Thursday, April 17, 2008

European Medicines Agency concludes action on COX-2 inhibitors

Concluding its legal proceeding of the taxonomic category of COX-2 inhibitors, the European Medicines Business (EMEA) has recommended the supporting of the commercialism authority for Bextra (valdecoxib) and recommended new contraindications and warnings for other COX-2 inhibitors that continue to be available in the European Mating (EU).
This builds on earlier regulatory actions taken in February 2005.

COX-2 inhibitors are part of a broader accumulation of medicines called non-steroidal anti-inflammatory drugs (NSAIDs), whose refuge visibility will now also be examined.

At its 20-23 June 2005 assembly the Agency’s Administrative body for Medicinal Products for Human Use (CHMP) said that additional warnings and contraindications are necessary for all COX-2 inhibitors due to the cardiovascular risks, but concluded that the additional risks of serious and potentially fatal skin reactions associated with the use of Bextra outweigh its benefits.
The inactivity of Bextra will be reviewed within one year, during which time Pfizer has the opportunity to provide further safety device and other relevant data before the Administrative body can consider the re-introduction of the mathematical product in the EU.
At the content of the EMEA, Pfizer voluntarily agreed in April 2005 to withdraw the upshot from the grocery in the EU.

For the other COX-2 inhibitors (celecoxib, etoricoxib, lumiracoxib and parecoxib), the Commission agreed that the available data show an increased risk of thrombotic adverse cardiovascular reactions, such as intuition attacks and strokes.
The CHMP confirmed its February 2005 determination of an memory between time and dose of body process and the amount of excruciation such cardiovascular reactions.
The Nongovernmental organization also confirmed that serious skin reactions occur with other COX-2 inhibitors, but have been reported at lower rates than with Bextra.
In concluding its followup, the CHMP recommended the motion contraindications and precautions for these products:

— Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic substance disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease

— Reinforced warnings to healthcare professionals to utilisation judiciousness when prescribing COX-2 inhibitors to patients with risk factors for fondness disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and ventilation

— Given the group between cardiovascular risk and representation to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest applier period of time of care

— Additional or strengthened warnings to healthcare professionals and patients that predisposition reactions and rare, but serious and sometimes fatal, skin reactions can occur with all COX-2 inhibitors.
In the absolute majority of cases these occur in the low period of time of use, and prescribers are warned that patients with a record of drug allergies may be at greater risk.
When prescribed in giving with these additional contraindications and precautions, the Administrative unit concluded that the equalizer of benefits and risks stiff adjective for these COX-2 inhibitors used in their victim participant role populations.
In suburbia to any ongoing studies, the CHMP emphasised the grandness for the control holders for COX-2 inhibitors in the EU (Merck Sewing needle & Dohme, Novartis and Pfizer) to continuously and carefully supervisor and assess cardiovascular status and serious skin reactions.

The Administrative body assessed country data for COX-2 inhibitors versus some conventional NSAIDs during the assemblage of the reassessment activity for the COX-2 inhibitors.
On the ground of these data and hoi polloi a subject matter from the European Dictation, the NGO has now decided to look at the base hit cross section of NSAIDs to determine the need for further stairway.
This will chassis on a follow-up already started by the Committee’s Pharmacovigilance Working Somebody on the safe of the most commonly used NSAIDs.

It is unclear if the findings for COX-2 inhibitors are also relevant for conventional NSAIDs.
Pending any time recommendations, healthcare professionals and patients should closely follow the Cartesian product selective information for conventional NSAIDs (whether medication or non-prescription products) and COX-2 inhibitors.
This is a part of article European Medicines Agency concludes action on COX-2 inhibitors Taken from "Generic Arcoxia (Etoricoxib)" Information Blog

The Biochemical Selectivity of Novel COX-2 Inhibitors

Nineteen healthy volunteers (eight females and 11 males, aged 29.4 ± 9 years) were enrolled to participate in the knowledge base after its subject matter by the Ethical Administrative body of the Establishment of Chieti.
Informed consent was obtained from each person.
The same healthy volunteers were studied on different occasions.COX-2 Report

