Summary
Background
Even though the acetylation of platelet cyclooxygenase (COX)‐1 at serine‐529 is the direct mechanism of action of low‐dose aspirin, its antiplatelet effect has been characterized ...using indirect indexes of COX‐1 activity.
Objectives
We performed a clinical study with enteric‐coated low‐dose aspirin (EC‐aspirin), in healthy subjects, to evaluate the effects on the extent and duration of platelet COX‐1 acetylation, using a novel proteomic strategy for absolute protein quantification (termed AQUA), as compared with traditional pharmacokinetic and pharmacodynamic parameters.
Subjects and methods
In a phase I, single‐arm, open‐label study of EC aspirin (100 mg day−1) administered to 24 healthy subjects, we compared, over a 24 h‐period on day 1 and 7, % platelet acetylated COX‐1 (AceCOX‐1) with traditional pharmacokinetic and pharmacodynamics i.e. serum thromboxane (TX) B2, platelet function by monitoring CEPI(collagen/epinephrine) closure time (CT) using whole‐blood PFA‐100 and urinary excretion of 11‐dehydro‐TXB2 parameters.
Results
Acetylation of platelet COX‐1 was measurable before detection of aspirin levels in the systemic circulation and increased in a cumulative fashion upon repeated dosing. After the last dose of EC‐aspirin, %AceCOX‐1, serum TXB2 and CEPI‐CT values were maximally and persistently modified throughout 24 h; they averaged 76 ± 2%, 99.0 ± 0.4% and 271 ± 5 s, respectively. EC‐aspirin caused 75% reduction in urinary 11‐dehydro‐TXB2 excretion. After chronic dosing with aspirin, the pharmacokinetics of acetylsalicylic acid was completely dissociated from pharmacodynamics.
Conclusions
The demonstrated feasibility of quantifying the extent and duration of platelet COX‐1 acetylation will allow characterizing the genetic, pharmacokinetic and pharmacodynamic determinants of the inter‐individual variability in the antiplatelet response to low‐dose aspirin as well as identifying extra‐platelet sites of drug action.
Celecoxib McCormack, Paul L.
Drugs (New York, N.Y.),
01/2011, Letnik:
71, Številka:
18
Journal Article
Recenzirano
Celecoxib (Celebrex®) was the first cyclo-oxygenase (COX)-2 selective inhibitor (coxib) to be introduced into clinical practice. Coxibs were developed to provide anti-inflammatory/analgesic activity ...similar to that of nonselective NSAIDs, but without their upper gastrointestinal (GI) toxicity, which is thought to result largely from COX-1 inhibition. Celecoxib is indicated in the EU for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. This article reviews the clinical efficacy and tolerability of celecoxib in these EU-approved indications, as well as overviewing its pharmacological properties.
In randomized controlled trials, celecoxib, at the recommended dosages of 200 or 400 mg/day, was significantly more effective than placebo, at least as effective as or more effective than paracetamol (acetaminophen) and as effective as non-selective NSAIDs and the coxibs etoricoxib and lumiracoxib for the symptomatic treatment of patients with active osteoarthritis, rheumatoid arthritis or ankylosing spondylitis.
Celecoxib was generally well tolerated, with mild to moderate upper GI complaints being the most common body system adverse events. In meta-analyses and large safety studies, the incidence of upper GI ulcer complications with recommended dosages of celecoxib was significantly lower than that with non-selective NSAIDs and similar to that with paracetamol and other coxibs. However, concomitant administration of celecoxib with low-dose cardioprotective aspirin often appeared to negate the GI-sparing advantages of celecoxib over NSAIDs.
Although one polyp prevention trial noted a dose-related increase in cardiovascular risk with celecoxib 400 and 800 mg/day, other trials have not found any significant difference in cardiovascular risk between celecoxib and placebo or non-selective NSAIDs. Meta-analyses and database-derived analyses are inconsistent regarding cardiovascular risk. At recommended dosages, the risks of increased thrombotic cardiovascular events, or renovascular, hepatic or hypersensitivity reactions with celecoxib would appear to be small and similar to those with NSAIDs.
Celecoxib would appear to be a useful option for therapy in patients at high risk for NSAID-induced GI toxicity, or in those responding suboptimally to or intolerant of NSAIDs. To minimize any risk, particularly the cardiovascular risk, celecoxib, like all coxibs and NSAIDs, should be used at the lowest effective dosage for the shortest possible duration after a careful evaluation of the GI, cardiovascular and renal risks of the individual patient.
