For this last week, I looked at the article titled, “Comparison
of the Intestinal Toxicity of Celecoxib, a Selective COX-2 Inhibitor, and
Indomethacin in the Experimental Rat”. In this article, celecoxib a highly
selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2
inhibitor, were given to rats to study and compare the effects on the
gastrointestinal system.
COX or cyclo-oxygenase is a key enzyme in prostaglandin synthesis.
COX or cyclo-oxygenase is a key enzyme in prostaglandin synthesis.
The toxicity of NSAIDs has been suggested to be due to the “topical”
effect in addition to the inhibition of the COX-2 enzyme. COX-2 selective inhibitors have great GI
tolerability, but this article set out to determine whether that was because of
their selectivity or the lack of a “topical” effect.
From what I found, a “topical” effect in terms of pharmaceuticals is speaking about it working locally, rather than systemically.
That being said, indomethacin is thought to be causing two types of damage: topical damage and COX-1 inhibitory damage.
The topical damage of NSAIDs is due to the uncoupling of mitochondrial oxidative phosphorylation and an increase of intestinal permeability and inflammation.
The damage caused by COX-1 inhibition is the drive of intestinal inflammation to ulcerative damage by vascular effect.
From what I found, a “topical” effect in terms of pharmaceuticals is speaking about it working locally, rather than systemically.
That being said, indomethacin is thought to be causing two types of damage: topical damage and COX-1 inhibitory damage.
The topical damage of NSAIDs is due to the uncoupling of mitochondrial oxidative phosphorylation and an increase of intestinal permeability and inflammation.
The damage caused by COX-1 inhibition is the drive of intestinal inflammation to ulcerative damage by vascular effect.
The hope of this experiment is that celecoxib can suppress
prostaglandin synthtesis at sites of inflammation, without inhibiting constructive
prostaglandin synthesis in the GI tract.
They tested the four different drugs through rats using
various tests. The different drugs and doses they used were: 10mg/kg of
indomethacin, 30mg/kg of celecoxib, 300mg/kg celecoxib, and 10mL of 10%
dimethyl sulfoxide (DMSO). To make this easier to read, I will keep the
information for each test separated.
Mitochondrial Experiment
The livers of the rats were removed from the rats and the oxygen consumption, Phosphate:Oxygen ratio, and respiratory control ratios were measured for each liver. They also took a baseline reading beforehand to compare these values to.
The results showed that indomethacin caused an initial increase in respiration percentage (up to 230%) and proceeded to inhibit respiration as the dosage increased, all the way until respiration was completely inhibited. DMSO and celecoxib had no effect on mitochondrial respiration.
Mitochondrial morphology was also assessed through electron microscopy. It was found that the indomethacin caused significant damage to the mitochondrial cells, while DMSO and celecoxib caused very little damage. The damage was measured in percentages.
The livers of the rats were removed from the rats and the oxygen consumption, Phosphate:Oxygen ratio, and respiratory control ratios were measured for each liver. They also took a baseline reading beforehand to compare these values to.
The results showed that indomethacin caused an initial increase in respiration percentage (up to 230%) and proceeded to inhibit respiration as the dosage increased, all the way until respiration was completely inhibited. DMSO and celecoxib had no effect on mitochondrial respiration.
Mitochondrial morphology was also assessed through electron microscopy. It was found that the indomethacin caused significant damage to the mitochondrial cells, while DMSO and celecoxib caused very little damage. The damage was measured in percentages.
Intestinal Permeability
Intestinal permeability was assessed through use of two 5-hour urinary 51-CrEDTA assessments. The first assessment starting one hour after the drugs were administered and the second starting 19 hours after the drugs were administered. The results of these assessments were compared to a previously recorded baseline testing done before the drugs were administered, following an overnight fast.
The results showed that indomethacin increased intestinal permeability significantly, while both doses of celecoxib had only a little effect on the 1-6 hour permeability and almost no effect on the 19-24 hour permeability.
Intestinal permeability was assessed through use of two 5-hour urinary 51-CrEDTA assessments. The first assessment starting one hour after the drugs were administered and the second starting 19 hours after the drugs were administered. The results of these assessments were compared to a previously recorded baseline testing done before the drugs were administered, following an overnight fast.
The results showed that indomethacin increased intestinal permeability significantly, while both doses of celecoxib had only a little effect on the 1-6 hour permeability and almost no effect on the 19-24 hour permeability.
Granulocyte Marker Protein (GMP)
Three days prior to drug administration, fecal samples were taken after an overnight fast to form a baseline. After dosing, fecal samples were taken for 7 days and the GMP levels were calculated by use of daily fecal weights. GMP was used as a measure of intestinal inflammation.
