COX-2 Isoenzyme Research Articles

Upregulation of Cyclooxygenases by Retinoic Acid in Rat Mesangial Cells

All-trans retinoic acid (ATRA) increases the expression of COX-1 and COX-2 and the production of PGE₂, a prostaglandin with anti-inflammatory effects in human mesangial cells (MC). COX-2 increased through a transcriptional mechanism independent of retinoic acid receptors (RAR) and retinoid X receptors (RXR) and dependent on extracellular regulated kinase-1/2 (ERK1/2), that became phosphorylated 5 min after ATRA addition. Here, in rat MC, ATRA also upregulated COX isoenzymes and PGE₂ production, but not in the same way as in human MC: (1) PGE₂ production increased only slightly; (2) RAR and RXR were involved in the transcriptional upregulation of COX-2 by ATRA since the RAR-pan-antagonist AGN193109 or the RXR-pan-antagonist HX531 abolished the induction of COX-2 mRNA whereas the RAR-pan-agonist TTNPB or the RXR-pan-agonist AGN194204 induced expression of COX-2, and (3) ERK1/2 phosphorylation, though important for COX-2 upregulation, took more than 1 h. Therefore the regulation of COX by ATRA exhibits striking differences between human and rat MC.

The neuronal excitability time-dependently changes after lipopolysaccharide administration in mice: Possible role of cyclooxygenase-2 induction

The parameters of pentylenetetrazol (PTZ)-induced seizures have been evaluated at various time intervals after lipopolysaccharide (LPS; Escherichia coli O111:B4, 100 μg/kg, i.p.) administration in mice. A proconvulsant effect occurred 4 h after LPS injection with decreased seizure latency and enhanced seizure intensity. In contrast, the incidence of seizures was reduced 18 h after LPS injection. There were no significant alterations on seizure parameters 2, 8, 12, and 24 h after LPS treatment. SC-58236, a selective cyclooxygenase (COX)-2 inhibitor (20 or 40 mg/kg, s.c.) treatment alone had no effect on PTZ-induced seizures, but reversed the antiseizure activity observed 18 h after LPS injection. However, SC-58236 treatment partially restored the proconvulsant changes that were observed 4 h after LPS administration. On the other hand, COX-1-selective inhibitor valeryl salicylate (20 or 40 mg/kg, s.c.) itself facilitated PTZ-induced seizures. Thus, it was not possible to evaluate the effects of valeryl salicylate on the excitability changes after LPS injection. These results indicate that the parameters of PTZ-induced seizures change time-dependently after LPS treatment, in which proconvulsant and anticonvulsant states could be seen in a sequence. It seems that COX-2 isoenzyme may be involved in the neuronal excitability changes due to LPS.

Involvement of endothelial thromboxane A2 in the vasoconstrictor response induced by 15-E2t-isoprostane in isolated human umbilical vein