The mechanism of action of low‐dose aspirin in the prevention of colorectal cancer (CRC) remains largely hypothetical. We aimed to compare the effects of low‐dose aspirin (100 mg/day for 7 days) ...given to 40 individuals undergoing CRC screening on the extent of cyclooxygenase (COX)‐1 acetylation at serine‐529 (AceCOX‐1), in blood platelets vs. colorectal mucosa, at 7 (group 1) and 24 h (group 2) after dosing. A significantly (P < 0.01) lower %AceCOX‐1 was detected in colonic and rectal mucosa (average 64%) vs. platelets (average 75%) in both groups. This effect was associated with an average 46% (P < 0.01) and 35% (P < 0.05) reduction in prostaglandin (PG) E2 levels and phosphorylated S6 (p‐S6) levels, respectively. Rectal mucosal levels of p‐S6/S6 significantly (P < 0.01) correlated with PGE2. These findings demonstrate that low‐dose aspirin produces long‐lasting acetylation of COX‐1 and downregulation of p‐S6 in human colorectal mucosa, an effect that may interfere with early colorectal carcinogenesis.
We investigated the occurrence of pharmacodynamic interaction between low-dose aspirin and naproxen.
The uncertainty of cardioprotection by naproxen has encouraged its combination with aspirin in ...patients with arthritis and cardiovascular disease.
The incubation of washed platelets with naproxen for 5 min before the addition of aspirin reduced the irreversible inhibition of thromboxane (TX)B2production by aspirin. The pharmacodynamic interaction between the two drugs was then investigated in four healthy volunteers who received aspirin (100 mg daily) for 6 days and then the combination of aspirin and naproxen for further 6 days: aspirin 2 h before naproxen (500 mg, twice-daily dosing). After 14 days of washout, naproxen was given 2 h before aspirin for further 6 days.
The inhibition of serum TXB2production (index of platelet cyclooxygenase COX-1 activity) and platelet aggregation ex vivo and urinary 11-dehydro-TXB2levels (index of TXB2biosynthesis in vivo) by aspirin alone (99 ± 0.2%, 95 ± 0.6%, and 81 ± 4%, respectively) was not significantly altered by the co-administration of naproxen, given either 2 h after aspirin or in reverse order. In a second study, the concurrent administration of a single dose of aspirin and naproxen did not affect platelet TXB2production and aggregation at 1 h after dosing, when aspirin alone causes maximal inhibitory effect. Moreover, the rapid recovery of platelet COX-1 activity and function supports the occurrence of a pharmacodynamic interaction between naproxen and aspirin.
Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin’s cardioprotective effects.
OBJECTIVE:Epoxyeicosatrienoic acids (EETs) act as vasodilators activating high conductance calcium-operated potassium (K) channels (Kca1.1, also named BK, MAXI-K). We found expression of MAXI-K ...channel in platelets. The present study aimed at defining its functionality in platelet using an in vitro model of platelet thrombosis.
DESIGN AND METHOD:We tested the effects of 5 μmol/L 11,12-EET and the pharmacological modulation of MAXI-K channel (agonists5 and 20 μmol/L BMS 191011, 5 μmol/L NS1619, 5 μmol/L NS11021). Platelet rich plasma was used to assess adhesion-induced thrombi formation under flow by microfluidics technology with collagen-coated microchips mimicking arterial blood flow. The kinetic of platelet responses to scalar doses of 0.3–10 μmol/L ADP, 0.05–2 μmol/L U46619 0.5–10 μg/mL collagen was determined by paired analysis using Born aggregometry. Flow-cytometry was used to analyse the expression of active fibrinogen receptor and P-selectin in stimulated platelets. The effects of 100 μmol/L aspirin and 1 μmol/L ticagrelor were also assessed.
RESULTS:In vitro thrombi formation was halved (expressed as platelet-covered area) by pre-treatment with either 11,12-EET (−45 ± 11%, n = 5, P < 0.001 vs control, Mean ± SD), aspirin (−66 ± 8%, n = 4, P < 0.001) or ticagrelor (−55 ± 8%, n = 4, P < 0.001). Similar results were obtained using BMS 5 μmol/L (−54 ± 17%, n = 6, P < 0.001), NS1619 (−50 ± 19%, n = 9, P < 0.001), NS11021 (−60 ± 21%, n = 6, P < 0.001). The addition of 20 μmol/L BMS191011 prior to platelet aggregation (EC502.67 μmol/L, 95%CI0.97–7.29, n = 36) significantly shifted to the right the dose response-curve to ADP (EC500.91 μmol/L, 0.43–1.92, n = 36). Platelet aggregation was further blunted by the addition of aspirin to BMS191011 (EC506.18 μmol/L, 2.11–18.09, n = 36). U46619- and collagen-induced aggregation was not altered. ADP-induced activation of the fibrinogen receptor (−48 ± 14% to −62 ± 10%, n = 7, P < 0.05) and P-selectin expression (−37 ± 15% to −41 ± 13%, n = 7, P < 0.01) were blunted by the activators of MAXI-K channel.
