|
Showing 1 - 6 of
6 matches in All Departments
In the two decades since the elusive "slow reacting substance of
anaphylaxis" (SRS-A) was identified as a product of the action of
the 5-lipoxygenase enzyme on arachidonic acid, it has been well
established that the leukotrienes are key mediators of both alIergy
and inflammation. Their release by alIergen or other challenge has
been demonstrated in the lungs of asthmatic subjects, and
measurement of urinary leukotriene concentrations in such patients
has been shown to be a valuable, non invasive indicator.
Significant progress has been made towards the characterization of
the leukotriene receptor subtypes, exemplified by the cloning of
the LTB4 receptor earlier this year. Coupled with this there has
been a continued elucidation of signal transduction mechanisms
underlying receptor activation. Consequent upon these advances has
been the development of potent antagonists of the CysLT receptor, J
and both these and inhibitors of leukotriene biosynthesis have
entered clinical practice in the therapy of asthma. In this
clinical setting antagonists of the CysLTJ receptor have been shown
to be an effective therapy in chronic asthmatics, against antigen-
and exercise-induced bronchoconstriction, and in aspirin-intolerant
asthmatics. The advent of this new class of agents promises to
change the way in which asthmatic patients are currently treated."
The mainstay of therapy for rheumatoid disease is the non-steroid
antiinflammatory drugs (NSAIDs), despite their inherent
gastrointestinal toxicity and ability to cause renal damage in
susceptible patients. The theory that the beneficial and toxic
effects of NSAIDs stem from a reduction in prostanoid production
through inhibition of cyclooxygenase implied that particular
toxicities were inevitable with NSAIDs and would always be
correlated with efficacy. However, over the years, it became
apparent that at therapeutic doses, some NSAIDs had greater toxic
side-effects than others, a fact not explained by the general
theory. A significant clarification arose from the discovery that
there are two distinct isoforms of COX, a constitutive enzyme
(COX-I) responsible for the production of prostanoids necessary for
platelet aggregation and protection of the gastric mucosa and
kidney; and an inducible enzyme (COX-2) that is newly synthesized
at sites of tissue damage and produces prostaglandins that manifest
pathological effects. It became clear that different NSAIDs had
greater or lesser effects on COX-I when used in therapeutic doses,
explaining the variation in side-effects. ' The elucidation of the
crystal structure of these different enzymes and the skills of
medicinal chemists have led to the synthesis of new chemicals with
a selectivity for the inducible enzyme, and thus with therapeutic
efficacy without those toxic effects result ing from inhibition of
the constitutive enzyme.
For the past 100 years the mainstay of therapy for rheumatoid
arthritis (RA) has been aspirin or other drugs of the non-steroid
anti-inflammatory group. In 1971 Vane pro posed that both the
beneficial and toxic actions of these drugs was through inhibition
of prostaglandin synthesis. The recent discovery that
prostaglandins responsible for pain and other symptoms at
inflammatory foci are synthesized by an inducible cyclooxygenase
(COX-2) that is encoded by a gene distinct from that of the consti
tutive enzyme (COX-I) provided a new target for therapy of RA. A
drug that would selectively inhibit COX-2 would hopefully produce
the symptomatic benefit provided by existing NSAIDs without the
gastrointestinal and renal toxicity due to the inhibition of COX-I.
Drugs selective for COX-2 are now available. Experimental studies
have shown them to be effective with minimal toxicity, and in
clinical trials gastric and renal toxicities are less. Highly
selective COX-2 inhibitors, perhaps designed with knowledge of the
crystal structures of COX-I and COX-2, are also available. Other
experimental studies, including those in animals lacking effective
genes for COX-lor COX-2 and in experimental carcinomas, suggest
there is still much to be learned of the pathophysiological
functions of these enzymes. The inflammatory response is a complex
reaction involving many mediators that derive from white blood
cells, endothelial cells and other tissues. Preliminary data have
revealed that inhibitors of the cytokines and adhesion molecules
that play a crucial role in the migration of white cells to
inflammatory sites may be useful in RA.
In 1971, Vane proposed that the mechanism of action of the
aspirin-like drugs was through their inhibition of prostaglandin
biosynthesis. Since then, there has been intense interest in the
interaction between this diverse group of inhibitors and the enzyme
known as cyclooxygenase (COX). It exists in two isoforms, COX-l and
COX-2 (discovered some 5 years ago). Over the last two decades
several new drugs have reached the market based on COX-l enzyme
screens. Elucidation of the three-dimensional structure of COX-l
has provided a new understanding for the actions of COX inhibitors.
The constitutive isoform of COX, COX-l has clear physiological
functions. Its activation leads, for instance, to the production of
prostacyclin which when released by the endothelium is
anti-thrombogenic and anti-atherosclerotic, and in the gastric
mucosa is cyto protective. COX-l also generates prostaglandins in
the kidney, where they help to maintain blood flow and promote
natriuresis. The inducible isoform, COX-2, was discovered through
its activity being increased in a number of cells by pro
inflammatory stimuli. A year or so later, COX-2 was identified as a
distinct isoform encoded by a different gene from COX-I. COX-2 is
induced by inflammatory stimuli and by cytokines in migratory and
other cells. Thus the anti-inflammatory actions of non-steroid
anti-inflammatory drugs (NSAIDs) may be due to the inhibition of
COX-2, whereas the unwanted side-effects such as irritation of the
stomach lining and toxic effects on the kidney are due to
inhibition of the constitutive enzyme, COX-I.
In the two decades since the elusive "slow reacting substance of
anaphylaxis" (SRS-A) was identified as a product of the action of
the 5-lipoxygenase enzyme on arachidonic acid, it has been well
established that the leukotrienes are key mediators of both alIergy
and inflammation. Their release by alIergen or other challenge has
been demonstrated in the lungs of asthmatic subjects, and
measurement of urinary leukotriene concentrations in such patients
has been shown to be a valuable, non invasive indicator.
Significant progress has been made towards the characterization of
the leukotriene receptor subtypes, exemplified by the cloning of
the LTB4 receptor earlier this year. Coupled with this there has
been a continued elucidation of signal transduction mechanisms
underlying receptor activation. Consequent upon these advances has
been the development of potent antagonists of the CysLT receptor, J
and both these and inhibitors of leukotriene biosynthesis have
entered clinical practice in the therapy of asthma. In this
clinical setting antagonists of the CysLTJ receptor have been shown
to be an effective therapy in chronic asthmatics, against antigen-
and exercise-induced bronchoconstriction, and in aspirin-intolerant
asthmatics. The advent of this new class of agents promises to
change the way in which asthmatic patients are currently treated."
This volume is the proceedings of the William Harvey Research
Conference held in Cannes, France, on the 20th and 21st March,
1997. It describes the present knowledge of the structures of the
cyclooxygenase isoforms and the experimental and clinical effects
of selective inhibitors of cyclooxygenase-2. The pathophysiological
significance of the cyclooxygenase enzymes in tumorigenesis,
programmed cell death, vascular disease and asthma is also covered.
|
You may like...
Loot
Nadine Gordimer
Paperback
(2)
R398
R330
Discovery Miles 3 300
|