COX-2 Inhibitors
Celecoxib (Celebrex) and rofecoxib (Vioxx) are the two available COX-2
inhibitors. Both lack a carboxylic group present in most NSAIDs and therefore
are able to orient into the COX-2 enzyme in a selective manner that differs
from that of other NSAIDs. They have low aque-ous solubility that prevents
parenteral administration.
As previously discussed, the
COX-2 inhibitors have se-lectivity for inhibition of the COX-2 enzyme, which
has low constitutive activity but is highly inducible at sites of tissue
injury. In addition to the peripheral role of COX-2 in inflammation, COX-2 may
play an important role in the CNS. COX-2 is expressed constitutively in some
excitatory neurons in the brain and spinal cord and is induced in traumatic
brain injury such as that in-duced by ischemia and seizures. It has been
hypothe-sized that COX-2 may also be involved in neurodegen-erative diseases,
since COX-2 inhibitors have shown some positive effects in Alzheimer’s disease.
Thus, the mechanism of action of COX-2 inhibitors may involve brain and spinal
cord sites as well as local sites of injury.
Celecoxib has been approved
for the treatment of os-teoarthritis and rheumatoid arthritis, and rofecoxib
has been approved for the treatment of osteoarthritis, acute pain and primary
dysmenorrhea. Celecoxib and rofe-coxib do not appear to differ in efficacy for
the treat-ment of osteoarthritis. However, neither drug has effi-cacy greater
than that of the non-selective NSAIDs. Since the COX-2 enzyme appears to play
an important role in colon cancer the COX-2 inhibitors may find fu-ture uses in
the treatment or prevention of colorectal cancer.
The major advantage of the
COX-2 inhibitors is their decreased GI effects and formation of gastric
ulcera-tions compared with the COX nonselective agents. However, once an ulcer
is present, COX-2 is induced in response, and the COX-2 enzyme is essential for
wound healing. Therefore, celecoxib and rofecoxib can delay in wound healing
and increase the time for ulcer repair and tissue regeneration. Patients with
gastric ulcers should be switched if possible to another antiinflamma-tory to
allow ulcers to heal.
Celecoxib is contraindicated
during pregnancy, since COX-2 levels must be maintained for ovulation and
on-set of labor. COX-2 seems to be involved into the regu-lation of the
renin–angiotensin system, and both cele-coxib and rofecoxib use are associated
with transient sodium retention.
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