Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 22, 2007
Contents
COX-2 Inhibition in Gastroenterology and Rheumatolgy:
Current Challenges and Perspectives for the Future
Executive Editor: Angel Lanas
Editorial Pp. 2214
Mechanisms Underlying the Cardiovascular Effects of
COX Inhibition: Benefits and Risks Pp. 2215-2227
J. Martínez-González and L. Badimon
[Abstract]
Efficacy of the Newest COX-2 Selective Inhibitors
in Rheumatic Disease Pp. 2228-2236
H.S.B. Baraf
[Abstract]
Global Gastrointestinal Safety Profile of Etoricoxib
and Lumiracoxib Pp. 2237-2247
Y. Yuan and R.H. Hunt
[Abstract]
How to Advise Aspirin Use in Patients Who Need NSAIDs
Pp. 2248-2260
F. Sopena and A. Lanas
[Abstract]
Prevention of Cancer in the Upper Gastrointestinal
Tract with COX-Inhibition. Still an Option Pp. 2261-2273
P. Jiménez, A. García, S. Santander and
E. Piazuelo
[Abstract]
Current and Future Clinical Strategies in Colon Cancer
Prevention and the Emerging Role of Chemoprevention
Pp. 2274-2282
B. Boursi and N. Arber
[Abstract]
General Articles
Development of Novel Inhibitors Targeting Intracellular Steps
of Peptidoglycan Biosynthesis Pp. 2283-2309
M. Kotnik, P.Š. Anderluh and A. Preželj
[Abstract]
Cooling the Injured Brain: How Does Moderate Hypothermia
Influence the Pathophysiology of Traumatic Brain Injury
Pp. 2310-2322
J. Sahuquillo and A. Vilalta
[Abstract]
Abstracts
[Back to top]
Editorial: COX-2 Inhibition in Gastroenterology and
Rheumatolgy: Current Challenges and Perspectives for the Future
For the last two years the field of COX inhibition has been
involved in an intense and hot debate regarding the benefits
and risks associated with the use of these drugs. For years,
the benefits of these drugs were focused on the relief of
pain and inflammation of different rheumatic conditions and
the side effects on those located in the upper gastrointestinal
tract. The introduction of the COX-2 selective inhibitors
in the market brought new hope since the hypothesis was that
these drugs were as effective as non-selective NSAIDs in treating
rheumatic conditions, were associated with less gastrointestinal
(GI) side effects than non-selective NSAIDs and were potentially
useful in the treatment and prevention of different gastrointestinal
and non-gastrointestinal malignancies. It was one of those
long-term colon cancer prevention trials which showed that
the use of rofecoxib was associated with increased incidence
of vascular occlusive diseases vs. placebo [1]. Other studies
have now shown that the effect observed with rofecoxib was
not drug-specific, but extensive to all COX-2 selective inhibitors
and probably to all non-selective NSAIDs [2,3]. Furthermore,
the mechanisms behind these cardiovascular side effects are
far from being clear. The COX-2 selective inhibition of endothelial
derived prostacycline and the lack of inhibition of the COX-1
platelet dependent thromboxane synthesis do not fully explain
the cardiovascular side effects associated with coxibs or
non-selective NSAIDs.
Now, more than two years after the withdrawal of rofecoxib
from the market, there is a new situation and a new perspective
for the use of these compounds, where many questions that
were open then haven been, at least partially, answered. This
issue of the Current Pharmaceutical Design Journal is written
under the new perspective and focused on the effects of COX
inhibition in rheumatology, in the cardiovascular system and
overall in the gastrointestinal tract with an extensive update
of the information available for traditional NSAIDs, celecoxib,
rofecoxib and the newer coxibs available in the market. Under
the general title of “COX-2 INHIBITION IN GASTRO- ENTEROLOGY
AND RHEUMATOLGY: CURRENT CHALLENGES AND PERSPECTIVES FOR THE
FUTURE”, the first article is an extensive “in
deep” review up to June 2006 of our current knowledge
of the cardiovascular effect of COX-2 and/or COX-1 inhibition
including the clinical manifestations and the mechanisms involved
in those side effects. This article has been written by Prof.