The present study was undertaken to evaluate the contractile response of several E- and F-ring isoprostanes (IsoP) in human umbilical vein (HUV) and to investigate the role of the endothelium on the effect of 15-E2t-IsoP, the most potent vasoconstrictor isoprostane, in human vessels. HUV rings with or without endothelium were suspended in an organ bath for recording the isometric tension in response to different agonists. The inhibitors to be evaluated were applied 30 min before the addition of the agonist. All of the compounds tested produced concentration-dependent contractions when tested on HUV rings with endothelium. Although these compounds were equieffective, significant differences were observed in their potency, with U46619 being the most potent followed by 15-E2t-IsoP > 15-E1t-IsoP = 15-F2t-IsoP > 15-F1t-IsoP = 9-epi-15-F2t-IsoP in descending rank order of potency. 15-E2t-IsoP was the most potent of the isoprostanes evaluated and, therefore, the one employed in the present study. When intact endothelium HUV rings were used, 15-E2t-IsoP-induced contraction was unaffected by the endothelin-converting enzyme inhibitor, phosphoramidon (10 microM), suggesting that short-term endothelin-1 release is not involved in this response. However, the non-selective cyclooxygenase (COX) inhibitor, indomethacin (10 and 30 microM), and the COX-2 selective inhibitor, NS-398 (3, 10 and 30 microM) produced inhibitory effects on 15-E2t-IsoP-induced contraction of HUV rings with endothelium. These results indicate that COX-derived contractile prostanoids are involved in this effect. Furthermore, the apparent pKb values estimated for indomethacin (5.5) and NS-398 (5.4) suggest that the prostanoids involved are derived from the COX-2 isoenzyme pathway. On HUV rings with endothelium, the phospholipase A2 inhibitor, oleyloxyethyl phosphorylcholine (30 and 100 microM), induced an inhibitory effect on 15-E2t-IsoP-induced contraction, suggesting that the phospholipase A2 pathway is also involved in this effect. In addition, the thromboxane A2 synthase inhibitor furegrelate (10 and 30 microM) also inhibited 15-E2t-IsoP-induced contraction of HUV rings with endothelium, indicating that thromboxane A2 is one of the contractile prostanoids involved in this response. Endothelium denudation clearly diminished the vasoconstrictor potency of 15-E2t-IsoP, demonstrating that the endothelium releases a vasoconstrictor factor in response to 15-E2t-IsoP. The absence of an inhibitory effect at the highest concentration of furegrelate (30 microM) on 15-E2t-IsoP-induced contraction of HUV rings without endothelium suggested that endothelium is the source of thromboxane A2. We conclude that prostanoids derived from the COX-2 isoenzyme pathway participate in 15-E2t-IsoP-induced vasoconstriction of isolated HUV rings. Our results also indicate that endothelial thromboxane A2 is one of the prostanoids involved in this effect.

Effect of valdecoxib pretreatment on pain and secondary hyperalgesia: a randomized controlled trial in healthy volunteers [ISRCTN05282752, NCT00260325

BackgroundInduction of the COX-2 isoenzyme appears to play a major role in the genesis of central sensitization after nociceptive stimulation. This study aimed to investigate the efficacy of a single, oral dose of the specific COX-2 inhibitor-valdecoxib in attenuating the central sensitization – induced secondary hyperalgesia in a heat/capsaicin pain model in healthy volunteers.MethodsThe study was a randomized, double blind, placebo controlled, crossover, single dose efficacy trial using 20 healthy volunteers. Two hours following placebo or 40 mg, PO valdecoxib, participants underwent skin sensitization with heat/capsaicin, as well as supra-threshold pain and re-kindling measurements according to an established, validated pain model. Subjects rated pain intensity and unpleasantness on a visual analog scale and the area of secondary hyperalgesia was serially mapped.ResultsThe area of secondary hyperalgesia produced after 40 mg of valdecoxib was no different than that after placebo. Furthermore, there were no significantly relevant differences when volunteers were treated with valdecoxib or placebo in relation to either cold- or hot pain threshold or the intensity of pain after supra-threshold, thermal pain stimulation.ConclusionWe demonstrated that a single, oral dose of valdecoxib when does not attenuate secondary hyperalgesia induced by heat/capsaicin in a cutaneous sensitization pain model in healthy volunteers.

Protective effect of cyclooxygenase‐2 (COX‐2) inhibitors but not non‐selective cyclooxygenase (COX)‐inhibitors on ethanol withdrawal‐induced behavioural changes