The results showed that indomethacin significantly raised GMP levels on days 2, 3, and, 4 after drug administration. After day 4, the GMP levels rapidly went back down to baseline.
Three days prior to drug administration, fecal samples were taken after an overnight fast to form a baseline. After dosing, fecal samples were taken for 7 days and the GMP levels were calculated by use of daily fecal weights. GMP was used as a measure of intestinal inflammation.
The results showed that indomethacin significantly raised GMP levels on days 2, 3, and, 4 after drug administration. After day 4, the GMP levels rapidly went back down to baseline.
Intestinal Prostaglandin E (PGE)
Rats were fasted and were administered the drugs three hours before samples were collected. Proximal small bowels were snap frozen with liquid nitrogen and ground up with mortar and pestle. The ground samples were mixed with buffer, purified, and then the PGE was extracted. The PGE levels were determined in duplicate by radioimmunoassy.
The results showed that the 30mg/kg dose of celecoxib slightly raised PGE levels, the 300mg/kg dose of celecoxib slightly lowered PGE levels, and indomethacin caused a significant decrease in PGE levels.
Rats were fasted and were administered the drugs three hours before samples were collected. Proximal small bowels were snap frozen with liquid nitrogen and ground up with mortar and pestle. The ground samples were mixed with buffer, purified, and then the PGE was extracted. The PGE levels were determined in duplicate by radioimmunoassy.
The results showed that the 30mg/kg dose of celecoxib slightly raised PGE levels, the 300mg/kg dose of celecoxib slightly lowered PGE levels, and indomethacin caused a significant decrease in PGE levels.
Macroscopic Damage
For this test, there were eight groups of rats. Four of the groups (one for each drug/dose) were sampled after 24 hours. The other four groups were sampled after 7 days. The small intestines of these rats were removed and examined for the presence of ulcers.
The results showed that there were no ulcers present in either dose of the celecoxib groups or the control group. There were ulcers present in both groups administered with indomethacin. There were significantly more ulcers in the group sampled 24 hours after the administration of indomethacin than the group sampled after 7 days.
For this test, there were eight groups of rats. Four of the groups (one for each drug/dose) were sampled after 24 hours. The other four groups were sampled after 7 days. The small intestines of these rats were removed and examined for the presence of ulcers.
The results showed that there were no ulcers present in either dose of the celecoxib groups or the control group. There were ulcers present in both groups administered with indomethacin. There were significantly more ulcers in the group sampled 24 hours after the administration of indomethacin than the group sampled after 7 days.
The take-home message here seems to be that celecoxib is a
better choice of NSAID, when compared to indomethacin, when it comes to GI
damage. The reasoning for this seems to be the fact that celecoxib is a COX-2
selective inhibitor and lacks a “topical” effect. The combination of these two
are present in indomethacin and that seems to be what is causing damage in the
GI tract.
What are your thoughts on this? Does this make you worry about the number of nonselective COX inhibitor NSAIDs out there? Should we exclusively use COX-2 selective inhibitor NSAIDs? Do you see any drawbacks of using COX-2 selective inhibitors?
My mistake. I forgot to add a link to the article when I first posted this.
Here is a lnk: http://ehis.ebscohost.com/ehost/pdfviewer/pdfviewer?sid=13076d80-a005-4fb3-9aed-255b1a91471e%40sessionmgr12&vid=2&hid=17
What are your thoughts on this? Does this make you worry about the number of nonselective COX inhibitor NSAIDs out there? Should we exclusively use COX-2 selective inhibitor NSAIDs? Do you see any drawbacks of using COX-2 selective inhibitors?
My mistake. I forgot to add a link to the article when I first posted this.
Here is a lnk: http://ehis.ebscohost.com/ehost/pdfviewer/pdfviewer?sid=13076d80-a005-4fb3-9aed-255b1a91471e%40sessionmgr12&vid=2&hid=17
ReplyDeleteThis makes me worry about the number of nonselective COX inhibitor NSAIDs out there, I remember couple years ago I was working on some paper and I came across a article from FDA about regulatory actions NSAIDs and it freak me out. I also search little more and I found the link.
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106148.htm
After reading this article I believe using COX 2 selective inhibitor NSAIDs be better choice than nonselective since there might not be any side effect associated with inhibiting just COX2. There is always some risks with any drugs we exposed to our body so I think selective COX2 inhibitors NSAIDs would have some problems too such as Bextra which increased risk of heart attack and stroke in USA.