Re: how rational are COX-2 inhibitors?

[Guest guest]

Hi,

Aren't all coxibs related in the sense that they share similiar organic

structure? If Rofecoxib showed the cardiac toxicity, shouldn't other coxibs be

also screened for same risk selectively, vigorously, independently and banned?

Vijay

>

> Dear Members,

>

> Selectivity for COX-2 reduces the risk of peptic ulceration, and is the main

> feature of celecoxib, rofecoxib and other members of this drug class. COX-2

> selectivity does not seem to reduce other adverse effects of NSAIDs (most

> notably an increased risk of renal failure), and some results have shown an

> increase in the risk for heart attack, thrombosis and stroke by a relative

> increase in thromboxane. Rofecoxib was taken off the market in 2004 because of

> these concerns.

>

>

> Dr. K. Jaiswal

> Lecturer, Dept of Pharmacology.

> GMC, Nagpur.

>

[Guest guest]

Dear members

Uses COX of -2 inhibitors.

COX-inhibitors are used in the traeatment of osteoarthritis,rheumatoid arthritis, dysmenorrhoea, ankylosing spondylitis.They can be used in gouty arthritis and acute musculoskeletal pain.

(COX-2) inhibitors are attracting attention as potential anti-cancer agents.Research is underway to determine if Celecoxib, is a useful drug in the treatment of cancer. Studies have shown that COX-2 is over-expressed in 90% of lung cancer tumors and is in other cancers as well. Based on animal studies, researchers think COX-2 inhibitors used with other medications may not get rid of tumors, but may control their growth. The drug has already been FDA-approved as a preventative treatment to keep familial adenomatous polyposis from developing into cancer.

Epidemiological evidence suggest that the reduction of COX may also slow down the progress of Alzeimer’s disease and raised levels of COX-2 have recently been shown in the frontal cortex of Alzeimer’s patientsat post mortem. . Recommended dosage

Celecoxib

Osteoarthritis: 200 mg/day administered as a single dose or as 100 mg twice/day.

Rheumatoid arthritis: 100 to 200 mg twice/day.

Acute pain and primary dysmenorrhea: 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed.Regards,Dr. K. M. Jaiswal.Lecturer, Dept. of PharmacologyGMC, Nagpur.

From: Vijay <drvijaythawani@...>Subject: Re: how rational are COX-2 inhibitors?netrum Date: Tuesday, 15 February, 2011, 11:24 AM

Hi,Aren't all coxibs related in the sense that they share similiar organic structure? If Rofecoxib showed the cardiac toxicity, shouldn't other coxibs be also screened for same risk selectively, vigorously, independently and banned?Vijay >> Dear Members,> > Selectivity for COX-2 reduces the risk of peptic ulceration, and is the main > feature of celecoxib, rofecoxib and other members of this drug class. COX-2 > selectivity does not seem to reduce other adverse effects of NSAIDs (most > notably an increased risk of renal failure), and some results have shown an > increase in the risk for heart attack, thrombosis and stroke by a relative > increase

in thromboxane. Rofecoxib was taken off the market in 2004 because of > these concerns.> > > Dr. K. Jaiswal> Lecturer, Dept of Pharmacology.> GMC, Nagpur.>

[Guest guest]

The following rules have applied to all -2 inhibitors that have been marketed:

Should not be used by patients who are allergic to sulfonamides

Should not be used by patients who have shown allergic reactions to other non-steroidal anti-inflammatory agents such as ibuprofen of naproxen.

Should not be used in patients who have aspirin-associated asthma.

The use of these drugs is specifically contraindicated in late pregnancy, since they may cause premature closure of the ductus arteriosus. The -2 inhibitors have not been studied in patients with advanced kidney disease, and their use is not recommendedRegards,Dr. K. M. Jaiswal.Lecturer, Dept. of PharmacologyGMC, Nagpur.:

..

[Guest guest]

Dear members

Celecoxib has the potential for a large number of drug interactions. Because it has a large number of possible adverse effects, it may interact with any other drug that causes a similar effect or increases the risk or severity of the problem. For example, since the -2 inhibitors commonly cause stomach upset, there will be an even greater risk of stomach distress when celecoxib is taken with another drug that causes stomach problems. Similarly, since the drug is metabolized by the liver, it will change the normal blood levels of other drugs that are metabolized in a similar manner, which may either increase or decrease the effects of these drugs.

