Research
Three studies have been published studies dealing with the efficacy of Deramaxx®, but to date, none dealing with questions of safety.
The following studies are ones that have studied Cox-2 inhibitors primarily in dogs along with some more general-purpose studies which have raised important questions about Cox-2 inhibitors. This is an area of considerable research because dogs are widely used in clinical trials for human drugs. Additional studies can be found at the National Center for Biotechnology Information database PubMed.
It is important in looking at these studies to remember that research in a lab dish often fails to be proven true when studied in the body of a living animal. Similarly, studies in one species of animal do not necessarily provide an understanding of what happens in another. Finally, it is important to note that none of the studies cited here dealt with Deramaxx®. The chemical structure of a drug plays an important role in how it is metabolized and how effective it is in reaching its target in the body.
A major question with Deramaxx® is how closely it parallels Celebrex chemical in terms of how it is metabolized.
The drugs are characterized this way by their manufacturer:
| Characteristic |
Deramaxx® (deracoxib) |
Celebrex® (celecoxib) |
| Empirical Formula |
C17-H14-F3-N3-03-S |
C17-H14-F3-N3-O2S |
| Molecular Weight |
397.38 |
381.38 |
| Chemical designation |
diaryl substituted pyrazole |
diaryl substituted pyrazole |
| benzenesulfonamide |
benzenesulfonamide |
|
| 4-[3-(difluoromethyl) |
3-(trifluoromethyl) |
|
| 5-(3-fluoro-4-methoxyphenyl) |
4-[5-(4-methylphenyl) |
|
| 1H-pyrazol-1-yl |
1H-pyrazol-1-yl |
CYP 450 Metabolic Pathway
Drug Metab Dispos 1999 Oct;27(10):1133-42
Evidence for polymorphism in the canine
metabolism of the cyclooxygenase 2 inhibitor, celecoxib.
Paulson SK, Engel L, Reitz B, Bolten S, Burton
EG, Maziasz TJ, Yan B, Schoenhard GL.
Department of Pharmacokinetics, Bioanalytical and Radiochemistry, G. D. Searle
& Co., Skokie, Illinois, USA. Susan.K.Paulson@monsanto.com
The pharmacokinetics of celecoxib, a cyclooxygenase-2 inhibitor, was characterized
in beagle dogs. Celecoxib is extensively metabolized by dogs to a hydroxymethyl
metabolite with subsequent oxidization to the carboxylic acid analog. There
are at least two populations of dogs, distinguished by their capacity to eliminate
celecoxib from plasma at either a fast or a slow rate after i.v. administration.
Within a population of 242 animals, 45.0% were of the EM phenotype, 53.5%
were of the PM phenotype, and 1.65% could not be adequately characterized.
The mean (+/-S.D.) plasma elimination half-life and clearance of celecoxib
were 1.72 +/- 0.79 h and 18.2 +/- 6.4 ml/min/kg for EM dogs and 5.18 +/- 1.29
h and 7.15 +/- 1.41 ml/min/kg for PM dogs. Hepatic microsomes from EM dogs
metabolized celecoxib at a higher rate than microsomes from PM dogs. The cDNA
for canine cytochrome P-450 (CYP) enzymes, CYP2B11, CYP2C21, CYP2D15, and
CYP3A12 were cloned and expressed in sf 9 insect cells. Three new variants
of CYP2D15 as well as a novel variant of CYP3A12 were identified. Canine rCYP2D15
and its variants, but not CYP2B11, CYP2C21, and CYP3A12, readily metabolized
celecoxib. Quinidine (a specific CYP2D inhibitor) prevented celecoxib metabolism
in dog hepatic microsomes, providing evidence of a predominant role for the
CYP2D subfamily in canine celecoxib metabolism. However, the lack of a correlation
between celecoxib and bufuralol metabolism in hepatic EM or PM microsomes
indicates that other CYP subfamilies besides CYP2D may contribute to the polymorphism
in canine celecoxib metabolism.
