Pharmacodynamic of cyclooxygenase inhibitors in humans

doi:10.1016/j.prostaglandins.2006.05.019

Prostaglandins & Other Lipid Mediators

Volume 82, Issues 1–4, January 2007, Pages 85-94

https://doi.org/10.1016/j.prostaglandins.2006.05.019 Get rights and content

Abstract

We provide comprehensive knowledge on the differential regulation of expression and catalysis of cyclooxygenase (COX)-1 and COX-2 in health and disease which represents an essential requirement to read out the clinical consequences of selective and nonselective inhibition of COX-isozymes in humans. Furthermore, we describe the pharmacodynamic and pharmacokinetic characteristics of major traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and coxibs (selective COX-2 inhibitors) which play a prime role in their efficacy and toxicity. Important information derived from our pharmacological studies has clarified that nonselective COX inhibitors should be considered the tNSAIDs with a balanced inhibitory effect on both COX-isozymes (exemplified by ibuprofen and naproxen). In contrast, the tNSAIDs meloxicam, nimesulide and diclofenac (which are from 18- to 29-fold more potent towards COX-2 in vitro) and coxibs (i.e. celecoxib, valdecoxib, rofecoxib, etoricoxib and lumiracoxib, which are from 30- to 433-fold more potent towards COX-2 in vitro) should be comprised into the cluster of COX-2 inhibitors. However, the dose and frequency of administration together with individual responses will drive the degree of COX-2 inhibition and selectivity achieved in vivo. The results of clinical pharmacology of COX inhibitors support the concept that the inhibition of platelet COX-1 may translate into an increased incidence of serious upper gastrointestinal bleeding but this effect on platelet COX-1 may mitigate the cardiovascular hazard associated with the profound inhibition of COX-2-dependent prostacyclin (PGI₂).

Section snippets

Regulation of COX-1 and COX-2 expression and activity

Despite COX-1 and COX-2 share the same catalytic activities, i.e. cyclooxygenase and peroxidase [15], they are differently regulated. In fact, it has been shown that COX-2 requires considerably lower levels of hydroperoxides to initiate cyclooxygenase catalysis than those required by COX-1 [16]. Moreover, the COX-2 activity occurs at lower levels of free AA than COX-1 activity [17]. Another important difference between the two pathways of prostanoid biosynthesis is related on the regulation of

Classification of COX inhibitors based on pharmacodynamic

The biochemical selectivity of COX inhibitors towards COX-2 is currently assessed using the human whole blood assays [55], [56]. These assays are based on the measurement of PGE₂ production, in response to LPS added to heparinized blood samples for 24 h which reflects the time-dependent induction of COX-2 in circulating monocytes [55]. The parallel measurement of TXB₂ production during whole blood clotting is used as an index of platelet COX-1 activity [56]. In fact, serum TXB₂ represents the

Development of biomarkers to define bioequivalent doses of COX inhibitors for efficacy and toxicity

It has been shown that COX-2 inhibition, as determined by PGE₂ levels in LPS-stimulated whole blood in vitro, can be used as a marker to predict drug efficacy in humans [5]. In fact, IC₈₀ values have been found to correlate directly with the analgesic/anti-inflammatory plasma concentrations of different COX inhibitors [5]. Cryer and Feldman reported that the inhibitory effects of tNSAIDs on gastric PGE₂ synthesis correlate with COX-1 inhibitory potency in clotting blood (P < 0.001) which can be

Conclusions

The knowledge of clinical pharmacology of COX inhibitors is of valuable help to give a mechanistic interpretation of the results of clinical trials assessing the efficacy and safety of COX inhibitors.

First of all we have understood that nonselective NSAIDs are only those tNSAIDs with a balanced inhibitory effect on both COX-isozymes. The substantial inhibition of platelet COX-1 will translate into an increased incidence of serious upper GI bleeding on the basis of the suggestion that a profound