The following is a partial list of drugs that interact with celecoxib:

Aspirin: Administration of aspirin with -2 inhibitors may result in an increased risk of GI ulceration and complications.

ACE-inhibitors: Reports suggest that NSAIDs, including the -2 inhibitors, may diminish the antihypertensive effect of ACE-inhibitors. The ACE-inhibitors include benazepril captopril , enalapril , fosinopril lisinopril , moexipril , perindopril , quinapril , ramipril , and trandolapril .

Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the sodium removing effect of furosemide and thiazide diuretics in some patients.

Anticonvulsants When these drugs are used together, the levels of -2 inhibitors may be reduced by over 25%. A dose adjustment may be required.

Warfarin: -2 inhibitors may increase the anticlotting effects of warfarin Patients taking these drugs together should have their coagulation times closely monitored until the doses can be adjusted.

Fluconazole and Ketoconazole: These antifungal drugs are metabolized by the same means as the -2 inhibitors and cause very significant increases in the blood levels of celecoxib and valdecoxib. The doses of the -2 inhibitors may have to be reduced.

Glyburide: Glyburide is used to treat diabetes. Whether there is a drug interaction seems to depend on the dose levels of the drugs, but at some dosages, the -2 inhibitors may increase the blood levels of glyburide, leading to a significant drop in blood sugar levels. If these drugs must be taken together, blood sugar levels should be closely monitored until the doses of the two drugs are fully adjusted. Regards,Dr. K. M. Jaiswal.Lecturer, Dept. of PharmacologyGMC, Nagpur.

..

[Guest guest]

Dear vijay sir

I thank you for your valuable input in the ongoing disscussion The coxibs with the shortest and longest half-lives have not shown an increased CV risk, whereas those with moderate half-lives have shown this risk .The three agents that have demonstrated an increased CV risk—rofecoxib, celecoxib, and valdecoxib—have half-lives ranging from 6 to 18 hours and the two agents without a demonstrated increased CV risk—lumira-coxib and etoricoxib—have half-lives of two to six hours and 20 to 26 hours, respectively.

COX-2 selectivity (i.e., the agent’s specificity and affinity for the COX-2 enzyme over the COX-1 enzyme) may also be a factor in the relationship of coxibs to the risk of CV events. rofecoxib has demonstrated the greatest risk, whereas celecoxib has shown an increased risk only sporadically. In assessments of COX-2 selectivity, rofecoxib has a higher selectivity (with a COX-2 : COX-1 ratio of 272 to 1) than celecoxib (with a ratio of 30 to 1) However, etoricoxib and lumiracoxib are the most COX-2 selective (with ratios of 344 to 1 and 700 to 1, respectively); neither agent has shown a comparable increased CV risk, as with rofecoxib and celecoxib.

All coxibs have similar mechanisms of action for COX-2 inhibition, but each one has a unique pharmacokinetic profile. Only rofecoxib does not undergo extensive metabolism via a CYP450 system. Instead, its metabolism is mediated through the reduction of cytosolic enzymes, with less than 1% of the drug being recovered unchanged in the urine. All other coxibs are eliminated predominantly by the CYP 450 system, either 3A4 (valdecoxib, etoricoxib) or 2C9 (celecoxib, valdecoxib, and lumiracoxib). In addition, enterohepatic recirculation is unique to rofecoxib and has been reported in both rat and human studies, with resultant biphasic serum peaks of drug.

Although the clinical significance of these differences in metabolism is unclear, these disparities might contribute to the variations in renal and cardiovascular effects. For instance, after cytosol reductase metabolism, rofecoxib may compete for the metabolism of aldosterone, with resulting increases in both sodium and fluid retention as well as the promotion of vascular remodeling. The consequences include an increased risk of edema, hypertension, and acute decompensation of chronic heart failure.

Alternatively, celecoxib does not compete for cytosol reductase; instead, it works as a carbonic anhydrase inhibitor and provides a diuretic effect in the kidney that counteracts potential increases in hypertension and edema. It is noteworthy that these renovascular outcomes that have been reported in multiple studies and analyses occur more often with rofecoxib than with any other coxib.

