A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors

2001 ◽  
Vol 357 (3) ◽  
pp. 709-718 ◽  
Author(s):  
Mark C. WALKER ◽  
Ravi G. KURUMBAIL ◽  
James R. KIEFER ◽  
Kirby T. MORELAND ◽  
Carol M. KOBOLDT ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Kinetic Mechanism ◽  
Time Dependent ◽  
Irreversible Inhibition ◽  
Inhibitory Mechanisms ◽  
Dependent Inhibition ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Time Dependent Inhibition ◽  
Cox 1

Cyclo-oxygenase (COX) enzymes are the targets for non-steroidal anti-inflammatory drugs (NSAIDs). These drugs demonstrate a variety of inhibitory mechanisms, which include simple competitive, as well as slow binding and irreversible inhibition. In general, most NSAIDs inhibit COX-1 and −2 by similar mechanisms. A unique class of diarylheterocyclic inhibitors has been developed that is highly selective for COX-2 by virtue of distinct inhibitory mechanisms for each isoenzyme. Several of these inhibitors, with varying selectivity, have been utilized to probe the mechanisms of COX inhibition. Results from analysis of both steady-state and time-dependent inhibition were compared. A generalized mechanism for inhibition, consisting of three sequential reversible steps, can account for the various types of kinetic behaviour observed with these inhibitors.

scholarly journals Kinetic basis for selective inhibition of cyclo-oxygenases

1999 ◽  
Vol 339 (3) ◽  
pp. 607-614 ◽  
Author(s):  
James K. GIERSE ◽  
Carol M. KOBOLDT ◽  
Mark C. WALKER ◽  
Karen SEIBERT ◽  
Peter C. ISAKSON
Keyword(s):  
Inhibitory Activity ◽  
Tight Binding ◽  
Selective Inhibition ◽  
Time Dependent ◽  
Experimental Conditions ◽  
Kinetic Behaviour ◽  
Competitive Kinetics ◽  
Binding Time ◽  
Cox 2 ◽  
Cox 1

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostaglandins by cyclo-oxygenases (COX). The discovery of a second COX isoform (COX-2) associated with inflammation led to agents that selectively inhibit COX-2, e.g. celecoxib. We evaluated the kinetics of inhibition of celecoxib and several NSAIDs. Celecoxib displays classic competitive kinetics on COX-1 (Ki = 10-16 μM). An initial competitive interaction with COX-2 can also be discerned with celecoxib (Ki = 11-15 μM), followed by a time-dependent interaction leading to potent inhibition, characterized as inactivation (Kinact = 0.03-0.5 s-1). Half-maximal inhibition (IC50) using end-point assays reflects the competitive component on COX-1 (IC50 = 4-19 μM) and the inactivation component on COX-2 (IC50 = 0.003-0.006 μM). NSAIDs exhibit four distinct modes of COX inhibition based on kinetic behaviour: (1) competitive, e.g. ibuprofen; (2) weak binding, time-dependent, e.g. naproxen, oxicams; (3) tight binding, time-dependent, e.g. indomethacin; (4) covalent, e.g. aspirin. In addition, most NSAIDs display different kinetic behaviour for each isoform. Weakly binding inhibitors show variable behaviour in enzyme assays, with apparent inhibitory activity being markedly influenced by experimental conditions; determination of kinetic constants with this class is unreliable and IC50 values are strongly dependent on assay conditions. Although IC50 determinations are useful for structure/activity analyses, the complex and distinct mechanisms of enzyme inhibition of each COX isoform by the NSAIDs renders comparison of inhibitory activity on COX-1 and COX-2 using IC50 ratios of questionable validity.

scholarly journals Effects of selective inhibition of cyclooxygenase and lipooxygenase pathways in follicle rupture and ovulation in the rat

