CHANCE TO FACE NSAIDs THREATENING?
Studio Eutropi, Patologia Clinica e Nutrizione, Via
Pompei 46, Ardea 00040, RM, Italy.
Anti-Inflammatory Drugs (NSAIDs), are widely used as first line of defense
against most of acute and chronic inflammatory diseases. However, in spite of
their apparent safer profile, as compared to steroids, they can also drive
into moderate and severe reactions. Since the very beginning foremost
concerns have been focused on the Gastric Damage coming from the inhibition
of COX-1 derived prostaglandins, which were found to play a fundamental
protective action on the overall stomach homeostasis . Thereafter indeed,
most efforts to improve NSAIDs therapeutic proficiency were aimed at
counteracting upper Gastrointestinal (GI) adverse reactions.
In this regard, the
concomitant administration of Proton Pump Inhibitors (PPI) in a way of
reducing hyperacidity and consequently counterbalancing the associated
incidence of heartburn, ulcers and bleeding, was one of the first and till
nowadays most used approaches. Nonetheless, in spite of the actual clinical
benefit in terms of gastric disturbances, on the other hand it has been
noticed that long term treatment with PPI might lead to
an impairment on minerals and vitamins absorption  as well as on enteric
microbiota equilibrium , driving therefore into many other systemic
In order to bypass such
adverse events, a parallel approach, triggering alternative compensatory
mechanisms while avoiding to negatively impact on Calcium and microbiota
homeostasis, was pursued by developing novel NSAID molecules harboring a
Nitric Oxide (NO) releasing moiety. Upon endogenous enzymatic cleavage, the
NO releasing moiety would provide a series of favorable compensatory actions
to preserve gastric safety . These dual action hybrid molecules, belonging
to a new class of drugs called CINODs (COX Inhibitors Nitric Oxide Donors),
were encouraging in fact large expectations.
However, a third
approach in parallel faced the problem from a different and apparently much
clever and radical point of view. Rather than triggering compensatory
mechanisms to counteract NSAIDs derived Gastric Damage the novel strategy
developed a new class of NSAIDs with a very specific Cycloxygesase inhibitory
activity: active on COX2 but not on COX1. In such a way the novel chemical
entities would retain anti-inflammatory actions by inhibiting COX2 while on
the other side they would be deprived of GI concerns as unable to inhibit the
beneficial COX1 derived Prostaglandins in the stomach. As a matter of fact,
given the early successful results from this third approach, at that time
CINODs became much less attractive and their development was almost
short after that it was noticed that following chronic treatment with COXIBs
it was registered a relevant increase on severe and fatal cardiovascular
events. Indeed, as later emerged from several studies it was realized that
whereas COX2 specific inhibitors might indeed provide a better upper GI
safety profile, on the other hand, within the vascular environment it might
be deleterious mainly in patients suffering from endothelial dysfunction .
At this point,
reconsidering the ubiquitous regulatory potential of NO, it resulted
opportune to “rescue” CINODs. Actually favorable NO compensatory mechanisms
are not limited to the upper GI Tract but also on the Vascular Bed. A
balanced COX inhibition while providing exogenous NO donation may grant a
much safer Cardio-Vascular profile . Moreover an adequate NO releasing
pattern could provide an extra benefit by synergizing with the
anti-inflammatory actions from the NSAID parent drug [7,8]. Unfortunately however,
spitefully of the very strong rational and the large and robust preclinical
evidence, the favorable results obtained on the main clinical trial carried
out by a relative small biotech (NicOx Spa)  were not convincing enough to
the FDA and were soliciting for further investment. An adequately extended
population size, a more appropriate identification of patients subpopulation
target as well as much more accurate definition of clinical end points and
biomarkers, would be strongly recommended in order to unequivocally convince
regulatory authorities. Moreover, last but not least, further attention
should be also invested on the incidence and relevance of NSAIDs adverse
effect on the Lower Intestinal Tract. Contrary to PPI co-administration and
COXIBs approaches, CINODs might exhibit a much safer profile in terms of
NSAIDs derived Lower Intestinal Damage , avoiding therefore many other
associated systemic disturbances.
It is obvious that
facing such kind of extended and complex clinical trials is an endeavor that
might require great investments, but on the other side continuing to face
huge NSAIDs adverse effects is certainly much more expensive in all sense to
the whole society.
altogether the strong scientific rational, the robust preclinical data and
the favorable clinical results so far collected, it might worth wondering
whether to further pursue the NO approach in order to globally face the insidious
and large spectrum of NSAIDs threatening.
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