The chemical structure of each coxib, excluding lumira-coxib, is classified as either a sulfone or a sulfonamide Lumiracoxib is classified as an arylacetic acid derivative. Its unique structure contributes to its very short half-life (two to six hours), compared with the other coxibs. The shorter half-life may decrease the overall exposure time of this drug in circulation and may potentially reduce thrombo-embolic riskCelecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide was the first selective COX-2 inhibitor introduced for clinical use, followed soon after by rofecoxib (4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone). More recently, valdecoxib [4-(5-methyl-3-phenyl-4-isox-azolyl) benzenesulfonamide], parecoxib [N-(5-methyl-3-phenylisoxazol-4-yl)-phenyl-sulfonyl] propanamide], and etoricoxib [5-chloro-2-(6-methylpiridine-3-yl)-3-(4-methylsulfonylphenyl] pyridine] were approved

for therapeutic use. . To gain a better understanding of their role in the development of these adverse effects, we need further investigations into the relevance of these differences in phar-macokinetic parameters and chemical structures.

E-mail (*)Regards,Dr. K. M. Jaiswal.Lecturer, Dept. of PharmacologyGMC, Nagpur.

[Guest guest]

Dear members,In conclusion I would like to say that some coxibs are there in the market with the following recommendations by the FDA.U.S. FDA panelists voted to allow sales of rofecoxib,celecoxib while at the same time

acknowledging the COX-2 drugs pose risks for heart problems. After weighing the

issue of benefits versus risks, the panel concluded that the benefits outweigh

possible risks to consumers and the COX-2 drugs should remain available to

people who need them. Since pain can be

a disabling symptom, and since some patients have no other good alternative for

relieving pain, the panel also said these drugs should continue to be made

available with the following

recommendations.

Celecoxib-celecoxib should continue to be available (with appropriate

warning labels and marketing changes) but that doses should be kept down to 200

mg.

Rofecoxib-The panel recommended that

rofecoxib should again be marketed. While rofecoxib was found to be

substantially riskier than other COX-2 drugs, the panel noted that this is the

only COX-2 drug available to treat juvenile rheumatoid arthritis, and the only

one that can be taken by patients allergic to sulfonamides. The panel

recommended eliminating the 50 mg dose of this drug, and reducing the standard

dose from 25 mg to 12.5 mg. Regards,Dr. K. M. Jaiswal.Lecturer, Dept. of PharmacologyGMC, Nagpur.From: Kavita Jaiswal <kp_jaiswal@...>netrum <netrum >Sent: Mon, 14 February, 2011 1:22:57 PMSubject: how rational are COX-2 inhibitors?

Dear Members,Selectivity

for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib

and other members of this drug class. COX-2 selectivity does not seem to reduce

other adverse effects of NSAIDs (most notably an increased risk of renal

failure), and some results have shown an increase in the risk for heart attack,

thrombosis and stroke by a relative increase in thromboxane.

Rofecoxib was taken off the market in 2004 because

of these concerns.

Dr.

K. Jaiswal

Lecturer,

Dept of Pharmacology.

GMC,

Nagpur.

[Guest guest]

Thanks Kavita. I am still not convinced about the safety profile of ibs.

To start with all ibs were effective AAAs. Then one by one, they are being

banned. The tragedy is that in growing economies the ibs which have been

banned else where, still continue to sell. This is happening because of the

insensitive DRAs which get greased by the pharmaceutical industry to let them

market the medicines which have been banned in other countries. It is a perfect

example why such countries are called " third world countries " - because they get

third rate, third class products as medicines.

Vijay Thawani

(from Dehradun)

>

> Dear vijay sir

> I thank you for your valuable input in the ongoing disscussion The coxibs

with the shortest and longest half-lives have not shown an increased CV risk,

whereas those with moderate half-lives have shown this risk   .The three

agents that have demonstrated an increased CV risk†" rofecoxib, celecoxib, and

valdecoxib†" have half-lives ranging from 6 to 18 hours and the two agents

without a demonstrated increased CV risk†" lumira-coxib and etoricoxib†" have

half-lives of two to six hours and 20 to 26 hours, respectively.