PMID: 10497139 [PubMed - indexed for MEDLINE]
J.Cell.Mol.Med. Vol 6, No 2, 2002 pp. 189-198
Cytochromes P450 and experimental models of drug metabolism
R. Zuber a,b *, Eva Anzenbacherová b, P. Anzenbacher a
a Department of Pharmacology, Faculty of Medicine
b Department of Medical Chemistry and Biochemistry, Faculty of Medicine, Palacky University at Olomouc, Czech Republic
For the development of new drugs, evaluation of drug-drug interactions with already known compounds, as well as for better understanding of metabolism pathways of various toxicants and pollutants, we studied the drug metabolism mediated by cytochromes P450. The experimental approach is based on animal drug-metabolising systems. From the ethical as well as rational reasons, the selection of an appropriate system is crucial. Here, it is necessary to decide on the basis of expected CYP system involved. For CYP1A-mediated pathways, all the commonly used experimental models are appropriate except probably the dog. On the contrary, the dog seems to be suitable for modelling of processes depending on the CYP2D. With CYP2C, which is possibly the most large and complicated subfamily, the systems based on monkey (Maccacus rhesus) may be a good representative. The CYP3A seems to be well modelled by pig or minipig CYP3A29. Detailed studies on activities with individual isolated CYP forms are needed to understand in full all aspects of inter-species differences and variations.
http://www.jcmm.org/reviste/06_02/pdf/4.pdf
Arch Biochem Biophys 1998 Sep 1;357(1):27-36
Expression and characterization of canine
cytochrome P450 2D15.
Roussel F, Duignan DB, Lawton MP, Obach RS, Strick CA,
Tweedie DJ.
Drug Metabolism Department, Molecular Sciences Department, Pfizer Inc., Eastern
Point Road, Groton, Connecticut 06340, USA. FROUSSEL@UTMB.EDU
CYP2D15 is the canine ortholog of human CYP2D6, the human CYP2D isoform involved
in the metabolism of drugs such as antiarhythmics, adrenoceptor antagonists,
and tricyclic antidepressants. Similar to human, canine CYP2D15 is expressed
in the liver, with detectable levels in several other tissues. Three different
CYP2D15 cDNA clones were obtained by RT-PCR from dog liver RNA. Two clones
corresponded to variant full-length CYP2D15 cDNAs (termed CYP2D15 WT2 and
CYP2D15 V1); the third was identified as a splicing variant missing exon 3
(termed CYP2D15 V2). Recombinant baculoviruses were constructed containing
full-length cDNAs and used to express CYP2D15 WT2 and CYP2D15 V1 in Spodoptera
frugiperda (Sf9) cells with expression levels of up to 0.14 nmol/mg cell protein.
As with human CYP2D6, the recombinant CYP2D15 enzymes exhibited bufuralol
1'-hydroxylaseand dextromethorphan O-demethylase activities whencoexpressed
with rabbit NADPH:P450 oxidoreductase. For bufuralol 1'-hydroxylase, apparent
Km values were 4.9, 3.7, and 2.5 microM and the Vmax values were 0.14, 0.034,
and 0.60 nmol/min/mg protein for dog liver microsomes, CYP2D15 WT2, and the
variant CYP2D15 V1, respectively. For dextromethorphan O-demethylase, apparent
Km values were 0.6, 0.6, and 2.0 microM and the Vmax values were 0.18, 0.034,
and 0.057 nmol/min/mg protein for dog liver microsomes, CYP2D15 WT2, and the
variant CYP2D15 V1, respectively. The human CYP2D6-specific inhibitor quinidine
and the rat CYP2D1-specific inhibitor quinine were both shown to be inhibitors
of bufuralol 1'-hydroxylase activity for dog liver microsomes, CYP2D15 WT2,
and the CYP2D15 V1 variant with nearly equal potency. Thus, the dog expresses
a CYP2D ortholog possessing enzymatic activities similar to human CYP2D6,
but is affected by the inhibitors quinine and quinidine in a manner closer
to that of rat CYP2D1. Copyright 1998 Academic Press.
PMID: 9721180 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9721180&dopt=Abstract
Drug Metab Dispos 1997 Oct;25(10):1130-6
In vitro comparison of cytochrome P450-mediated
metabolic activities in human, dog, cat, and horse.
Chauret N, Gauthier A, Martin J, Nicoll-Griffith DA.
Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec,
Canada.
As domestic animals such as cat, horse, and dog increasingly become the clinical
targets for drug discovery programs, the need to understand how these animals
metabolize xenobiotics becomes more important. In the present study, substrates
and inhibitors that were reported to be selective for particular P450 isozymes
were used as probes to study in vitro metabolism in horse, dog, cat, and human
liver microsomes. Seven selective catalytic activity markers for cytochrome
P450-mediated reactions were measured: phenacetin O-deethylase (P4501A1/2),
coumarin 7-hydroxylase (P4502A6), tolbutamide hydroxylase (P4502C8/9), S-mephenytoin
4'-hydroxylase (P4502C19), dextromethorphan O-demethylase (P4502D6), chlorzoxazone
6-hydroxylase (P4502E1), and testosterone 6beta-hydroxylase (P4503A4). Metabolic
activity was found in every species with each substrate. Under the conditions
of this study, it was observed that no one species was more active for any
given substrate. However, rather large interspecies differences were observed.
There was no marked sex difference in the way the various species metabolized
the different substrates. The effect of selective P450 inhibitors on the various
activities was tested with furafylline (P4501A2), mouse monoclonal antibody
inhibitory to CYP2A6, sulfaphenazole (P4502C9), tranylcypromine (P4502C19),
quinidine (P4502D6), diethyldithiocarbamate (P4502E1), and troleandomycin
(P4503A4). In most cases, these inhibitors were effective to varying degrees
against the activity seen in horse, dog, and cat liver microsomes. However,
even at high concentrations, furafylline did not inhibit phenacetin O-deethylase
activity in cat and troleandomycin did not affect testosterone 6beta-hydroxylase
activity in horse. Sulfaphenazole was not tested in dog and cat because of
the low tolbutamide hydroxylase activity. Overall, these results show that
there are also large interspecies differences in the way the selective P450
inhibitors affect the in vitro metabolism of the various substrates in horse,
dog, and cat liver microsomes.
PMID: 9321515 [PubMed - indexed for MEDLINE]
Clin Pharmacokinet 2000 Mar;38(3):225-42
Clinical pharmacokinetics and pharmacodynamics
of celecoxib: a selective cyclo-oxygenase-2 inhibitor.
Davies NM, McLachlan AJ, Day RO, Williams KM.
Faculty of Pharmacy, University of Sydney, New South Wales, Australia. ndavies@pharm.usyd.edu.au
Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), is the first specific
inhibitor of cyclo-oxygenase-2 (COX-2) approved to treat patients with rheumatism
and osteoarthritis. Preliminary data suggest that celecoxib also has analgesic
and anticancer properties. The selective inhibition of COX-2 is thought to
lead to a reduction in the unwanted effects of NSAIDs. Upper gastrointestinal
complication rates in clinical trials are significantly lower for celecoxib
than for traditional nonselective NSAIDs (e.g. naproxen, ibuprofen and diclofenac).
The rate of absorption of celexocib is moderate when given orally (peak plasma
drug concentration occurs after 2 to 4 hours), although the extent of absorption
is not known. Celexocib is extensively protein bound, primarily to plasma
albumin, and has an apparent volume of distribution of 455+/-166L in humans.
The area under the plasma concentration-time curve (AUC) of celecoxib increases
in proportion to increasing oral doses between 100 and 800mg. Celecoxib is
eliminated following biotransformation to carboxylic acid and glucuronide
metabolites that are excreted in urine and faeces, with little drug (2%) being
eliminated unchanged in the urine. Celecoxib is metabolised primarily by the
cytochrome P450 (CYP) 2C9 isoenzyme and has an elimination half-life of about
11 hours in healthy individuals. Racial differences in drug disposition and
pharmacokinetic changes in the elderly have been reported for celecoxib. Plasma
concentrations (AUC) of celecoxib appear to be 43% lower in patients with
chronic renal insufficiency [glomerular filtration rate 2.1 to 3.6 L/h (35
to 60 ml/min)] compared with individuals with healthy renal function, with
a 47% increase in apparent clearance. Compared with healthy controls, it has
been reported that the steady-state AUC is increased by approximately 40%
and 180% in patients with mild and moderate hepatic impairment, respectively.
