTI-I NFL AMM ATOR Y DR UGS 285
Bitensky, L., Cas hma n. B., Chaye n, J., Henderson, 8.. Higgs, G . A., Salmo n,J. A. & Vane, J. R.
Borgeat , P. & Samuelsson , B. (1 979). Arachidonic acid metabolism in polymorphonuclear
leuk ocytes. Effects ofiono phore A2 3187. Proc. Nat. Acad. Sei .. USA. 76,21 48-2152.
phases of granuloma development in the rat. Bioche m . Pharmac.. 28, 1581-1 586.
Bragt, P. C & Bonta, I. L. (1980). Indom eth acin inhibits th e formation of the lipox ygenase
Bray, M. A., Gordon, D. & Morley, J. (1975). Macrophages on intrauterine contrace ptive
devices produce prostaglandin s, Nature. 257, 227-228.
Brocklehurst, W. E. (1 967). Prop erti es which distinguish SRS-A from brad ykinin. In The Th ird
Brune, K., G latt, M., Kalin , H. & Peskar , B. A. (1 978). Pharma cological control of
prostagiandin and thromboxane release from macrophages. Nature, 274,261-263.
Chang, W. C, Murota, S-1. & Tsurufuji, S. (1977). Thromboxane B2 transformed from
arachidonic acid in carrageenin-induced granuloma. Prostaglandins, 13, 17-24.
Eakins, K. E., Higgs, G . A., Mon cada, S., Salmon, J. A. & Spayne, J. A. (1980 ). Th e effects of
arachidon ate lipoxygenase products on plasma exudation in rabb it skin. 1. Physiol.. in
Ferreira , S. H. (1972 ). Prostaglandins, aspirin-like drugs and analgesia. N ature, 240,200-203 .
H. pp . 348-398 . Handbook ofExperimental Pharmacology, 50/11. Springer Verlag.
Flower, R. J. & Blackwell, G . J. (1979). Anti-intlarnmatory steroids induce bio synthesis of a
phosph olipase A2 inhibitor which prevents prostagiandin generation. Na ture , 278,
Ford-Hutchinson , A. W., Bray, M. A. Shipley, M. E., Doig, M. V. & Sm ith , M. J. H. (1980).
Leu kotriene B: a biologicall y active release product of polymorphonuclear leuk ocytes. In
Goetzl, E. J. & Sun , F. F. (1979). Generat ion of un ique rnono-h ydro xy eicosatetraenoic acids
from arachidonic acid by human neutrophils. J. exp. Me d., 150,406-411.
Greaves, M. W. & McDonald-Gibson , W. J. (1972). Inhibition ofprostaglandin biosynthesis by
cortico-steroids. Brit. m ed. J.. 2,83-84.
Hamberg, M. & Samuelsson , B. (1 974). Prostagiandin endoperoxides. No vel transform at ions of
arachidonic acid in human platelets. Proc. Nat. Acad. Sei. US A. 71, 3400 -3404.
Harnberg, M., Svensson , J. & Sam uelsson, 8. (1975). Th rom boxanes: A new gro up of
biologicall y act ive compo unds derived from prostagiand in endo peroxi des. Proc. Nat .
Acad. Sei. USA. 72, 2994-2998.
Hammarstrom, S., Hamberg, M., Samuelsson , B., Duell, E. A., Staw iski, M. & Voorhees, J. J.
(1 975). Increased concentrations of free arachidonic acid, pro staglandins E2and FlQ and
of 12L-h ydroxy-5,8,1O,14-eicosatetraenoic acid (HETE) in epidermis of psoriasis: Evidence
286 G. A. HIGGS & B.J. R. WHITTLE
for perturbed regulation of arachidonic acid levels in psoriasis. Proc. Nat. Acad. Sei.
Higgs, E. A., Moncada, S. & Vane , J. R. (1978). Inflammatory effects ofprostacyclin (PGh) and
6-oxo-PGF, a in the rat paw . Prostaglandins, 16, 153-161.
Higgs, G. A., Bunting, S., Moncada, S. & Vane , J. R. (1976). Polymorphonuclear leukocytes
produce thromboxane As-likeactivity during phagocytosis. Prostaglandins, 12,749-757.
Higgs, G . A., Eakins, K. E., Mugridge, K. G ., Moncada, S. & Vane, J. R. (1980). The effects of
non-steroid anti-inflammatory drugs on leukocyte migration in carrageenin-induced
inflammation. Eur. J. Pharmac., 66,81-86
Higgs, G. A., Flower, R. J. & Vane, J. R, (1979). A new approach to anti-inflammatory drugs .
Biochem. Pharmac.. 28, 1959-1961. .
Higgs, G . A., McCall, M. E. & Youlten, L. J. F. (1975). A chemotactic role for prostaglandins
released from polymorphonuclear leukocytes during phagocytosis. Brit. 1. Pharmac.. 53,
Higgs, G . A., Moncada, S. & Vane , J. R. (1978). Prostacyclin reduces the number of 'slow
moving' leukocytes in hamster cheek pouch venules. 1. Physiol.. 280, 55-56p.