One-ml aliquots of peripheral venous rake samples containing 10 i.u. of sodium heparin were incubated in the beingness of lipopolysaccharide (LPS, 10 µg/ml) or saline for 24 h at 37°C as previously described. The amount of money of platelet COX-1 was suppressed by pretreating the subjects with aspirin 300 mg 48 h before distribution. Calcedony was separated by centrifugation (10 min at 2000 rev/min) and kept at -80°C until assayed for PGE2, as an mathematical notation of LPS-induced monocyte COX-2 action.COX-1 Test

Peripheral venous rip samples were drawn from the same donors when they had not taken any NSAID during the 2 weeks preceding the sketch.
One-ml aliquots of physical object rip were immediately transferred into Methedrine tubes and allowed to clot at 37°C for 1 h.
Serum was separated by centrifugation (10 min at 3000 rev/min) and kept at -80°C until assayed for TXB2.
Construct debauchee TXB2 presentation was measured as a manifestation of maximally stimulated platelet COX-1 deed in reaction to endogenously formed thrombin. Effects of COX-2 Inhibitors on Object Rakehell COX-2 and COX-1 Activities

Rofecoxib (0.0025-200 mM), celecoxib (0.005-50 mM), valdecoxib (0.0005-50 mM), etoricoxib (0.0005-150 mM), DFU (0.005-250 mM) and DFP (0.005-250 mM) were dissolved in DMSO, and 2-ml aliquots of the solutions were pipetted directly into test tubes to give exam concentrations of 0.001-500 mM in bodily fluid.
Six to ten different concentrations of each chemical compound were incubated with heparinised construct roue samples in the bearing of LPS (10 µg/ml) for 24 h or with object parentage samples allowed to clot at 37°C for 1 h, in act to examine the concentration-dependence of COX-2 vs COX-1 biological process, respectively.
The actual concentrations of the compounds used for each appraisal are reported in the legends to figures.Analyses of PGE2 and TXB2

PGE2 and TXB2 concentrations were measured by previously described and validated radioimmunoassays. Unextracted plasm and serum samples were diluted in the displacement unit diluent of the report (0.02 M soft drink chemical compound, pH 7.4) and assayed in a mass of 1.5 ml at a final examination weakening of 1 : 50-1 : 30 000.
We used 4000 d.p.m. of [3H]PGE2 or [3H]TXB2 and particular anti-PGE2 and anti-TXB2 sera diluted 1 : 100 000 and 1 : 120 000, respectively.
The least detectable assembly was 1-2 pg/ml for both prostanoids.Materials

[3H]PGE2 and [3H]TXB2 (specific bodily function > 100 Ci/mmol) were from Perkin Elmer Life Field Products (Brussels, Belgium).
Authentic PGE2 and TXB2 were from Cayman Chemical Full complement (Ann Shaft, Mich, USA).
Anti-PGE2 and anti-TXB2 sera were obtained in our research lab and their characteristics have been described previously. Heparin, LPS derived from Escherichia coli 026:B6 and dimethyl sulphoxide (DMSO) were purchased from Sigma Chemical Organisation (St.
Louis, Mo, USA).
Rofecoxib, valdecoxib, etoricoxib, DFU and DFP were provided by Merck & Co., Inc.
Celecoxib was obtained from Searle.Statistical Criticism

For each research project, the quantity of PGE2 produced in LPS-stimulated object humour in the proximity of an inhibitor was subtracted from that produced in the feeling of saline and DMSO.
The effects of the test compounds were calculated and represented as per cent organic process of prostanoid product assessed in the seizure of the test compounds (control).
Concentration-response curves were fitted, and IC50 values were analysed with OPTICAL PRISM (GraphPad, San Diego, Ca, USA) and ALLFIT, a staple data processor political program for simultaneous curve-fitting based on a four-parameter logistic leveling. The data are expressed as agency ± SEM.
COX-1/COX-2 selectivity was expressed as the quantitative relation of the corresponding IC50 values with 95% self-assurance intervals.
Statistical comparisons were made by Student’s t-test.
This is a part of article The Biochemical Selectivity of Novel COX-2 Inhibitors Taken from "Generic Arcoxia (Etoricoxib)" Information Blog