Celecoxib does not appear to interact with warfarin, ketoconazole or methotrexate;
however, clinically significant drug interactions with fluconazole and lithium
have been documented. As celecoxib is metabolised by CYP2C9, increased clinical
vigilance is required during the coadministration of other substrates or inhibitors
of this enzyme.
PMID: 10749518 [PubMed - indexed for MEDLINE]
Renal Effects of Cox-2 Inhibitors
Hypertension 2002 Nov;40(5):721-8
Role of cyclooxygenase-2 in the prolonged
regulation of renal function.
Roig F, Llinas MT, Lopez R, Salazar FJ.
Departamento de Fisiologia, Facultad de Medicina, Murcia, Spain.
The role of cyclooxygenase-2 (COX-2) in the prolonged regulation of renal
function was evaluated during changes in sodium intake and reduction of NO
synthesis. It was evaluated in conscious dogs by administering a selective
inhibitor (nimesulide) during 8 consecutive days. Nimesulide administration
to dogs with normal or high sodium load did not modify glomerular filtration
rate but reduced renal blood flow (16%; P<0.05). The vasoconstriction elicited
by COX-2 inhibition was greater when NO production was inhibited because glomerular
filtration rate decreased by >25% when nimesulide was administered to dogs
with a reduced NO synthesis. During low sodium intake, COX-2 inhibition elicited
a decrease (P<0.05) of both glomerular filtration rate (34%) and renal
blood flow (31%). Sodium excretion only decreased (P<0.05) during the first
day of COX-2 inhibition in dogs with normal or high sodium load. The increase
in plasma potassium levels elicited by COX-2 inhibition was greater in dogs
with low sodium intake and was enhanced when NO production was inhibited.
This change in potassium was not secondary to a decrease in plasma aldosterone
levels. The results of this study suggest that COX-2-derived metabolites (1)
play a more important role in the long-term regulation of renal hemodynamic
when sodium intake is low, (2) protect the renal vasculature from the vasoconstriction
secondary to a reduction in NO, (3) are only acutely involved in regulating
urinary sodium excretion, and (4) play a more important role in regulating
plasma potassium concentration when NO synthesis is reduced.
PMID: 12411468 [PubMed - indexed for MEDLINE]
Am J Med Sci 2001 Mar;321(3):181-90
NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors
safe?
Eras J, Perazella MA.
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
06520-8029, USA.
Selective cyclooxygenase-2 (COX-2) inhibitors have provided relief for patients
suffering from chronic pain and other inflammatory conditions and have reduced
adverse gastrointestinal effects. The documented reduction in gastric erosions,
ulcerations, and perforations during the use of COX-2-selective inhibitors
raises the question: would the kidney be similarly spared? Our understanding
of these enzyme isoforms in the kidney is incomplete. However, kidney tissue
seems to possess "constitutive" or homeostatic COX-2 enzyme, suggesting
a role for prostaglandins produced by this isoform. In addition, studies evaluating
the renal effects of the selective nonsteroidal anti-inflammatory drugs (NSAIDs)
are inconclusive, and available data on the renal effects of COX-2-selective
inhibitors are conflicting. Inadequate numbers, varied baseline patient characteristics,
and different doses and lengths of drug treatment hampers comparison of the
small number of clinical investigations available for review. Therefore, this
article reviews the role of cyclooxygenase enzyme activity and associated
prostaglandins in the kidney and the adverse renal effects of nonselective
NSAIDs. We also touch on the COX-1/COX-2 selectivity of NSAIDs, the localization
of COX enzymes in kidneys, and clinical studies examining the renal effects
of selective COX-2 inhibitors.
