BIOL 4050U Study Guide - Winter 2018, Comprehensive Midterm Notes - Protein, Dna, Inflammation
BIOL 4050U
MIDTERM EXAM
STUDY GUIDE
Fall 2018
Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors
NAIDS = nonsteroidal anti-inflammatory agents
NAIDS and aspirin – significant gastric toxicity – related to COX-1 inhibition – inhibit prostaglandin
synthesis
COX-1 is expressed in platelets and mediate production of thromboxane A potent platelet activator
and aggregator
Novel COX protein – COX-2 is homologous to COX-1 – inhibitors introduced in 1999 celecoxib and
rofecoxib
COX-1 predominates in the gastric mucosa whereas COX-2 is induced in inflammation (via PGI2
production) leading to pain, swelling and discomfort
Note: PGI2 production (from COX-2 activation) acts as a vasodilator and inhibits platelet aggregation
COX-2 inhibitors are therefore good at reducing inflammation without gastric toxicity however,
inhibitors decrease PGI2 production and may have prothrombotic activity (leading to increased risk of
cardiovascular thrombotic events)
NSAIDs inhibit the production of both thromboxane and PGI2 COX-2 inhibitors have no effect on
thromboxane but decrease PGI2 production – may tip the balance between prothrombotic
thromboxane A and antithrombotic PGI2, leading to increases in thrombotic cardiovascular events
In this review, analyzed randomized trials to determine whether COX-2 inhibitors are associated with
protective or hazardous effect on the risk of cardiovascular events
Used MEDLINE – trials from 1998 to 2001
VIGOR trial, CLASS trial, Study 085 and 090, Adverse Event Reporting System and Comparison with
Contemporary Meta-analysis
VIGOR trial – 8076 patients with rheumatoid arthritis – patients with previous cardiovascular events
(within 2 years) were not included in this trial and aspirin was not permitted
VIGOR examined rofecoxib (50mg/day) and naproxen (1000mg/day)
Results from this study can be explained by a significant pro-thrombotic effect from rofecoxib (COX-2
inhibitor) or a significant anti-thrombotic effect from naproxen (NSAID)
Differential effects on platelet aggregation – naproxen significant anti-platelet effects (93%) – thus
naproxen (not ibuprofen or diclofenac) resulted in platelet aggregation inhibition similar to aspirin
Indobufen, flurbiprofen – other NSAIDs were also as effective as aspirin
Due to anti-platelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular
events (CEs) was due to a benefit from naproxen or a prothrombotic effect from rofecoxib. Therefore…
examine results from a meta-analysis – further demonstrated prothombotic effect of COX-2 inhibitors
(rofecoxib and celecoxib)… therefore increased rates of CEs are due to the prothrombic effect, not
merely a failure of COX-2 inhibitors to provide the protection of NSAIDs and aspirin
find more resources at oneclass.com
find more resources at oneclass.com
The risk of serious CEs (MI) was 111 patients taking rofecoxib and 50 patients taking naproxen
Events in the rofecoxib group were 2.2 times higher than naproxen group
CLASS study – 8059 patients – aspirin use was permitted
Examined the effect of celecoxib (400mg twice a day), ibuprofen (800mg 3 times a day), and diclofenac
(75mg twice a day)
Results revealed no significant difference between cardiovascular events with COX-2 inhibitor
(celecoxib) and NSAIDs (aspirin and diclofenac) possibly due to the low-dose aspirin or
pharmacological differences in the NSAIDs used Diclofenac and ibuprofen have significantly less
anti-platelet effects when compared with naproxen – and to have a protective effect, near complete
inhibition of thromboxane is needed – may not have been enough
Furthermore, diclofenac exhibits more of an effect on PGI2 inhibition than naproxen
94% inhibition of COX-2 activity by diclofenac compared to 71% inhibition by naproxen – therefore
diclofenac may have intrinsic prothrombotic effects among NSAIDs due to inhibition of vasodilatory
PGI2
The MI rate for celecoxib was similar to rofecoxib
It has been shown that upregulation of COX-2 activity has plays an essential role in cardio-protection –
further suggests the potential deleterious effects of COX-2 inhibition
Study 085 (1042 patients) and Study 095 (978 patients) – in both studies patients were allowed to take
low-dose aspirin
Study 085 – effects of rofecoxib (12.5mg/day) vs nabumetone (1000mg/day) after 6 weeks treatment
for osteoarthritis of the knee
Observed total of 3 CEs
1 in the rofecoxib group, 2 in the nabumetone group and no events in placebo group
Study 090 – effects of forecoxib vs nabumetone (same design)
Reported a total of 9 serious CEs
6 in rofecoxib group, 2 in nubumetone group and 1 in placebo
Adverse Event Reporting System – revealed 144 thrombotic cases for celecoxib and 159 cases for
rofecoxib
These results, compared to VIGOR, did not demonstrate significant increases in CEs – may be due to
smaller sample sizes and the fact only 25% of the dose of rofecoxib used in VIGOR was used –
therefore prothrombotic effect of rofecoxib may be dose dependent
Contemporary meta-analysis
MI rate for placebo was 0.52%, VIGOR and CLASS trials were higher 0.74% with rofecoxib compared
to placebo and 0.80% for celecoxib when compared to placebo
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Risk of cardiovascular events associated with selective cox-2 inhibitors. Naids and aspirin significant gastric toxicity related to cox-1 inhibition inhibit prostaglandin synthesis. Cox-1 is expressed in platelets and mediate production of thromboxane a potent platelet activator and aggregator. Novel cox protein cox-2 is homologous to cox-1 inhibitors introduced in 1999 celecoxib and rofecoxib. Cox-1 predominates in the gastric mucosa whereas cox-2 is induced in inflammation (via pgi2 production) leading to pain, swelling and discomfort. Note: pgi2 production (from cox-2 activation) acts as a vasodilator and inhibits platelet aggregation. Cox-2 inhibitors are therefore good at reducing inflammation without gastric toxicity however, inhibitors decrease pgi2 production and may have prothrombotic activity (leading to increased risk of cardiovascular thrombotic events) In this review, analyzed randomized trials to determine whether cox-2 inhibitors are associated with protective or hazardous effect on the risk of cardiovascular events. Used medline trials from 1998 to 2001.