Humes, J. L., Bonney, R. J., Pelus, L., Dahlgren, M. E., Sadowski, S. J., Kuehl, F. A. & Davies,
P. (1977). Macrophages synthesise and release prostaglandins in response to inflammatory
stimuli. Nature, 269, 149-151.
Lewis, G. P. & Piper, P. J. (1975). Inhibition of release of prostaglandins as an explanation of
some ofthe actions ofanti-inflammatory cortico-steroids. Nature, 254, 308-311.
McCarty, J. & Goetzl, E. J. (1979). Stimulation of human T-Iymphocyte chemokinesis by
arachidonic acid . Celllmmuno/.. 43, 103-112.
Meacock, S. C. R. & Kitchen, E. A. (1979). Effects of the non-steroid anti-inflamrnatory drug
benoxaprofen on leukocyte migration. J. Pharm. Pharmac., 31, 366-370.
Moncada, S., Gryglewski, R. J., Bunting, S. & Vane, J. R. (1976). An enzyme isolated from
arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits
platelet aggregation. Nature. 263,663-665.
Moncada, S. & Vane, J. R. (1979). Pharmacology and endogenous roles of prostagiandin
endoperoxides, thromboxane A2 and prostacyclin. Pharmac.Rev.•30,293-331.
Morris, H. R., Taylor, G. W., Piper, P. J. & Tippins, J. R. (1980). Structure of slow-reacting
substance ofanaphylaxis from guinea-pig lung. Nature. 285, 104-106.
Murota, S-l., Kawamura, M. & Morita, 1. (1978). Transformation of arachidonic acid into
thromboxane B2 by the homogenates of activated macrophages. Biochim. Biophys. Acta,
Murphy, R. c., Hammarstrom, S. & Samuelsson, B. (1979). Leukotriene C: A slow-reacting
substance from murine mastocytoma cells . Proc. Nat. Acad.Sei. USA, 76,4275-4279.
Nugteren, D. A. (1975). Arachidonate lipoxygenase in blood platelets. Biochim. Biophys. Acta.
Orange, R. P. (1974). The formation of slow reacting substance of anaphylaxis in human lung
tissue. In Progress in lmmunology. 11, Vol. 4, ed. Brent, L. & Holborow, T., pp . 29-39.
Ryan, G . B. & Majno, G . (1977). Acute Inflammation. Am. J. Path., 86, 184-276.
Samuelsson, B., Goldyne, M., Granstrom, E., Hamberg, M., Hammarstrom, S. & Malmsten, C.
(1978). Prostaglandins and thromboxanes. Ann. Rev. Biochem.. 47,997-1029.
Schiffman, E., Corcoran, B. A. & Wahl, S. M. (1975). N-formylmethionyl peptides as
chemoattractants for leukocytes. Proc. Nat. Acad. Sei . U.S.A ., 72, 1059-1062.
Tateson, J. E., Moncada, S. & Vane, J. R. (1977). Effects ofprostacyclin (PGX) on cyclic AMP
concentrations in human platelets. Prostaglandins, 13,389-399.
Trang , L. E., Granstrom, E. & Lovgren, O. (1977). Levels of prostagiandin Fw E2 and
thromboxane B2injoint l1uidin rheumatoid arthritis. Scand. J. Rheumat.. 6, 151-154.
Turner, S. R., Tainer, J. A. & Lynn, W. S. (1975). Biogenesis of chemotactic molecules by the
arachidonate lipoxygenase system ofplatelets. Nature, 257,680-681.
Walker, J. R. & Dawson, W. (1980). Inhibitory effect ofbenoxaprofen and BW755C on rabbit
Schwarz, N. Lancaster: MTP Press, in press.
Walker, J. R., Smith, M. J. H. & Ford-Hutchinson, A. W. (1976). Anti-inl1ammatory drugs,
prostaglandins and leukocyte migration . Agents & Actions, 6, 602-606 .
Weksler, B. B., Knapp, J. M. & Jaffe, E. A. (1977). Prostacyclin (PGh) synthesised by cuItured
endothelial cells modulates polymorphonuclear leukocyte function . Blood, 50, Suppl. I,
Whittle, B. J. R. (1977). Mechanisms underl ying gastric mucosal damage induced by
indomethacin and bile salts, and the actions of prostagland ins. Brit. J. Pharmac., 60,
Whittle, B. J. R., Boughton-Smith, N. K., Moncada, S. & Vane, J. R. (1978). Actions of
prostacyclin (PGh) and its product, 6-oxo-PGF1a on the rat gastric mucosa in vivo and in
vitro. Prostaglandins, 15,955-967.
Whittle, B. J. R., Higgs, G. A., Eakins, K. E., Moncada, S. & Vane, J. R. (1980). Selective
inhibition of prostaglandin production in inl1ammatory exudates and gastric mucosa .
Williams, T. J. & Piper, P. J. (1980). The actions of chemically pure SRS-A on the
microc irculation in vivo. Prostaglandins, 19, 779-789
The non-steroidal anti-inflammatory drugs still form the mainstay of drug therapy
function and give considerable symptomatic relief.