CONCLUSIONS:Activation of the MAXI-K channel by 11,12-EET and all the tested synthetic compounds is associated with reduced sensitivity to ADP and reduced thrombus generation through the inhibition of the amplificatory phase of platelet activation. The present results reveal new mechanisms of platelet activation and suggest that targeting MAXI-K might be of potential pharmacological interest for the prevention of atherothrombosis.
Inflammation, oxidative damage, and platelet activation are hypothesized biological mechanisms driving the disablement process. The aim of the present study is to assess whether biomarkers ...representing these mechanisms predicted major adverse health-related events in older persons.
Data are from 2,234 community-dwelling nondisabled older persons enrolled in the Health Aging and Body Composition study. Biomarkers of lipid peroxidation (ie, urinary levels of 8-iso-prostaglandin F(2α)), platelet activation (ie, urinary levels of 11-dehydro-thromboxane B(2)), and inflammation (serum concentrations of interleukin-6) were considered as independent variables of interest and tested in Cox proportional hazard models as predictors of (severe) mobility disability and overall mortality.
The sample's (women 48.0%, whites 64.3%) mean age was 74.6 (SD 2.9) years. During the follow-up (median 11.4 years), 792 (35.5%), 269 (12.0%), and 942 (42.2%) events of mobility disability, severe mobility disability, and mortality occurred, respectively. Only interleukin-6 showed significant independent associations with the onset of all the study outcomes. Higher levels of urinary 8-iso-prostaglandin F(2α) and 11-dehydro-thromboxane B(2) independently predicted increased risk of death (hazard ratio 1.10, 95% confidence interval 1.03-1.19 and hazard ratio 1.14, 95% confidence interval 1.06-1.23, respectively). No significant interactions of gender, race, cardiovascular disease, diabetes, and antiplatelet drugs were detected on the studied relationships.
The inflammatory marker interleukin-6 is confirmed to be a robust predictor for the onset of negative health-related events. Participants with higher urinary levels of 8-iso-prostaglandin F(2α) and 11-dehydro-thromboxane B(2) presented a higher mortality risk.
Non-steroidal anti-inflammatory drugs (NSAIDs), which act via inhibition of the cyclooxygenase (COX) isozymes, were discovered more than 100 years ago. They remain a key component of the ...pharmacological management of acute and chronic pain. The COX-1 and COX-2 isozymes have different biological functions; analgesic activity is primarily (although not exclusively) associated with inhibition of COX-2, while different side effects result from the inhibition of COX-1 and COX-2. All available NSAIDs, including acetaminophen and aspirin, are associated with potential side effects, particularly gastrointestinal and cardiovascular effects, related to their relative selectivity for COX-1 and COX-2. Since all NSAIDs exert their therapeutic activity through inhibition of the COX isozymes, strategies are needed to reduce the risks associated with NSAIDs while achieving sufficient pain relief. A better understanding of the inhibitory activity and COX-1/COX-2 selectivity of an NSAID at therapeutic doses, based on pharmacokinetic and pharmacodynamic properties (eg, inhibitory dose, absorption, plasma versus tissue distribution, and elimination), and the impact on drug tolerability and safety can guide the selection of appropriate NSAIDs for pain management. For example, many NSAIDs with moderate to high selectivity for COX-2 versus COX-1 can be administered at doses that maximize efficacy (~80% inhibition of COX-2) while minimizing COX-1 inhibition and associated side effects, such as gastrointestinal toxicity. Acidic NSAIDs with favorable tissue distribution and short plasma half-lives can additionally be dosed to provide near-constant analgesia while minimizing plasma concentrations to permit recovery of COX-mediated prostaglandin production in the vascular wall and other organs. Each patient's clinical background, including gastrointestinal and cardiovascular risk factors, should be taken into account when selecting appropriate NSAIDs. New methods are emerging to assist clinicians in the selection of appropriate NSAIDs and their doses/schedules, such as biomarkers that may predict the response to NSAID treatment in individual patients.