Reproduction ◽  
2006 ◽  
Vol 132 (4) ◽  
pp. 571-577 ◽  
Author(s):  
M Gaytán ◽  
C Bellido ◽  
C Morales ◽  
J E Sánchez-Criado ◽  
F Gaytán
Keyword(s):  
Selective Inhibition ◽  
Spatial Targeting ◽  
Follicle Rupture ◽  
Immature Rats ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors ◽  
Cox 1

Treatment with non-steroidal anti-inflammatory drugs, either non-selective or selective cyclooxygenase-2 (COX-2) inhibitors, consistently impairs ovulation, indicating the essential role of COX-2/prostaglandins in the ovulatory process. Indomethacin, a potent inhibitor of both COX-1 and COX-2, induced several ovulatory alterations, consisting of a decrease in the number of oocytes effectively ovulated, trapping of oocytes inside the luteinized follicle, as well as abnormal follicle rupture at the basolateral sides, with release of the oocyte and follicular fluid to the interstitium. Yet, the precise role of prostaglandins in ovulation and whether some of the ovulatory defects induced by indomethacin are due to interference with additional components of the ovulatory cascade, beyond prostaglandin synthesis, are not completely understood. We have used gonadotrophin-primed immature rats to analyse whether, compared to indomethacin, selective inhibition of COX-2, with or without concomitant inhibition of COX-1, or selective inhibition of the lipooxygenase (LOX) pathway, induce similar ovulatory alterations. Immature rats (27 days of age) were injected PMSG (10 IU), and 48 h later hCG (10 IU) subcutaneously, and different anti-inflammatory drugs. Animals were killed at 21 h after hCG injection. Rats treated with the selective COX-2 inhibitor NS398 (10 mg/kg body weight, (bw)) showed alterations in follicle rupture as those treated with indomethacin (0.5 mg/rat), albeit affecting a lower number of follicles, irrespective of the concomitant inhibition of COX-1 with the selective inhibitor SC560 (10 mg/kg bw). Rats treated with the LOX inhibitor NDGA (300 mg/kg bw) did not show ovulatory alterations. These data indicate that the characteristic alterations of follicle rupture induced by indomethacin, are also induced by selective COX-2 inhibitors, strengthening the contention that prostaglandins play a crucial role in the spatial targeting of follicle rupture at the apex.

The Renal Effects of NSAIDs in Dogs

2015 ◽  
Vol 51 (3) ◽  
pp. 197-203 ◽  
Author(s):  
Amy L. Lomas ◽  
Gregory F. Grauer
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Adverse Drug Events ◽  
Important Species ◽  
Federal Drug Administration ◽  
Renal Effects ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 1

The quality of life for dogs with osteoarthritis can often be improved with nonsteroidal anti-inflammatory drugs (NSAIDs); however, the number of adverse drug events associated with NSAID use reported to the Federal Drug Administration Center for Veterinary Medicine is higher than that for any other companion animal drug. Of those events, adverse renal reactions are the second most reported. NSAIDs produce pharmacologic effects via inhibition of cyclooxygenase (COX), which decreases production of prostanoids. Prostaglandins are synthesized by both the COX-1 and COX-2 enzymes in the healthy kidney and influence renal blood flow, glomerular filtration rate, renin release, and Na excretion. There are important species differences in the renal expression of COX-1 and COX-2. For example, dogs have higher basal levels of COX-2 expression in the kidney compared with humans. In addition, in dogs with chronic kidney disease, an increase in COX-2 expression occurs and synthesis of prostaglandins shifts to the COX-2 pathway. For those reasons, NSAIDs that target COX-2 may be expected to adversely affect renal function in dogs, especially dogs with chronic kidney disease. The purpose of this review was to evaluate the literature to report the renal effects of NSAIDs in dogs.

scholarly journals Meloxicam in pain syndrome treatment of comorbid diseases patients

2021 ◽  
pp. 209-215
Author(s):  
O. A. Shavlovskaya ◽  
I. A. Bokova ◽  
N. I. Shavlovskiy
Keyword(s):  
Gastrointestinal Tract ◽  
Pain Syndrome ◽  
Cardiovascular Risks ◽  
Lower Back ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Comorbid Diseases ◽  
Per Oral ◽  
Cox 1

