Transcript Principles of Biochemistry 4/e

Some naturally occurring fatty acids in animals
Phospholipases hydrolyze phospholipids
- PLA2 will hydrolyze an arachidonate from the carbon-2
position of a membrane phospholipid in an immune response
Arachidonic acid is a precursor to eicosanoids,
multi-functional hormones
Prostaglandins, Thromboxanes, and Leukotrienes
Eicosanoids
- Eicosanoids are oxygenated derivatives of C20 polyunsaturated
fatty acids (e.g. arachidonic acid)- mediate many pathological
responses
20:4D5,8,11,14
Prostaglandin E2 – can cause constriction of blood vessels
Eicosanoids
Thromboxane A2 – involved in blood clot formation
Leukotriene D4 – mediator of smooth-muscle contraction and
provokes bronchial constriction seen in asthmatics.
Aspirin alleviates pain, fever, and inflammation by inhibiting
cyclooxygenase (COX), an enzyme critical for the synthesis of
Prostaglandins. (NSAID family of compounds)
Advil (Ibuprofen)
An inhibitor of mammalian
eicosanoid hormone synthesis
Cyclooxygenase (COX) has two well-studied isoforms, called COX-1
and COX-2. COX-1 mediates the synthesis of prostaglandins responsible
for protection of the stomach lining, while COX-2 mediates the synthesis
of prostaglandins responsible for pain and inflammation. By creating
“selective” NSAIDs that inhibit COX-2, but not COX-1, the same pain
relief as traditional NSAIDs is offered, but with greatly reduced risk of
fatal or debilitating peptic ulcers. Rofecoxib is a selective COX-2
inhibitor or coxib (CycloOXygenase-2 Inhibitors).
Rofecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that has
now been withdrawn over safety concerns. It was marketed by Merck
& Co. to treat osteoarthritis and acute pain conditions. Rofecoxib was
approved as safe and effective by the Food and Drug Administration
(FDA) on May 20, 1999, and was subsequently marketed under the
brand names Vioxx, Ceoxx, and Ceeoxx.
Rofecoxib gained widespread acceptance among physicians treating
patients with arthritis and other conditions causing chronic or acute
pain. Worldwide, over 80 million people were prescribed rofecoxib at
some time.
On September 30, 2004, Merck voluntarily withdrew rofecoxib from
the market because of concerns about increased risk of heart attack
and stroke associated with long-term, high-dosage use. Rofecoxib was
one of the most widely used drugs ever to be withdrawn from the
market. In the year before withdrawal, Merck had sales revenue of
$2.5 billion from Vioxx.