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class with anti-inflammatory, analgesic, and antipyretic properties. Contrary to the action of many traditional ...NSAIDs, diclofenac inhibits cyclooxygenase (COX)-2 enzyme with greater potency than it does COX-1. Similar to other NSAIDs, diclofenac is associated with serious dose-dependent gastrointestinal, cardiovascular, and renal adverse effects. Since its introduction in 1973, a number of different diclofenac-containing drug products have been developed with the goal of improving efficacy, tolerability, and patient convenience. Delayed- and extended-release forms of diclofenac sodium were initially developed with the goal of improving the safety profile of diclofenac and providing convenient, once-daily dosing for the treatment of patients with chronic pain. New drug products consisting of diclofenac potassium salt were associated with faster absorption and rapid onset of pain relief. These include diclofenac potassium immediate-release tablets, diclofenac potassium liquid-filled soft gel capsules, and diclofenac potassium powder for oral solution. The advent of topical formulations of diclofenac enabled local treatment of pain and inflammation while minimizing systemic absorption of diclofenac. SoluMatrix diclofenac, consisting of submicron particles of diclofenac free acid and a proprietary combination of excipients, was developed to provide analgesic efficacy at reduced doses associated with lower systemic absorption. This review illustrates how pharmaceutical technology has been used to modify the pharmacokinetic properties of diclofenac, leading to the creation of novel drug products with improved clinical utility.
Novel coxibs (i.e. etoricoxib, valdecoxib, parecoxib and lumiracoxib) with enhanced biochemical cyclooxygenase (COX)-2 selectivity over that of rofecoxib and celecoxib have been recently developed. ...They have the potential advantage to spare COX-1 activity, thus reducing gastrointestinal toxicity, even when administered at high doses to improve efficacy. They are characterized by different pharmacodynamic and pharmacokinetics features. The higher biochemical selectivity of valdecoxib than celecoxib, evidenced in vitro, may be clinically relevant leading to an improved gastrointestinal safety. Interestingly, parecoxib, a pro-drug of valdecoxib, is the only injectable coxib. Etoricoxib shows only a slightly improved COX-2 selectivity than rofecoxib, a highly selective COX-2 inhibitor that has been reported to halve the incidence of serious gastrointestinal toxicity compared to nonselective nonsteroidal antiinflammatory drugs (NSAIDs). Lumiracoxib, the most selective COX-2 inhibitor in vitro, is the only acidic coxib. The hypothesis that this chemical property may lead to an increased and persistent drug accumulation in inflammatory sites and consequently to an improved clinical efficacy, however, remains to be verified. Several randomized clinical studies suggest that the novel coxibs have comparable efficacy to nonselective NSAIDs in the treatment of osteoarthritis, rheumatoid arthritis and acute pain, but they share similar renal side-effects. The apparent dose-dependence of renal toxicity may limit the use of higher doses of the novel coxibs for improved efficacy. Large-size randomized clinical trials are ongoing to define the gastrointestinal and cardiovascular safety of the novel coxibs.
Selective cyclooxygenase 2 (COX2) inhibitors (COXIBs) are effective anti-inflammatory and analgesic drugs with improved gastrointestinal (GI) safety compared to nonselective nonsteroidal ...anti-inflammatory drugs known as traditional (tNSAIDs). However, their use is associated with a cardiovascular (CV) hazard (i.e. increased incidence of thrombotic events and hypertension) due to the inhibition of COX2-dependent vascular prostacyclin. Aiming to design COX2-selective inhibitors with improved CV safety, new NO-releasing COXIBs (NO-COXIBs) have been developed. In these hybrid drugs, the NO-mediated CV effects are expected to compensate for the COXIB-mediated inhibition of prostacyclin. This study evaluates the potential CV beneficial effects of VA694, a promising NO-COXIB, the anti-inflammatory effects of which have been previously characterized in several in vitro and in vivo experimental models. When incubated in hepatic homogenate, VA694 acted as a slow NO-donor. Moreover, it caused NO-mediated relaxant effects in the vascular smooth muscle. The chronic oral administration of VA694 to young spontaneously hypertensive rats (SHRs) significantly slowed down the age-related development of hypertension and was associated with increased plasma levels of nitrates, stable end-metabolites of NO. Furthermore, a significant improvement of coronary flow and a significant reduction of endothelial dysfunction were observed in SHRs submitted to chronic administration of VA694. In conclusion, VA694 is a promising COX2-inhibiting hybrid drug, showing NO releasing properties which may mitigate the CV deleterious effects associated with the COX2-inhibition.
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