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COX-1 ensures adequate synthesis of prostanoids responsible for maintaining physiological homeostasis [13], whereas COX-2 is involved in the inflammatory response [26,27] and is vasoprotective [12,28]. COX-1 is involved in the production of prostaglandin E2 (PG-E2), which helps to protect the gastric epithelium from acid injury and has a role in gut homeostasis, as well as thromboxane A2 (TX-A2), which is released by thrombocytes following trauma [12,25]. This role is quite different from that of COX-2, which catalyses the synthesis of molecules which promote inflammation.
We examined how topically-applied naproxen sodium affects human nasal epitheliocytes in culture.
Samples of healthy human primary nasal epithelium (NE) harvested during septoplasty from volunteers without rhinosinusitis were incubated in cell culture. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays may be utilised when assessing cellular damage (toxicity), as evidenced by DNA fragmentation, nuclear condensation, alteration in the outer plasma membrane and cytoskeletal alteration. This was the method used in the study. Cultured epitheliocytes were incubated with naproxen sodium for 24 h at 37 °C. The MTT assay was then performed and the cells' morphology was examined by confocal microscopy. Additionally, cellular proliferation was assessed by the artificial scratch method followed by light microscopy.
The results indicated that naproxen sodium does not cause any cytotoxic effects upon nasal epithelial cells when applied topically. There was no evidence indicating cytotoxicity on the nasal epitheliocytes in culture for the 24 h period over which the drug was applied. In particular, there was no alteration in cellular morphology, damage to the intracellular organelles structure or the cytoskeleton secondary to naproxen sodium. Furthermore, cellular proliferation occurred normally in these conditions, as on scratch test.
Topical naproxen sodium may be used on nasal epithelial cells without inducing toxicity. This agent is therefore suitable, given its known anti-inflammatory effects, for use in patients suffering from diseases involving nasal and paranasal sinusal inflammation, including rhinosinusitis (both chronic and acute) and nasal polyposis which should be investigated. In the future, topical medication forms for nasal usage should be developed.
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Non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat pain, fever, and inflammation. Historically, NSAIDs have been categorized as traditional NSAIDs and newer cyclooxygenase (COX)-2 inhibitors (coxibs). However, traditional NSAIDs also inhibit the COX-1 and COX-2 enzyme isoforms to a varying degree. This diversity of COX-1 and COX-2 selectivity within the class of traditional NSAIDs has proven clinically important, with evidence accumulating on the cardiovascular risks associated with selective COX-2 inhibition. Thus, the relative COX-2 selectivity of traditional NSAIDs correlates with their cardiovascular risk profile, being more favourable for non-selective NSAIDs, such as naproxen and low-dose ibuprofen, and less favourable for more COX-2 selective agents, such as diclofenac. To enhance clinically relevant terminology, we advocate categorizing all non-aspirin NSAIDs—including traditional NSAIDs—according to their relative COX-1 and COX-2 selectivity as either COX-1 inhibitors, non-selective NSAIDs, or COX-2 inhibitors. We further recommend subcategorizing COX-2 inhibitors as newer COX-2 inhibitors (coxibs) or older COX-2 inhibitors. Finally, we recommend examining the effects of the individual NSAIDs included in each of the proposed categories. Adhering to these recommendations will align future studies, advance interpretation of COX-specific adverse cardiovascular effects, and provide better guidance to clinicians prescribing NSAIDs.
Les anti-inflammatoires non stéroïdiens (AINS) différents de l'aspirine sont fréquemment utilisés pour traiter la douleur, la fièvre et l'inflammation. Les AINS étaient d'habitude classés en deux catégories : les AINS classiques et les nouveaux inhibiteurs de la cyclooxygénase (COX)-2. Or, les AINS classiques inhibent aussi, à divers degrés, les isoformes enzymatiques COX-1 et COX-2. Cette sélectivité variable envers la COX-1 et la COX-2 au sein de la classe des AINS classiques s'est avérée pertinente sur le plan clinique, puisque de plus en plus de données font état des risques cardiovasculaires associés à l'inhibition sélective de la COX-2. Par conséquent, la sélectivité relative des AINS classiques pour la COX-2 est corrélée avec leur profil de risque cardiovasculaire, qui est plus favorable dans le cas des AINS non sélectifs tels que le naproxène et l'ibuprofène à faible dose, et moins favorable avec les agents plus sélectifs de la COX-2 tels que le diclofénac. Afin que la terminologie reflète mieux des aspects pertinents sur le plan clinique, nous préconisons de classer tous les AINS différents de l'aspirine, y compris les AINS classiques, selon leur sélectivité relative à l’égard de la COX-1 et de la COX-2, en trois catégories : inhibiteurs de la COX-1, AINS non sélectifs, et inhibiteurs de la COX-2. Nous recommandons également des sous-catégories d'inhibiteurs de la COX-2 : nouveaux inhibiteurs de la COX-2 (coxibs) et anciens inhibiteurs de COX-2. Enfin, nous recommandons d’évaluer les effets de chaque AINS inclus dans chaque catégorie proposée. Le respect de ces recommandations permettra d'harmoniser les futures études, de mieux interpréter les effets indésirables cardiovasculaires propres aux inhibiteurs de la COX et de mieux orienter les décisions des cliniciens en matière de prescription d'AINS.
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ReviewPharmacodynamic of cyclooxygenase inhibitors in humans

Abstract

Section snippets

Regulation of COX-1 and COX-2 expression and activity

Classification of COX inhibitors based on pharmacodynamic

Development of biomarkers to define bioequivalent doses of COX inhibitors for efficacy and toxicity

Conclusions

Lancet

J Thorac Cardiovasc Surg

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Lancet

J Biol Chem

Eur J Vasc Endovasc Surg

Biochem Biophys Res Commun

Blood

Anal Biochem

J Biol Chem

J Biol Chem

J Biol Chem

Blood

J Thromb Haem

J Am Coll Cardiol

Thromb Res

Am J Med

The coxibs, selective inhibitors of cyclooxygenase-2

N Engl J Med

Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities

J Clin Invest

COX-2 and beyond: approaches to prostaglandin inhibition in human disease

Nat Rev Drug Discov

Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition

Pharmacol Rev

Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors

Rheumatology (Oxford)

Comparison of upper GI toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group

N Engl J Med

Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention

N Engl J Med

Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial

N Engl J Med

Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery

N Engl J Med

Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction

Circulation

Review
Pharmacodynamic of cyclooxygenase inhibitors in humans