Cyclooxygenase (COX) is reported to play a significant role in neurodegeneration. Recent studies have shown that chronic ethanol administration up-regulates cyclooxygenase expression. In the present study we examined the effect of nimesulide (a preferential COX-2 inhibitor), rofecoxib (a highly selective COX-2 inhibitor) or naproxen (a non-selective COX-inhibitor displaying high affinity towards the COX-1 isoenzyme) on alcohol-induced withdrawal symptoms. Mice were made physically dependent on alcohol by the chronic administration of ethanol (2 g/kg of 10% v/v), intragastrically, twice on day 1 and then once-daily on successive days for a total of 7 days. Nimesulide [2.5 mg/kg, intraperitoneally (i.p.)], rofecoxib (2 mg/kg, i.p.) or naproxen (7 mg/kg, i.p.) were administered daily for 7 days before administering alcohol intragastrically. After 24 hours of the last alcohol administration, the treatments were reversed and the mice were tested for withdrawal, so that the animals that had received COX-inhibitors followed 30 minutes later by ethanol on days 1-7 were challenged with saline. Similarly, the animals which received saline followed 30 minutes later by ethanol received only saline. Behavioural analysis revealed hyperlocomotor activity, increased anxious response and increased hyperalgesia in mice. Also, alcohol withdrawal decreased the threshold for Pentylenetetrazole-(PTZ)-induced convulsions. Pretreatment with COX-inhibitors rofecoxib (2 mg/kg, i.p.) or nimesulide (2.5 mg/kg, i.p.) displayed significant protection against ethanol-induced withdrawal symptoms, while naproxen (7 mg/kg, i.p.) was not effective in reversing alcohol-induced withdrawal symptoms. The results of the present study suggest strongly the possible role of cyclooxygenases, particularly COX-2 inhibitors, on ethanol-induced withdrawal symptoms and the potential use of COX-2 inhibitors in their prevention and treatment.

Role of cyclooxygenase isoforms in gastric mucosal defense and ulcer healing

The rationale for the development of selective inhibitors of cyclooxygenase-2 (COX-2) was the proposal that this enzyme plays an important role in inflammation but does not contribute to the resistance of the gastrointestinal mucosa against injury. However, studies from several groups have established that both COX-1 and COX-2 have important functions in the maintenance of gastrointestinal mucosal integrity. Thus, in the normal rat stomach lesions only develop when both COX-1 and COX-2 are inhibited. On the other hand, in specific pathophysiological situations the isolated inhibition of either COX-1 or COX-2 without simultaneous suppression of the other COX isoenzyme is ulcerogenic. Furthermore, COX-2 plays an important role in the healing of gastric ulcers and inhibition of COX-2 delays ulcer healing. From these findings the initial concept that only inhibition of COX-1 interferes with gastrointestinal defense has to be re-evaluated.

Discovering COX-Inhibiting Constituents ofMorusRoot Bark: Activity-Guided versus Computer-Aided Methods

The aim of this study was to compare the efficiency of two well known approaches for the discovery of the bioactive principle/s in medicinal plants, namely the activity-guided isolation versus the computer-aided drug discovery by means of virtual screening (VS) techniques. Morus root bark of Morus sp. L. (Moraceae) was selected as application example for the discovery of compounds with anti-inflammatory activity. The two cyclooxygenase isoenzymes COX-1 and COX-2 were chosen as targets and the corresponding pharmacophore models were generated by our research. The activity-guided fractionation of the methanol extract of the root bark resulted in the isolation of nine compounds. Their structures were elucidated by mass spectrometry, 1- and 2-dimensional NMR experiments and identified as moracins B, M, the regioisomers O/P as a mixture, and sanggenons B, C, D, E and O. The COX-1 and COX-2 inhibiting activities of these compounds were established in an enzyme assay and compared with the predicted hits obtained from the VS. Sanggenons C, E, and O, that were tested the first time for an inhibitory effect on COX-1 and -2, showed IC50 values of 10-14 microM, and 40-50 microM, respectively. The results show that the COX activities obtained for the sanggenons are correctly predicted by the in silico filtering experiment. In the case of the isolated moracins, however, it failed because the COX inhibiting activities of moracins M and P/O were not retrieved by the VS. Structure-activity relationships of the isolated compounds are discussed as well as potential pitfalls and advantages of the applied strategies.

