Sunday, March 23, 2008

Risks versus Benefits of COX-2-selective NSAIDs

Intent: A summary of the BASIC field underlying the line controversies regarding cyclooxygenase-2 (COX-2)-selective nonsteroidal antiinflammatory drugs (NSAIDs), including data on their cardiovascular base hit, their gastrointestinal (GI) benefits, cost-effectiveness, physician-prescribing trends, and recommendations for prescribing these agents is presented.

Summary: A issue of randomized controlled trials (RCTs) have reported that COX-2-selective NSAIDs amount cardiovascular events, although there appear to be gradations of risks among the COX-2-selective NSAIDs.
In constituent, traditional NSAIDs may growth the risk for cardiovascular events, complicating the rendering of RCTs that use traditional NSAIDs as comparators.
Selective inhibitors of COX-2-selective NSAIDs are effective antiinflammatory and analgesic drugs with improved upper-GI contraceptive compared to traditional NSAIDs.
Data on the cost-effectiveness of COX-2-selective NSAIDs indicate that they should be limited to patients at high risk for upper-GI adverse effects.
However, they had been increasingly used in patients with lower GI risks until recent events reversed that style.
Observance under which COX-2-selective NSAIDs may be appropriate are in patients at high GI risk and in patients who did not respond to multiple traditional NSAIDs.
The national public eye in the United States on NSAID-related adverse events and recent lawsuits against welfare care providers prescribing COX-2-selective NSAIDs further highlights the need for provider-patient connection and risk disclosure.
The soul cardiovascular risks of NSAIDs are similar in ratio to other currently prescribed therapies.
Ending: Status care providers must consider the efficacy, GI and cardiovascular risks, concomitant medications, and costs when determining the properness of COX-2-selective NSAID therapy.Intro

Cyclooxygenase-2 (COX-2)-selective nonsteroidal antiinflammatory drugs (NSAIDs) have often been used in recent gathering due to their apparent gastrointestinal (GI) country reward over traditional or nonselective NSAIDs (hereafter referred to as traditional NSAIDs).
In the United States, there were triplet COX-2-selective NSAIDs available (celecoxib, rofecoxib, valdecoxib).
The labeling for celecoxib, rofecoxib, and valdecoxib was approved by the Food and Drug Organisation (FDA) in December 1998, May 1999, and November 2001, respectively.
Celecoxib is the only representative in this aggregation currently available in the United States.
In Aggregation, digit additional agents are available: lumiracoxib, etoricoxib, and parecoxib, the parenteral form of valdecoxib.

Although traditional and COX-2-selective NSAIDs have commonly been used for their antiinflammatory and analgesic effects in many diseases, such as rheumatoid arthritis (RA) and osteoarthritis (OA), concerns regarding the prophylactic of these drugs have been raised, particularly for increased risk of arterial thrombotic events (i.e., myocardial infarction, unstable cardiopathy, cardiac thrombus, resuscitated cardiac catch, sudden or unexplained destruction, ischemic motility, and vibration ischemic attacks).
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Tuesday, March 18, 2008

Drug Insight: Cyclo-Oxygenase-2 Inhibitors–A Critical Appraisal

COX2 inhibitors currently in use are the sulfonamide celecoxib, the methylsulfone etoricoxib and the phenylacetic acid legal instrument lumiracoxib.
Of these, celecoxib is the only COX2 inhibitor available in the US.
Another COX2 inhibitor, marketed in the European Labor union for communication of postoperative pain, is parecoxib, an injectable prodrug of valdecoxib.

Pharmacological data of COX2 inhibitors used for oral discussion of arthritic pain are compiled in Assemblage 1 .
Differences in physicochemical characteristics are reflected in different pharmacokinetic demeanor.
Accordingly, the nonacidic compounds celecoxib and etoricoxib distribute homogenously in the body whereas the acidic lumiracoxib, like other acetic acid derivatives (e.g., diclofenac), distributes unequally to prototype in liquid body substance, inflamed tissue paper, kidney and somebody. Owing to its very high lipophilicity, the organic process of celecoxib is relatively slow and incomplete; this chemical undergoes considerable commencement pass metabolization (20–60% oral bioavailability) and its rate of liquidation (t1/2 = 6–12 h approx.) seems to be highly variable quantity. Etoricoxib is eliminated from the body slowly (t1/2 = 20–26 h approx.) and is absorbed at a fast rate, which seems to campaign its fast operation of legal proceeding.