PMID: 11269794 [PubMed - indexed for MEDLINE]
J Clin Invest, July 2002, Volume 110, Number
1, 61-69
Copyright ©2002 by the American Society for Clinical Investigation
Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II
Zhonghua Qi1, Chuan-Ming Hao1, Robert I. Langenbach2, Richard M. Breyer1,3, Reyadh Redha1, Jason D. Morrow1,3 and Matthew D. Breyer1,4,5
1 Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 2 Laboratory of Experimental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA 3 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 4 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 5 Veterans Administration Medical Center, Nashville, Tennessee, USA
Address correspondence to: Matthew D. Breyer, F-427 ACRE Building, Veterans Administration Medical Center, Nashville, Tennessee 37212, USA. Phone: (615) 327-4751 ext. 5492; Fax: (615) 343-7156; E-mail: Matthew.Breyer@mcmail.vanderbilt.edu.
Therapeutic use of cyclooxygenase-inhibiting (COX-inhibiting) nonsteroidal antiinflammatory drugs (NSAIDs) is often complicated by renal side effects including hypertension and edema. The present studies were undertaken to elucidate the roles of COX1 and COX2 in regulating blood pressure and renal function. COX2 inhibitors or gene knockout dramatically augment the pressor effect of angiotensin II (Ang II). Unexpectedly, after a brief increase, the pressor effect of Ang II was abolished by COX1 deficiency (either inhibitor or knockout). Ang II infusion also reduced medullary blood flow in COX2-deficient but not in control or COX1-deficient animals, suggesting synthesis of COX2-dependent vasodilators in the renal medulla. Consistent with this, Ang II failed to stimulate renal medullary prostaglandin E2 and prostaglandin I2 production in COX2-deficient animals. Ang II infusion normally promotes natriuresis and diuresis, but COX2 deficiency blocked this effect. Thus, COX1 and COX2 exert opposite effects on systemic blood pressure and renal function. COX2 inhibitors reduce renal medullary blood flow, decrease urine flow, and enhance the pressor effect of Ang II. In contrast, the pressor effect of Ang II is blunted by COX1 inhibition. These results suggest that, rather than having similar cardiovascular effects, the activities of COX1 and COX2 are functionally antagonistic.
This article has been cited by other articles:
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Am J Nephrol 2001 Jan-Feb;21(1):1-15
Renal effects of COX-2-selective inhibitors.
Brater DC, Harris C, Redfern JS, Gertz BJ.
Department of Medicine, Indiana University School of Medicine, Indianapolis
46202, USA. dbrater@iupui.edu
Although nonsteroidal anti-inflammatory drugs (NSAIDs) effectively treat a
variety of inflammatory diseases, these agents may cause deleterious effects
on kidney function, especially with respect to solute homeostasis and maintenance
of renal perfusion and glomerular filtration. NSAIDs act by reducing prostaglandin
biosynthesis through inhibition of cyclooxygenase (COX) which exists as two
isoforms (COX-1 and COX-2). NSAID-induced gastrointestinal toxicity is generally
believed to occur through blockade of COX-1 activity, whereas the anti-inflammatory
effects of NSAIDs are thought to occur primarily through inhibition of the
inducible isoform, COX-2. However, the situation in the kidney may be somewhat
different. Recent studies have demonstrated that COX-2 is constitutively expressed
in renal tissues of all species; this isoform may, therefore, be intimately
involved in prostaglandin-dependent renal homeostatic processes. Drugs that
selectively inhibit COX-2 might, therefore, be expected to produce effects
on renal function similar to nonselective NSAIDs which inhibit both COX-1
and COX-2. This assertion is borne out by recent clinical studies showing
that the COX-2 inhibitors rofecoxib and celecoxib procedure qualitative changes
in urinary prostaglandin excretion, glomerular filtration rate, sodium retention,
and their consequences similar to nonselective NSAIDs. It, therefore, seems
unlikely that these COX-2 inhibitors (and perhaps their successors) will offer
renal safety benefits over nonselective NSAID therapies, and, at this juncture,
it is reasonable to assume that all NSAIDs, including COX-2-selective inhibitors,
share a similar risk for adverse renal effects.
PMID: 11275626 [PubMed - indexed for MEDLINE]
Negative Effects of Cox-2 Inhibition
Am J Med 1999 Dec 13;107(6A):78S-88S; discussion 89S
Rationalizing cyclooxygenase (COX) inhibition
for maximal efficacy and minimal adverse events.
Freston JW.
Department of Medicine, University of Connecticut Health Center, Farmington
06030-2806, USA.