Cardiovascular and gastrointestinal effects of COX-2 inhibitors and NSAIDs: achieving a balance

Conventional 'nonselective' nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation; however, the potential gastrointestinal risks associated with their use can be a cause for concern. In response to the adverse effects that can accompany nonselective NSAID use, selective cyclo-oxygenase (COX)-2 inhibitors were developed to target the COX-2 isoenzyme, thus providing anti-inflammatory and analgesic benefits while theoretically sparing the gastroprotective activity of the COX-1 isoenzyme. Data from large-scale clinical trials have confirmed that the COX-2 inhibitors are associated with substantial reductions in gastrointestinal risk in the majority of patients who do not receive aspirin. However, some or all of the gastrointestinal benefit of COX-2 inhibitors may be lost in patients who receive low, cardioprotective doses of aspirin, and recent evidence suggests that some of these agents, at some doses, may be associated with an increased risk for cardiovascular adverse events compared with no therapy. The risks and benefits of conventional NSAIDs and of COX-2 inhibitors must be weighed carefully; in clinical practice many patients who might benefit from NSAID or COX-2 therapy are likely to be elderly and at relatively high risk for gastrointestinal and cardiovascular adverse events. These patients are also more likely to be taking low-dose aspirin for cardiovascular prophylaxis and over-the-counter NSAIDs for pain. Identifying therapies that provide relief from arthritis related symptoms, confer optimum cardioprotection, and preserve the gastrointestinal mucosa is complex. Factors to consider include the interference of certain NSAIDs with the antiplatelet effects of aspirin, differences in the adverse gastrointestinal event rates among nonselective NSAIDs and selective COX-2 inhibitors, emerging data regarding the relative risks for cardiovascular events associated with these drugs, and the feasibility and cost of co-therapy with proton pump inhibitors.

Role of COX-1 Isoenzyme on Angiotensin II-Induced Endothelial Dysfunction in Murine Mesenteric Small Arteries

Role of COX-1 Isoenzyme on Angiotensin II-Induced Endothelial Dysfunction in Murine Mesenteric Small Arteries

Integrin-mediated Adhesion and Soluble Ligand Binding Stabilize COX-2 Protein Levels in Endothelial Cells by Inducing Expression and Preventing Degradation

Cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin synthesis, is highly expressed during inflammation and cellular transformation and promotes tumor progression and angiogenesis. We have previously demonstrated that endothelial cell COX-2 is required for integrin alphaVbeta3-dependent activation of Rac-1 and Cdc-42 and for endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047; Dormond, O., Bezzi, M., Mariotti, A., and Ruegg, C. (2002) J. Biol. Chem. 277, 45838-45846). In this study, we addressed the question of whether integrin-mediated cell adhesion may regulate COX-2 expression in endothelial cells. We report that cell detachment from the substrate caused rapid degradation of COX-2 protein in human umbilical vein endothelial cells (HUVEC) independent of serum stimulation. This effect was prevented by broad inhibition of cellular proteinases and by neutralizing lysosomal activity but not by inhibiting the proteasome. HUVEC adhesion to laminin, collagen I, fibronectin, or vitronectin induced rapid COX-2 protein expression with peak levels reached within 2 h and increased COX-2-dependent prostaglandin E2 production. In contrast, nonspecific adhesion to poly-L-lysine was ineffective in inducing COX-2 expression. Furthermore, the addition of matrix proteins in solution promoted COX-2 protein expression in suspended or poly-L-lysine-attached HUVEC. Adhesion-induced COX-2 expression was strongly suppressed by pharmacological inhibition of c-Src, phosphatidylinositol 3-kinase, p38, extracellular-regulated kinase 1/2, and, to a lesser extent, protein kinase C and by the inhibition of mRNA or protein synthesis. In conclusion, this work demonstrates that integrin-mediated cell adhesion and soluble integrin ligands contribute to maintaining COX-2 steady-state levels in endothelial cells by the combined prevention of lysosomal-dependent degradation and the stimulation of mRNA synthesis involving multiple signaling pathways.