Of the COX2 inhibitors, lumiracoxib has peculiar pharmacodynamic and pharmacokinetic features, which include having the highest selectivity towards COX2 in vitro and the shortest pharmacological half life (t1/2 = 2–6 h approx.).
Lumiracoxib, living thing an amphiphilic material, persists for a long time in the synovial matter, which might explain the long-lasting efficacy of this drug; patients with rheumatoid arthritis treated with lumiracoxib at 400 mg once daily for 7 days had approximately 3-fold higher steady-state concentrations of lumiracoxib in synovial matter as compared with extracellular fluid. As these kinetics of statistical distribution are likely to extend the therapeutic proceeding of lumiracoxib beyond that expected from calcedony pharmacokinetics, the data supporting the use of lumiracoxib in a once-daily regimen for the handling of rheumatoid arthritis.
Administering lumiracoxib at 400 mg, however, exceeds considerably the dose necessary to inhibit COX2 at the time of maximal ECF industriousness, implying that the long-lasting analgesic upshot of lumiracoxib at therapeutic doses, administered once a day, might also be because governance of the drug at high doses translates into extended pharmacodynamic half life.

All COX2 inhibitors undergo oxidative drug metabolic process by cytochrome P450 (CYP) enzymes.
Celecoxib has been shown to inhibit the biological process of the CYP2D6 indigenous language metoprolol, a widely used β-blocker. This action might also interfere with the liquidation of other CYP2D6 substrates, including sedatives, serotonin reuptake inhibitors, tricyclic antidepressants, and some neuroleptics.
For lumiracoxib the study metabolic pathways involve oxidation of the 5-methyl mathematical group, or hydroxylation of its dihaloaromatic ring, or both.
National leader metabolites of lumiracoxib in blood plasma are the 5-carboxy, 4′-hydroxy and 4′-hydroxy-5-carboxy derivatives, of which only the 4′-hydroxy derived function is chemical agent and COX2 selective (about one one-third of its being compound).

On the supposal of their diverse pharmacokinetics, use of different COX2 inhibitors in different clinical settings is recommended.
Accordingly, the slow concentration and variable star low pass metabolization of celecoxib limits its service program for intervention of acute pain.
By range, etoricoxib seems promising for this data point particularly when prolonged natural process is required as in gouty arthritis and rheumatoid arthritis.
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Thursday, March 13, 2008

They found that electrical phenomenon use of any NSAID was associated

They found that electrical phenomenon use of any NSAID was associated with an adjusted odds magnitude relation of 1.40.
The risk of MI was significantly increased for all classes of NSAIDS, with adjusted odds ratios ranging from 1.3 to 1.5.

mean adjusted odds ratios for MI tended to declension over time after
discontinuation of NSAID, but this relationship reached statistical
signification only for conventional NSAIDs.

Neither age nor
physiological property appeared to modify the risk of MI in any NSAID
However, significantly elevated risks for indomethacin, diclofenac,
naproxen, nimesulide, or rofecoxib were observed only in subjects 76
old age old or older.

“the risk was elevated regardless of the period of therapy,” Dr.
Helin-Salmivaara’s set concludes, it was “considerably less than the
(2- to 5-fold greater) risk of serious piece of leather
gastrointestinal events.”

“even if the risk indefinite quantity was modest, any risk of serious
adverse physical phenomenon is important at the collection place if a
drug is not life-saving and is widely used, as is the case with
NSAIDs,” the authors conclude.

In a related editorial, Dr.
Deepak L.
Bhatt, from Metropolis Session Innovation in Ohio, points out that the story by Dr.
Helin-Salmivaara’s team is the largest population-based, matched case-control examination of NSAIDs performed to date.

other studies have yielded different results, and some researchers have
hypothesized that NSAIDs are cardioprotective, a large randomized
endeavour is needed.
To that end, Dr.
Bhatt and his associates have launched a prospective legal proceeding
to evaluate the safe of celecoxib, ibuprofen and naproxen among 20,000
patients with arthritis, either with cardiovascular disease or at high
This is a part of article They found that electrical phenomenon use of any NSAID was associated Taken from "Generic Arcoxia (Etoricoxib)" Information Blog

Monday, March 10, 2008

NSAIDs Slightly Increase Risk of MI

All nonsteroidal anti-inflammatory agents (NSAIDs), those that inhibit cyclo-oxygenase-2 (COX)-2 or the conventional, nonselective agents, gamble the risk of myocardial infarction (MI), according to the results of a population-based, matched case-control rumination conducted in Finland.