New information indicates that cyclooxygenase-2 (COX-2) is constitutively
expressed in several tissues, including brain, lung, pancreas, kidney, and
ovary, and plays an important role in renal and gastrointestinal function.
Selective COX-2 inhibition has been associated in animal studies with impairment
of ulcer healing and renal function and inhibition of prostacyclin, an effect
that inhibits vasodilation without inhibiting platelet aggregation. The clinical
consequences, if any, of these effects remain to be determined in long-term
studies in humans. The premise that selective COX-2 inhibitors will cause
less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that
inhibit both COX isoforms needs to take into account the low toxicity of nabumetone.
The gastrointestinal safety profile of this nonacidic, dual COX inhibitor
that does not undergo enterohepatic circulation has been evaluated in extensive
clinical trials. The data submitted to the US Food and Drug Administration
in the New Drug Application for nabumetone (Relafen), the comparative trials
subsequently completed, the published databases of the comparative gastrointestinal
toxicity of various nonsteroidal anti-inflammatory drugs (NSAIDs), and the
meta-analysis published in this issue of The American Journal of Medicine
(Schoenfeld, page 48S) indicate that nabumetone has the lowest incidence of
gastrointestinal toxicity among the extensively studied NSAIDs. Overall, the
incidence is approximately 10-fold less than with comparator drugs. This rate
is an appropriate current reference against which the gastrointestinal toxicity
of COX-2 inhibitors can be compared.
PMID: 10628597 [PubMed - indexed for MEDLINE]
Curr Med Chem 2000 Nov;7(11):1121-9
Cyclooxygenase-2 inhibition and side-effects of non-steroidal anti-inflammatory
drugs in the gastrointestinal tract.
Meyer-Kirchrath J, Schror K.
Institut fur Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universityf,
Dusseldorf, Germany.
Inhibition of prostaglandin biosynthesis via inhibition of the fatty acid
cyclooxygenase (COX) is the mechanism of action of non-steroidal anti-inflammatory
drugs (NSAIDs). This results in an inhibition of the inflammatory and pain-producing
activities of prostaglandins at a site of tissue injury but also in inhibition
of prostaglandin production in the gastrointestinal tract (GI) and platelets,
i.e. sites where endogenous prostaglandins are possibly involved in control
of physiological functions. The discovery of two COX isoenzymes, COX-1 and
COX-2, and the detection of their separate function and regulation, has initiated
the search for new and putatively more selective inhibitors of prostaglandin
biosynthesis. Specifically, selective inhibitors of COX-2 were developed in
order to improve the anti-inflammatory and analgetic specificity and potency
of the compounds and to reduce side-effects in the GI tract. Available experimental
and clinical data of selective COX-2 inhibitors, including flosulide, celecoxib
or rofecoxib, suggest improved gastric tolerance as compared to conventional,
non-selective NSAIDs. However, experimental evidence suggests that both, the
analgetic and anti-inflammatory action of COX-inhibitors, might also require
inhibition of COX-1. COX-2-selective compounds at anti-inflammatory doses
might have other side-effects, and for example reduce vascular prostacyclin
production. Evidence is accumulating that COX-2 might not only be considered
as a putatively detrimental enzyme but rather a highly regulated enzyme that
also contributes to tissue protection and is even constitutively expressed
in healthy human stomach mucosa. This paper reviews some of these newer aspects
of COX-2-selective inhibitors in clinical use and discusses their possible
benefits and risks.
PMID: 11032962 [PubMed - indexed for MEDLINE]
J Pharmacol Exp Ther 2002 Feb;300(2):367-75
Cyclooxygenase-2--10 years later.
Hinz B, Brune K.
Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich
Alexander University Erlangen-Nurnberg, Erlangen, Germany. hinz@pharmakologie.uni-erlangen.de
The enzyme cyclooxygenase (COX) catalyzes the first step of the synthesis
of prostanoids. In the early 1990s, COX was demonstrated to exist as two distinct
isoforms. COX-1 is constitutively expressed as a "housekeeping"
enzyme in most tissues. By contrast, COX-2 can be up-regulated by various
pro-inflammatory agents, including lipopolysaccharide, cytokines, and growth
factors. Whereas many of the side effects of nonsteroidal anti-inflammatory
drugs (NSAIDs) (e.g., gastrointestinal ulceration and bleeding, platelet dysfunctions)
are caused by a suppression of COX-1 activity, inhibition of COX-2-derived
prostanoids facilitates the anti-inflammatory, analgesic, and antipyretic
effects of NSAIDs. During the past few years specific inhibitors of the COX-2
enzyme have emerged as important pharmacological tools for treatment of pain
and arthritis. However, although COX-2 was initially regarded as a source
of pathological prostanoids only, recent studies have indicated that this
isoenzyme mediates a variety of physiological responses within the organism.
The present review assesses recent advances in COX-2 research, with particular
emphasis on new insights into pathophysiological and physiological functions
of this isoenzyme.
PMID: 11805193 [PubMed - indexed for MEDLINE]
Pharmacol Res 2001 May;43(5):429-36
Anti-inflammatory drugs: new multitarget
compounds to face an old problem. The dual inhibition concept.
Celotti F, Laufer S.
Institute of Endocrinology, University of Milano, Italy. fabio.celotti@unimi.it
In this short review we have tried to focus on some new relevant aspects of
the pharmacological control of inflammation. The clinical availability of
new drugs able to produce a selective inhibition of type 2 cyclooxygenase
(COX-2), the enzyme thought to be mainly responsible for generating arachidonic-acid-derived
inflammatory mediators, has been the origin of much hope. However, expectations
of having an effective and completely safe non-steroidal anti-inflammatory
drug (NSAID) have been only partially fulfilled. Emerging information has
challenged some aspects of the original hypothesis indicating COX-2 as devoid
of 'housekeeping' physiological functions. Moreover, the recently available
clinical studies have indicated only a relatively small improvement in the
tolerability of the newer 'selective' COX-2 inhibitors over the classical
COX-1/COX-2 mixed type NSAIDs. The new appreciation of the role of other arachidonic
acid derivatives, the leukotrienes (LTS), in producing and maintaining inflammation
has generated considerable interest in drugs able to block LTS receptors or
to produce a selective inhibition of 5-lipoxygenase (5-LO), the initial key
enzyme of the leukotriene pathway. These drugs are now included among the
effective therapies of asthma but appear, in the few clinical studies performed,
to be an insufficient single therapeutic approach in other inflammatory diseases.
Drugs able to block equally well both COX and 5-LO metabolic pathways (dual
inhibitors) have been developed and experimentally evaluated in the last few
years, but none are available on the market yet. The pharmacological rationale
at the basis of their development is strong, and animal studies are indicative
of a wide range of anti-inflammatory activity. What appears most impressive
from the available studies on dual inhibitors is their almost complete lack
of gastric toxicity, the most troublesome side effect of NSAIDs. The mechanism
of the gastric-sparing properties of these drugs is not yet completely understood;
however, it appears that leukotrienes significantly contribute to gastric
epithelial injury particularly when these compounds represent the major arachidonic
acid derivatives present in the gastric mucosa after inhibiton of prostanoid
production. Copyright 2001 Academic Press.
PMID: 11394934 [PubMed - indexed for MEDLINE]
BioDrugs 2001;15(1):1-9
Potential adverse effects of cyclooxygenase-2
inhibition: evidence from animal models of inflammation.
Colville-Nash PR, Gilroy DW.
Department of Experimental Pathology, St Bartholomew's and The Royal London
School of Medicine and Dentistry, Charterhouse Square, London, England.
Cyclooxygenase (COX; prostaglandin H synthase, prostaglandin endoperoxidase)
is the key enzyme in the synthesis of the prostaglandin and thromboxane families
of eicosanoid mediators, and is the target for the nonsteroidal anti-inflammatory
drugs (NSAIDs). The identification of an inducible COX isoform, COX-2, and
the demonstration of its specific expression at sites of inflammation suggested
that it may provide a useful therapeutic target for novel anti-inflammatory
drugs. Inhibition of an enzyme that is not expressed in most healthy tissues
would potentially avoid most of the adverse effects associated with NSAIDs,
which target a constitutively expressed isoform, COX-1. The development of
novel 'super aspirins' with high selectivity towards the inhibition of COX-2
showed that this hypothesis was well-founded and that high levels of these
drugs could be tolerated without these serious adverse effects. The first
two of these new generation NSAIDs, celecoxib and rofecoxib, are now in clinical
use.