The issue nonsteroidal anti-inflammatory drugs (NSAIDs) use safety is associated with a high frequency of adverse events (AEs) from the gastrointestinal tract and cardiovascular risks. Patients with lower back pain (LBP) and osteoarthritis (OA), as a rule, have comorbid diseases, such as arterial hypertension (AH), coronary heart disease (CHD), gastrointestinal tract (GIT) diseases, which significantly complicates the appointment of NSAIDs. The main guideline in NSAIDs appointment is the selective ability to inhibit cyclooxygenase-1 and -2 (COX). The ratio of the activity of NSAIDs when blocking COX-1/COX-2 allows us to judge their potential toxicity. And, then higher the selectivity of NSAIDs, then lower its toxicity. For example, the ratio of COX-1/COX-2 in meloxicam is 0.33, diclofenac – 2.2, tenoxicam – 15, piroxicam – 33, indomethacin – 107. To the predominantly selective COX-2 NSAIDs include meloxicam, which has little effect on the GIT, the lowest relative risk (RR) of complications from the cardiovascular system (CVS). The therapeutic efficacy of meloxicam is comparable to piroxicam and diclofenac. A number of studies have shown the high efficacy of meloxicam, both with per oral (p/o) administration (7.5–15 mg/d), and with intramuscular (i/m) administration (1.5 ml), and when injected into trigger zones. Both with p/o and the injectable form of meloxicam has minimal GIT AEs and absence local reaction in the injection area. The drug can be recommended both as a combination therapy and prescribed in monotherapy.

Involvement of cyclooxygenase 2 (COX-2) in intrinsic tone of isolated guinea pig

1995 ◽  
Vol 73 (11) ◽  
pp. 1561-1567 ◽  
Author(s):  
L. Charette ◽  
C. Misquitta ◽  
J. Guay ◽  
D. Riendeau ◽  
T. R. Jones
Keyword(s):  
Guinea Pig ◽  
Time Course ◽  
Cyclooxygenase 2 ◽  
Maximal Response ◽  
Pharmacological Agents ◽  
Cyclooxygenase 1 ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Indomethacin and related nonsteroidal anti-inflammatory drugs relax prostanoid-dependent intrinsic tone of isolated guinea pig trachea by inhibiting cyclooxygenase (COX). Recently, a second isoform of COX (COX-2) was discovered, which differed from COX-1 with respect to protein structure, transcriptional regulation, and susceptibility to inhibition by pharmacological agents. It is now known that indomethacin nonselectively inhibits COX-1 and COX-2, whereas NS-398 is a selective inhibitor of COX-2. In the present study we compared the activity of a selective (NS-398) and nonselective (indomethacin) COX-2 inhibitor on intrinsic tone of isolated guinea pig trachea. NS-398 ≥ indomethacin produced a reversal of intrinsic tone with a similar concentration-dependent (10 nM to 1 μM) time course (Tmax approximately 20–45 min), potency (EC50 1.7 and 5.6 nM, respectively), and maximal response. Contractions to cholinergic nerve stimulation (45 V, 0.5 ms, 0.1–32 Hz) and histamine were similarly modulated in tissues relaxed with the selective or nonselective COX-2 inhibitors. Immunoblot analyses showed that COX-2 protein synthesis was induced in both the cartilage and smooth muscle portions of the trachea during changes in intrinsic tone. These findings are consistent with pharmacological results and provide the first demonstration that prostanoid tone in isolated guinea pig trachea is dependent on COX-2 activity. The results also suggest that the activity of indomethacin in this preparation is likely related to COX-2 inhibition.Key words: cyclooxygenase 2, relaxation, guinea pig trachea, cyclooxygenase 1.

Sign in / Sign up

Export Citation Format

Share Document