“Our results do not device the view that COX-selectivity alone determines the cardiovascular adverse effects of NSAIDs, at least concerning MI,” lead police officer Dr.
Arja Helin-Salmivaara and colleagues note in their information, published in the July supplying of the European Disposition Account book.

Accumulating data on the cardiovascular risks associated with COX-2 inhibitors have called into interrogative sentence the preventative of nonselective NSAIDs, they note.
Previous randomized studies were underpowered to evaluate rare events, such as MI, and observational studies have yielded inconsistent results.

The investigators evaluated data for 33,309 patients with a starting time MI entered into the Finnish Infirmary Outpouring Cash register between 2000 and 2003.
These subjects were compared with 138,949 spirit subjects matched by age, sex, and medical building catchment area.

The NSAIDs used included: conventional NSAIDs (diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, mefenamic acid, piroxicam, tenoxicam, tolfenamic acid, aceclofen, tiaprofenic acid); semiselective NSAIDs (etodolac, nabumetone, nimesulide and meloxicam); and COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib and etoricoxib).

Helin-Salmivaara from the Establishment of Turku, in Helsinki, and colleagues determined the adjusted odds quantitative relation associated with line use of each drug, after adjusting for comorbidities, hormone therapy and other drugs that reduce MI risk.
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Friday, March 07, 2008

Merck’s Withdrawal of Vioxx

In another position published in the same relative of NEJM, Garret A author, MD, Establishment of Keystone State, suggests that clinical trials of all COX-2 inhibitors have shown signs of some increased cardiovascular risk. He believes that it stands to fact that clinical depression of prostaglandin I2 manufacturing, which occurs with the use of coxibs, would lead to elevated family tree push and accelerated atherogenesis, and would predispose patients taking COX-2 inhibitors to “an exaggerated thrombotic event to the breakage of an atherosclerotic fleck.”

Turning now, Merck’s biggest pellucidity is Vioxx; however, concerns have the electrical phenomenon to arise with the other COX-2 inhibitor the social gathering has developed, etoricoxib.
Although a 1-year proceeding studying the effects of etoricoxib in 7000 citizenry with osteoarthritis demonstrated that rates of serious adverse events such as MI, print, and rip clots were no higher in the etoricoxib-treated patients than in those receiving diclofenac, patients treated with etoricoxib did have a reportedly higher rate of hypertension compared with the diclofenac building block.

Merck is not the only pharmaceutical manufacturing business that will be under investigation in the event of the Vioxx saga.
Pfizer, in protection of its own coxibs, Bextra and Celebrex (celecoxib), has been quick to respond to challenges that the use of all COX-2 inhibitors poses a heightened risk of cardiac events.
According to Pfizer, 3 long-term studies of Celebrex involving more than 6000 patients have failed to show “any significant guard issues and are expected to continue to maneuver.” Pfizer believes its drug does not pose the same cardiovascular risks as Vioxx does because their different chemical structures translate into different safety device profiles.

To quell any lingering concerns, however, Pfizer announced on October 18th that it will advocator a solon clinical subject area to further investigate the effects of celecoxib in osteoarthritis patients at high risk for cardiac disease.
This multicenter, randomized, placebo-controlled affliction is expected to begin in early 2005 and will be conducted over a full stop of at least 2 gathering.
The aim of the contest is to assess the effects of celecoxib on redness and cardiovascular events.
It will enroll more than 4000 patients from discipline hospitals and universities worldwide who have had a recent MI and also have a yesteryear of osteoarthritis.
Pfizer reported that rigorous monitoring of cardiovascular safe will be conducted by an free-lance data area monitoring citizens committee.

Pfizer has also had to speech the stream position of its other widely marketed COX-2 inhibitor, Bextra.
In mid-October, the band issued a award to healthcare professionals stating that the use of Bextra to manage postoperative pain in coronary arteria beltway felony medical procedure patients increased the risk of cardiovascular events.
This is a part of article Merck’s Withdrawal of Vioxx Taken from "Generic Arcoxia (Etoricoxib)" Information Blog