>

> COX-2 selectivity (i.e., the agent’s specificity and affinity for the COX-2

enzyme over the COX-1 enzyme) may also be a factor in the relationship of coxibs

to the risk of CV events.  rofecoxib has demonstrated the greatest risk,

whereas celecoxib has shown an increased risk only sporadically. In assessments

of COX-2 selectivity, rofecoxib has a higher selectivity (with a COX-2 : COX-1

ratio of 272 to 1) than celecoxib (with a ratio of 30 to 1)  However,

etoricoxib and lumiracoxib are the most COX-2 selective (with ratios of 344 to 1

and 700 to 1, respectively); neither agent has shown a comparable increased CV

risk, as with rofecoxib and celecoxib.

>  

> All coxibs have similar mechanisms of action for COX-2 inhibition, but each

one has a unique pharmacokinetic profile. Only rofecoxib does not undergo

extensive metabolism via a CYP450 system. Instead, its metabolism is mediated

through the reduction of cytosolic enzymes, with less than 1% of the drug being

recovered unchanged in the urine. All other coxibs are eliminated predominantly

by the CYP 450 system, either 3A4 (valdecoxib, etoricoxib)  or 2C9 (celecoxib,

valdecoxib, and lumiracoxib). In addition, enterohepatic recirculation is unique

to rofecoxib and has been reported in both rat and human studies, with resultant

biphasic serum peaks of drug.

> Although the clinical significance of these differences in metabolism is

unclear, these disparities might contribute to the variations in renal and

cardiovascular effects. For instance, after cytosol reductase metabolism,

rofecoxib may compete for the metabolism of aldosterone, with resulting

increases in both sodium and fluid retention as well as the promotion of

vascular remodeling. The consequences include an increased risk of edema,

hypertension, and acute decompensation of chronic heart failure.

> Alternatively,  celecoxib does not compete for cytosol reductase; instead, it

works as a carbonic anhydrase inhibitor and provides a diuretic effect in the

kidney that counteracts potential increases in hypertension and edema. It is

noteworthy that these renovascular outcomes that have been reported in multiple

studies and analyses occur more often with rofecoxib than with any other coxib.

> The chemical structure of each coxib, excluding lumira-coxib, is classified as

either a sulfone or a sulfonamide  Lumiracoxib is classified as an arylacetic

acid derivative. Its unique structure contributes to its very short half-life

(two to six hours), compared with the other coxibs. The shorter half-life may

decrease the overall exposure time of this drug in circulation and may

potentially reduce thrombo-embolic riskCelecoxib

(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide

was the first selective COX-2 inhibitor introduced for clinical use, followed

soon after by rofecoxib (4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone).

More recently, valdecoxib [4-(5-methyl-3-phenyl-4-isox-azolyl)

benzenesulfonamide], parecoxib

[N-(5-methyl-3-phenylisoxazol-4-yl)-phenyl-sulfonyl] propanamide], and

etoricoxib [5-chloro-2-(6-methylpiridine-3-yl)-3-(4-methylsulfonylphenyl]

pyridine] were approved for therapeutic use. . To gain a

> better understanding of their role in the development of these adverse

effects, we need further investigations into the relevance of these differences

in phar-macokinetic parameters and chemical structures.

>

>

>

>

> E-mail (*)

> Regards,

> Dr. K. M. Jaiswal.

> Lecturer, Dept. of Pharmacology

> GMC, Nagpur.

>

>

>

>

>

>

>  

>

[Guest guest]

Dear sir, Despite demonstration of Class Effect by many coxibs, leaving of -2 inhibitors in the market indicates that regulatory agencies are more sensitive to the concerns of pharma companies than to patients’ safety. Patients remain exposed to a documented risk of adverse effects from medicines that have no proven therapeutic advantages, while prescribers are left wasting their time picking through the debris.Regards,Dr. Mangesh From: drvijaythawani <drvijaythawani@...>Subject: Re: how rational are COX-2 inhibitors?netrum Date: Thursday, 17 February, 2011, 12:38 PM

Thanks Kavita. I am still not convinced about the safety profile of ibs.