Badimon’s group that have made seminal contributions
in the field of the cardiovascular system [4]. The next one
is written by Dr. Herbert Baraf, a renowned expert on the
rheumatology field, and it is mainly focused on the efficacy
of the newest COX-2 selective inhibitors (etoricoxib and lumiracoxib)
in patients suffering from different rheumatic conditions.
The article has put the information in clear perspective when
compared to non-selective NSAIDs and other COX-2 selective
inhibitors and taking into account the potential side effects
derived from their use [5]. From a GI perspective, Professor
Richard Hunt and Dr Yuan from MacMaster University have written
another extensive and outstanding review of the information
available for both lumiracoxib and etoricoxib [6].
One of the most difficult questions in clinical practice is
the management of patients who need NSAIDS and are taking
low-dose aspirin. This is a frequent clinical situation that
can be seen in more than 20% of patients who need NSAIDs.
The combination of these drugs increases the risk of GI complications
and probably the risk of developing cardiovascular side effects.
Dr Sopeña and myself have tried to put the issue in
perspective and come out with practical recommendations based
on the available evidence [7].
Two articles of this issue deal with the current situation
on chemoprevention of GI cancers. Dr Jimenez and colleagues
from Zaragoza, Spain, are currently working on potential chemoprevention
strategies. They have written an excellent and interesting
article on another difficult question which is whether COX-Inhibition
is still an option in the prevention of cancer of the upper
gastropintestinal tract. They have considered not only the
potential effects of COX-2 inhibition but also other potential
targets and agents related with COX-1 inhibition, the lypo-oxygenase
pathway and prostaglandin receptors [8]. Finally, the renowned
expert on GI cancer prevention, Nadir Arber, and colleague
from Israel review this field on colon cancer and face the
options available today under the perspective of the new data
available in chemoprevention [9].
References
[1] Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius
B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam
MA, Baron JA; Adenomatous Polyp Prevention on Vioxx (APPROVe)
Trial Investigators. Cardiovascular events associated with
rofecoxib in a colorectal adenoma chemoprevention trial. N
Engl J Med 2005; 352(11): 1092-10.
[2] Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal
anti-inflammatory drugs and risk of serious coronary heart
disease: an observational cohort study. Lancet 2002; 359(9301):
118-23.
[3] Chan AT, Manson JE, Albert CM, Chae CU, Rexrode KM, Curhan
GC, Rimm EB, Willett WC, Fuchs CS. Nonsteroidal antiinflammatory
drugs, acetaminophen, and the risk of cardiovascular events.
Circulation 2006; 113(12): 1578-87.
[4] Martinez-Gonzalez J, Badimon L. Cardiovascular effects
of COX-inhibition: Benefits and risks. Curr Pharm Des 2007;
13(22): 2215-2227.
[5] Baraf HS. Efficacy of the newest COX-2 selective inhibitors
in rheumatic disease. Curr Pharm Des 2007; 13(22): 2228-2236.
[6] Yuan Y, Hunt R. Global GI safety profile of etoricoxib
and the newest COX-2 selective inhibitors. Curr Pharm Des
2007; 13(22): 2237-2247.
[7] Sopeña F, l Lanas A. How do I advise patients who
take aspirin and need NSAIDs? Curr Pharm Des 2007; 13(22):
2248-2260.
[8] Jiménez P, García-Gonzalez MA, Santander
S, Piazuelo E. Prevention of Cancer in the Upper Gastropintestinal
Tract. COX-Inhibition: Still An Option?. Curr Pharm Des 2007;
13(22): 2261-2273.
[9] Boursi B, Arber N. Current and Future Clinical Strategies
in Colon Cancer Prevention. Focus on chemoprevention with
COX-inhibitors. Curr Pharm Des 2007; 13(22): 2274-2282.