A wide range of non-steroidal anti-inflammatory drugs is now available for use
(Table I). Classifying the sub-groups ofthis dass ofdrugs is difficult. The drugs have
much in common, they are all analgesic, in single dosage, and when given regularly
in ade quate dosage have an anti-inflammatory effect which develops over the course
Table 1 Non-steroidalanti-inflammatory drugs
i Salicylicacids: aspirin, diflunisal
ii Anthranilic acids: flufenamic,mefenamic
i Aryl aceticacids: alclofenac, diclofenac
ii Aryl proprionic acids: ibuprofen, flurbiprofen, ketoprofen,naproxen, fenoprofen
iii Heteroarylaceticacids: tolmetin, fenclozicacid
iv Indole and indene acetic acids: indomethacin, sulindac
v Benzoxazole derivatives: benoxaprofen
Phenylbutazone, oxyphenbutazone, azapropazone, feprazone
NON-STEROIDAL ANTI-INFLAMMATOR Y DRUGS 289
swelling in a number of rheumatic conditions (Champion, Day , Graham & Paull,
1975; Brooks & Buchanan, 1976), but significant differences between non-steroidal
anti-inflammatory drugs (NSAID) have been more difficult to demonstrate (Lee,
Anderson, Miller, Webb & Buchanan, 1976). The major differences between the
drugs often comes in their ability to produce side effects. Individual variation in
response to these drugs occurs (Huskisson, Woolf, Balrne, Scott & Franklin, 1976)
both in pain relief and the occurrence of side effects. Because of this a number of
NSAID often have to be tried before the appropriate one is found for that particular
patient and that particular rheumatic disease.
Salicylates are widely used for the treatment of rheumatic diseases desp ite weil
documented toxicity (Huskisson, 1977; Buchanan, Rooney & Rennie, 1979): The
recent development of enteric-coated and sustained release formulations have
enabled therapeutic plasma salic ylate levels to be maintained on a twice daily dosage
regime (Bensen, Laskin . Paton , Little & Farn , 1979). The newer ent eric-coated and
susta ined release salicylate preparations demonstrate good bioa vailability (Da y,
Paull, Champion & Graharn, 1976; Brooks, Roberts & Patel, 1978) and a reduced
incidence of gastric side effects and blood loss (Baum , 1970). Salicylate metabolism
has been found to be dose dependent (Levy, Tsuchiya & Amsel, 1972) and a great
variation in serum concentration and half-life of salicylate has been reported in
patients with rheumatoid arthritis (Paulus, 1970). Recently it has been shown that
These recent advances in our understanding of salicylate metabolism only
emphasize the importance of serum salicylate determination in planning the
optimum dosage regime for patients with arthritis.
The other major problem with aspirin apart from its variable metabolism is the
production ofside effects. These are seen particularly in the renal and gastro intestinal
systems. The question as to whether aspirin alone causes analgesic nephropathy
remains unanswered. There is no doubt that aspirin administration increases the
excretion of renal tublar cells (Scott, Denman & Dorling, 1963) and decreases renal
blood flow (Beeley & Kendall, 1971; Kimberly, Bowden , Keiser & Plotz , 1978), but
these changes are often transient (Brooks & Cossum, 1978). Isolated case reports have
linked analgesic nephropathy and the ingestion of aspirin alone but no correlation
has been found in prospective studies of pat ients with rheumatoid arthritis between
aspirin consumption and impairment ofrenal function (Macklon, Craft, Thompson
& Kerr, 1974; New Zealand Rheumatism Study , 1974).
There is no doubt that aspirin increases faecal blood loss. but the linking ofaspirin
ingestion and chronic peptic ulceration or acute gastrointestinal bleeding is less c1ear
(New Zealand Rheumatism Association, 1974; Levy, 1974). Th ere is no evidence that
healing rates for gastric ulcers are dela yed by the continued use of aspirin (Piper.
Greig, Coupland. Hobbin & Shinn ers, 1975) and similarly there is no evidence of an
increa sed incidence of gastrointestinal bleeding in gastric ulcer pati ent s given aspirin
(Wood, Scott & SI. 1. Dixon, 1961). Considering the number of aspirin tablets
consumed the problem ofgastric bleeding with this drug is relatively small and it may
be that the drug itself, being a source of dyspepsia (Capell , Rennie, Rooney,
Murdoch, Hole, Dick & Buchanan, 1979) dissuades its prolonged use in most subjects
susceptible to peptic ulceration.
With careful monitoring salicylates still have a place in the initial management of
acute and chronic rheumatic diseases. They can be extremely effective in reducing
pain and swelling particularly in rheumatoid arthritis and with the use of enteric-
coated or sustained release preparations simple regimes can be instituted to increase
compliance and reduce side etfects.
Potential drug interactions at protein binding sites may occur with salicylates and
anti-coagulants (Prescott, 1969) and oral hypoglycaemic agents (Anderson, 1977). In
practice drug interactions of a protein binding nature rarely have c1inical
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