To start with all ibs were effective AAAs. Then one by one, they are being banned. The tragedy is that in growing economies the ibs which have been banned else where, still continue to sell. This is happening because of the insensitive DRAs which get greased by the pharmaceutical industry to let them market the medicines which have been banned in other countries. It is a perfect example why such countries are called "third world countries" - because they get third rate, third class products as medicines.

Vijay Thawani

(from Dehradun)

>

> Dear vijay sir

> I thank you for your valuable input in the ongoing disscussion The coxibs with the shortest and longest half-lives have not shown an increased CV risk, whereas those with moderate half-lives have shown this risk   .The three agents that have demonstrated an increased CV riskâ€"rofecoxib, celecoxib, and valdecoxibâ€"have half-lives ranging from 6 to 18 hours and the two agents without a demonstrated increased CV riskâ€"lumira-coxib and etoricoxibâ€"have half-lives of two to six hours and 20 to 26 hours, respectively.

>

> COX-2 selectivity (i.e., the agent’s specificity and affinity for the COX-2 enzyme over the COX-1 enzyme) may also be a factor in the relationship of coxibs to the risk of CV events. rofecoxib has demonstrated the greatest risk, whereas celecoxib has shown an increased risk only sporadically. In assessments of COX-2 selectivity, rofecoxib has a higher selectivity (with a COX-2 : COX-1 ratio of 272 to 1) than celecoxib (with a ratio of 30 to 1) However, etoricoxib and lumiracoxib are the most COX-2 selective (with ratios of 344 to 1 and 700 to 1, respectively); neither agent has shown a comparable increased CV risk, as with rofecoxib and celecoxib.

> Â

> All coxibs have similar mechanisms of action for COX-2 inhibition, but each one has a unique pharmacokinetic profile. Only rofecoxib does not undergo extensive metabolism via a CYP450 system. Instead, its metabolism is mediated through the reduction of cytosolic enzymes, with less than 1% of the drug being recovered unchanged in the urine. All other coxibs are eliminated predominantly by the CYP 450 system, either 3A4 (valdecoxib, etoricoxib) or 2C9 (celecoxib, valdecoxib, and lumiracoxib). In addition, enterohepatic recirculation is unique to rofecoxib and has been reported in both rat and human studies, with resultant biphasic serum peaks of drug.

> Although the clinical significance of these differences in metabolism is unclear, these disparities might contribute to the variations in renal and cardiovascular effects. For instance, after cytosol reductase metabolism, rofecoxib may compete for the metabolism of aldosterone, with resulting increases in both sodium and fluid retention as well as the promotion of vascular remodeling. The consequences include an increased risk of edema, hypertension, and acute decompensation of chronic heart failure.

> Alternatively, celecoxib does not compete for cytosol reductase; instead, it works as a carbonic anhydrase inhibitor and provides a diuretic effect in the kidney that counteracts potential increases in hypertension and edema. It is noteworthy that these renovascular outcomes that have been reported in multiple studies and analyses occur more often with rofecoxib than with any other coxib.

> The chemical structure of each coxib, excluding lumira-coxib, is classified as either a sulfone or a sulfonamide Lumiracoxib is classified as an arylacetic acid derivative. Its unique structure contributes to its very short half-life (two to six hours), compared with the other coxibs. The shorter half-life may decrease the overall exposure time of this drug in circulation and may potentially reduce thrombo-embolic riskCelecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide was the first selective COX-2 inhibitor introduced for clinical use, followed soon after by rofecoxib (4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone). More recently, valdecoxib [4-(5-methyl-3-phenyl-4-isox-azolyl) benzenesulfonamide], parecoxib [N-(5-methyl-3-phenylisoxazol-4-yl)-phenyl-sulfonyl] propanamide], and etoricoxib [5-chloro-2-(6-methylpiridine-3-yl)-3-(4-methylsulfonylphenyl] pyridine] were approved for therapeutic use. .

To gain a

> better understanding of their role in the development of these adverse effects, we need further investigations into the relevance of these differences in phar-macokinetic parameters and chemical structures.

>

>

>

>

> E-mail (*)

> Regards,

> Dr. K. M. Jaiswal.

> Lecturer, Dept. of Pharmacology

> GMC, Nagpur.

>

>

>

>

>

>

> Â

>