Angel Lanas
Service of Gastroenterology
University of Zaragoza. University Clinic Hospital
Instituto Aragonés de Ciencias de la Salud, CIBERehd
Zaragoza Spain
[Back to top]
Mechanisms Underlying the Cardiovascular Effects of
COX Inhibition: Benefits and Risks
J. Martínez-González and L. Badimon
Selective inhibitors of cyclooxygenase-2 (COX-2) were designed
to minimize gastrointestinal complications of traditional
non-steroidal anti-inflammatory drugs (NSAIDs) attributed
to the suppression of COX-1-derived prostanoids. Selective
COX-2 inhibitors (coxibs) are effective anti-inflammatory
and analgesic drugs. However, recently it has become apparent
that some coxibs increase the risk of serious cardiovascular
events, including myocardial infarction and stroke. This has
led to the withdrawal of rofecoxib from markets and has raised
the concern about an inherent atherothrombotic risk of this
class of drugs. This question should be carefully analyzed
in the light of the current knowledge on COX-2 functions in
the cardiovascular system. COX-2 is regarded as an inducible
enzyme involved in the pathophysiology of inflammation and
pain. In the cardiovascular system, COX-2 has also been associated
with pro-inflammatory/pro-atherogenic stages, due to its up-regulation
in monocyte-derived macrophages present in atherosclerotic
lesions. However, experimental and clinical studies suggest
that COX-2 is "constitutively" expressed in some
tissues, among them in the vascular endothelium, where COX-2-derived
prostanoids, especially prostacyclin (PGI2),
contribute in the maintenance of vascular homeostasis and
integrity. This review provides an updated overview on the
functions of COX-2 in the cardiovascular system addressing
key issues that could help to understand why chronic COX-2
inhibition may have undesirable effects in patients at cardiovascular
risk.
[Back to top]
Efficacy of the Newest COX-2 Selective Inhibitors
in Rheumatic Disease
H.S.B. Baraf
Non-steroidal antiinflammatory drugs (NSAIDs) are standard
treatment for the pain and inflammation associated with arthritis.
Traditional NSAIDs and cyclooxygenase-2 (COX-2) selective
inhibitors exhibit comparable efficacy, with different safety
profiles. Traditional NSAIDs are associated with an increased
risk of serious gastrointestinal (GI) adverse events versus
COX-2 selective inhibitors, and chronic use frequently necessitates
adjunctive therapy with gastroprotective agents. COX-2 selective
inhibitors are often used in preference to avoid these GI
adverse events. Recent studies have raised the concern that
COX-2 selective inhibitors and traditional NSAIDs appear to
be associated with a higher incidence of thrombotic cardiovascular
events versus placebo. The key in prescribing these agents
is for the physician to take a proactive approach to patient
management and evaluation of GI and cardiovascular risk factors.
This review examines the role of the newest COX-2 selective
inhibitors, etoricoxib and lumiracoxib, in treating rheumatic
disease.
[Back to top]
Global Gastrointestinal Safety Profile of Etoricoxib
and Lumiracoxib
Y. Yuan and R.H. Hunt
Cyclo-oxygenase (COX)-2 selective inhibitors (coxibs) were
designed to reduce the incidence of gastrointestinal (GI)
adverse events (AEs) which occur with non-selective NSAIDs
(ns-NSAIDs). Etoricoxib and lumiracoxib are regarded as second
generation coxibs because of their higher COX-2 selectivity.
There are three published pooled analyses relating to the
GI tolerability of etoricoxib (60-120mg/day) and lumiracoxib
(200-400mg/day) which used individual patient’s data
from studies sponsored by the manufacturers. We also reviewed
new clinical trials published after the pooled analyses, to
determine the global GI safety profiles of etoricoxib and
lumiracoxib. We included discontinuations due to GI events,
endoscopic ulcers, symptomatic ulcers, and ulcer complications.
Current evidence suggests that etoricoxib and lumiracoxib
have significantly more favorable GI profiles than ns-NSAIDs,
and are similar to first generation coxibs with respect to
GI safety. The most clinically important benefit of the coxibs
is seen in the reduced rate of symptomatic ulcer and ulcer
complications, which are still common in chronic NSAIDs users
especially in high risk patients. In the largest GI outcome
study of any coxib, TARGET, involving more than 18000 patients,
lumiracoxib was associated with a 79% reduction in ulcer complications
in patients not taking aspirin. The differences between etoricoxib
or lumiracoxib and ns-NSAIDs in relation to ulcer complications
are apparent early during treatment and remain constant over
time during the course of treatment; therefore, benefit of
etoricoxib and lumiracoxib can be seen in patients with high
GI ulcer complication risk who require NSAIDs from the beginning
of use to throughout the prescription duration.