More recently, however, concern has been expressed that COX-2 inhibition may in fact have a number of potential, previously hidden, pitfalls. These have arisen from the demonstration that COX-2 induction is not exclusively associated with the onset of an inflammatory reaction, with expression limited to inflammatory sites. In fact, COX-2 is expressed more chronically, and is also seen during the resolution of inflammation and in areas of wound-healing. The application of COX-2-selective inhibitors during these periods has been shown to be deleterious in that resolution of inflammation is delayed, gastric ulcer healing is delayed and, in some patients, ulcers have been shown to progress further to perforation. The suggestion has now been made that, in these situations, COX-2 may help resolve the pathology, perhaps by generating alternative series of prostaglandins such as the cyclopentenone prostaglandins. The finding that these prostaglandins can affect proteins by direct chemical modifications as well as having their own receptor families has rekindled debate on the deleterious and beneficial effects of prostanoids, and the implications of inhibiting the production of these mediators, in the body. Therefore, in this review we discuss the role of COX-2 in inflammation and the potential adverse effects of its inhibition.
PMID: 11437671 [PubMed - indexed for MEDLINE]
CMAJ 2002 Nov 12;167(10):1131-7
The double-edged sword of COX-2 selective
NSAIDs.
Wright JM.
Dr. Wright is with the Departments of Pharmacology and Therapeutics and of
Medicine, University of British Columbia, Vancouver Hospital, UBC site, Vancouver,
BC.
THE LAUNCH OF THE CYCLOOXYGENASE-2 (COX-2) selective NSAIDs was based on 2
hypotheses: (1) the major adverse effects limiting the usefulness of nonselective
NSAIDs are gastrointestinal in nature and (2) COX-2 selective NSAIDs are associated
with fewer gastrointestinal adverse effects than nonselective NSAIDs. At the
time of the launch, neither of these hypotheses had been proven and, as documented
in this review, both remain uncertain. The increased incidence of total and
nongastrointestinal serious adverse events, with the COX-2 selective NSAIDs
as compared with nonselective NSAIDs, in the Celecoxib Long-term Arthritis
Safety Study (CLASS) and the Vioxx Gastrointestinal Outcomes Research (VIGOR)
study remains a major concern. The increased morbidity associated with the
COX-2 selective NSAIDs may be a manifestation of the COX-2 selectivity of
rofecoxib and celecoxib or the supramaximal doses of these drugs used in the
trials. Proof that the increased harm was not caused by the COX-2 selectivity
of the drugs depends on demonstration in a randomized controlled trial that
COX-2 selective NSAIDs at usual doses are as effective as nonselective NSAIDs
and cause fewer gastrointestinal serious adverse events without increasing
the incidence of total nongastrointestinal serious adverse events.
PMID: 12427705 [PubMed - in process]
Am J Med 2001 Feb 19;110 Suppl 3A:6S-12S
Efficacy of cyclooxygenase-2-specific inhibitors.
Cannon GW, Breedveld FC.
Veterans Affairs Medical Center, and the Division of Rheumatology, Department
of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1
(COX-1) and cyclooxygenase-2 (COX-2). The clinical efficacy of NSAIDs is primarily
related to the inhibition of COX-2 activity, whereas much of the toxicity,
particularly gastrointestinal toxicity, is related to COX-1 inhibition. In
vitro and in vivo assays indicate that both COX-2-specific inhibitors and
conventional NSAIDs are equally effective in inhibiting COX-2, suggesting
that the clinical efficacy of COX-2-specific inhibitors should be similar
to that of conventional NSAIDs. Multiple studies in patients with osteoarthritis,
rheumatoid arthritis, and acute pain have now confirmed that the clinical
efficacy of COX-2-specific inhibitors is similar to that of conventional NSAIDs.
PMID: 11173044 [PubMed - indexed for MEDLINE]