[Back to top]
How to Advise Aspirin Use in Patients Who Need NSAIDs
F. Sopena and A. Lanas
NSAIDs are widely used all over the world. NSAID use is rising
due to increasing availability without a prescription, use
of aspirin for prevention of thrombotic disorders and the
ageing population. Aspirin is used as an analgesic drug in
many countries, but the main current indication is low-dose
aspirin for the prevention of cardiovascular events. However,
NSAIDs and aspirin use account for approximately 20-25% of
all reported drug adverse events. Most of those are gastrointestinal
including dyspepsia, hemorrhage, perforation and even death.
The COX-2- selective inhibitors (coxibs) have demonstrated
equivalent efficacy to nonspecific NSAIDs in the management
of arthritis and pain but have less gastrointestinal adverse
events, although coxibs and probably all NSAIDs, significantly
increase risk of serious thromboembolic events. Concomitant
use of low-dose aspirin is present in more than 20% of all
patients taking either NSAIDs or coxibs, thus increasing the
risk of gastrointestinal side effects. Furthermore, at present,
it is not known whether aspirin decreases the cardiovascular
risks of COX-2 inhibitors or NSAIDs. Appropriate strategies
for gastrointestinal risk reduction with NSAIDs and aspirin
must consider the overall health status of our patients including
the presence of cardiovascular and gastrointestinal risk factors.
Use of the lowest possible dose of these drugs, gastroprotectants,
especially proton pump inhibitors and Helicobacter pylori
eradication will reduce the risk of gastrointestinal side
effects in patients taking low-dose aspirin and NSAIDs or
coxibs.
[Back to top]
Prevention of Cancer in the Upper Gastrointestinal
Tract with COX-Inhibition. Still an Option
P. Jiménez, A. García, S. Santander and
E. Piazuelo
Epidemiological studies have shown that the regular use of
nonsteroidal anti-inflammatory drugs (NSAIDs) is associated
with a reduction of gastrointestinal cancer risk. Since up-regulation
of COX-2 has been reported in different stages of the esophageal
and gastric carcinogenic sequence, the cyclooxygenase-2 selective
inhibitors (COXIBs) were considered a good alternative to
traditional NSAIDs since they cause less injury to the gastrointestinal
mucosa. However, recent chemoprevention trial data reporting
an increased risk of cardiovascular events have raised serious
concerns on the safety of COXIBs in chemoprevention strategies.
Moreover, low expression of COX-2 has been reported in a subset
of gastrointestinal cancers due to COX-2 methylation, indicating
that these patients could be less responsive to treatment
by specific COX-2 inhibitors. Furthermore, the COX-1 isoform
may have a potential role in the angiogenic process associated
with esophageal adenocarcinoma, which suggests that inhibition
of COX-1 may be another effective therapeutic target in upper
gastrointestinal cancer. Finally, lipoxygenase-derived products
may be increased following COX-inhibition due to shunting
of the arachidonic acid metabolism. Specifically, the 5-LOX
pathway seems to be relevant in gastrointestinal cancer development.
Taken together, these data indicate that a re-evaluation of
potential chemoprevention strategies for cancers of the upper
gastrointestinal tract needs to be considered.
[Back to top]
Current and Future Clinical Strategies in Colon Cancer
Prevention and the Emerging Role of Chemoprevention
B. Boursi and N. Arber
In the third millennium preventive medicine is becoming a
corner stone in our concept of health. Colorectal cancer (CRC)
fits the criteria of a disease suitable for prevention interventions.
It is a prevalent disease that is associated with considerable
mortality and morbidity rates, with more than 1,000,000 new
cases and 500,000 deaths annually. CRC has a natural history
of transition from precursor to malignant lesion that spans,
on average, 10-15 years, providing a window of opportunity
for effective interventions and prevention. Indeed, CRC is
preventable in up to 90% of the cases. Simple life style modifications
(balanced diet avoidance of smoking and alcohol, and moderate
physical activity) can prevent up to 50% of the cases of colorectal
cancer. compliance with current screening methods is a major
barrier to the achievement of optimal results, a large part
of the average risk population has not been screened by any
method. Several newly developed screening modalities, such
as the virtual colonoscopy and stool genetic testing may improve
compliance. In addition, chemoprevention, a new science that
has emerged during the last decade, presents an alternative
approach to reducing mortality from colorectal cancer as well
as other cancers. Chemoprevention involves the long-term use
of a variety of oral agents that can delay, prevent or even
reverse the development of adenomas in the large bowel. In
light of the recent evidence of the efficacy of chemoprevention
in persons at high risk for CRC cancer, it seems only appropriate
to consider similar strategies for the general population.
[Back to top]
Development of Novel Inhibitors Targeting Intracellular Steps
of Peptidoglycan Biosynthesis
M. Kotnik, P.Š. Anderluh and A. Preželj
The widespread emergence of pathogenic bacterial strains with
resistance to antibiotics is becoming a serious threat to
public health. Continuous development of novel antibacterials
therefore remains one of the biggest challenges to science
and unmet needs in the clinics. The biosynthetic pathway of
bacterial peptidoglycan, an essential building block of cell
walls, has been well studied and appears to be a rich source
of attractive enzyme targets for new antibacterials. We have
therefore reviewed the intracellular part of peptidoglycan
biosynthesis, including the enzymes GlmS, GlmM, GlmU for formation
of UDP-GlcNAc, subsequent pentapeptide synthesis by MurA-MurF,
and its connection to lipid carrier by MraY and MurG. Naturally
occurring inhibitors and the development of low-molecular
weight inhibitors of the intracellular part of peptidoglycan
synthesis are presented.
[Back to top]
Cooling the Injured Brain: How Does Moderate Hypothermia
Influence the Pathophysiology of Traumatic Brain Injury
J. Sahuquillo and A. Vilalta
Neither any neuroprotective drug has been shown to be beneficial
in improving the outcome of severe traumatic brain injury
(TBI) nor has any prophylactically-induced moderate hypothermia
shown any beneficial effect on outcome in severe TBI, despite
the optimism generated by preclinical studies. This contrasts
with the paradox that hypothermia still is the most powerful
neuroprotective method in experimental models because of its
ability to influence the multiple biochemical cascades that
are set in motion after TBI. The aim of this short review
is to highlight the most recent developments concerning the
pathophysiology of severe TBI, to review new data on thermoregulation
and induced hypothermia, the regulation of core and brain
temperature in mammals and the multiplicity of effects of
hypothermia in the pathophysiology of TBI. Many experimental
studies in the last decade have again confirmed that moderate
hypothermia confers protection against ischemic and non-ischemic
brain hypoxia, traumatic brain injury, anoxic injury following
resuscitation after cardiac arrest and other neurological
insults.
Many posttraumatic adverse events that occur in the injured
brain at a cellular and molecular level are highly temperature-sensitive
and are thus a good target for induced hypothermia. The basic
mechanisms through which hypothermia protects the brain are
clearly multifactorial and include at least the following:
reduction in brain metabolic rate, effects on cerebral blood
flow, reduction of the critical threshold for oxygen delivery,
blockade of excitotoxic mechanisms, calcium antagonism, preservation
of protein synthesis, reduction of brain thermopooling, a
decrease in edema formation, modulation of the inflammatory
response, neuroprotection of the white matter and modulation
of apoptotic cell death. The new developments discussed in
this review indicate that, by targeting many of the abnormal
neuro-chemical cascades initiated after TBI, induced hypothermia
may modulate neurotoxicity and, consequently, may play a unique
role in opening up new therapeutic avenues for treating severe
TBI and improving its devastating effects.
Furthermore, greater understanding of the pathophysiology
of TBI, new data from both basic and clinical research, the
good clinical results obtained in randomized clinical trials
in cardiac arrest and better and more reliable cooling methods
have given hypothermia a second chance in treating TBI patients.
A critical evaluation of hypothermia is therefore mandatory
to elucidate the reasons for previous failures and to design
further multicenter randomized clinical trials that would
definitively confirm or refute the potential of this therapeutic
modality in the management of severe traumatic brain injuries.
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