Novel Insights and Therapeutical Applications in the Field of Inhibitors of COX-2

The discovery of the two isoenzymes COX-1 and COX-2 and the knowledge of their function, localisation and regulation has initiated the development of COX-2 selective inhibitors (coxibs). Inducible COX-2 at the peripheral site of inflammation has been detected in the early 1990s, the involvement of recently detected spinal COX-2 has led to new insights into mechanisms of pain and may explain analgesic and antipyretic properties of COX-2 selective inhibitors. The coxibs rofecoxib and celecoxib have been introduced into therapy and seem to offer some advantages over the classical non-selective NSAIDs. The search for new COX-2 inhibitors is going on, the development of etoricoxib and lumiracoxib is a step ahead concerning efficacy, tolerability and safety. Until today COX-2 selective inhibitors have found their place in therapy of arthritis, osteoarthritis, dysmenorrhea and acute pain. A new paradigm in pain therapy seems to justify their use in perioperative settings in a preemptive or multimodal therapeutical strategy. In the future COX-2 selective inhibitors as opioid sparing agents could become an important tool in pain therapy. Even a therapeutical benefit of COX-2 selective inhibitors in the treatment of Alzheimer's Disease or in the prevention or treatment of colorectal or prostate cancer is presently intensely investigated. Recently some authors reported on COX-3, a splicing variant of COX-1. If COX-3 really represents the target for acetaminophen must be called into question.

COX-3 and the mechanism of action of paracetamol/acetaminophen

Paracetamol produces analgesia in the mouse writhing test through a central action which is paralleled by a reduction in brain PGE 2 concentrations. In contrast, diclofenac has a peripheral analgesic action in this test. Paracetamol-induced hypothermia is also accompanied by a reduction in brain PGE 2 concentrations in C57/Bl6 mice. This hypothermic effect of paracetamol was reduced in COX-1 but not in COX-2 gene-deleted mice. These results support the view that analgesia and hypothermia due to paracetamol are mediated by inhibition of a third COX isoenzyme (designated COX-3). In cultured mouse macrophages, COX-2 is induced by treatment with LPS or with high concentrations of diclofenac. Diclofenac-induced COX-2 is inhibited with low concentrations of paracetamol, whereas LPS-induced COX-2 is insensitive to paracetamol inhibition. The mechanisms of induction and possibly the functions of these two COX-2 enzymes are also different.

Participation of cyclooxygenase-1 in prostaglandin E 2 release from synovitis tissue in primary osteoarthritis in vitro

Objectives To investigate the relative contribution of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2 to prostaglandin E 2 (PGE 2) release from inflamed synovial tissue in N=10 patients with primary osteoarthritis (OA) in vitro and to determine possible effects of COX inhibitors on the gene expression of synovial COX-1 and COX-2. Design The effects of a COX-unspecific nonsteroidal anti-inflammatory drug (NSAID; diclofenac), a selective COX-1 inhibitor (SC-560) and a selective COX-2 inhibitor (SC-58125) on PGE 2 release from inflamed synovial tissue (0.1–10 μM, 3 and 6 h incubation time) were compared. Release of PGE 2 into the incubation media was measured by means of the enzyme-linked immunosorbent assay. Expression of synovial COX-1/-2 was quantified by means of real-time reverse transcriptase polymerase chain reaction (RT-PCR). Results All agents inhibited synovial PGE 2 release dose-dependently. Compared to short-term incubations, the inhibitory potency of diclofenac, SC-58125 and SC-560 was increased (0.1–10 μM) and decreased (0.1–1 μM), respectively, during 6 h: At 10 μM, SC-560 and SC-58125 had obviously lost their specificity for COX-1 and COX-2, respectively, indicated by a comparable inhibitory potency of the selective COX-1 inhibitor (86.6%) and the selective COX-2 inhibitor (96.6%) within identical tissue specimens. In contrast, at 1 μM, 83% and 62.8% inhibition was seen for diclofenac and SC-58125, respectively. SC-560 showed 30.6% inhibition ( P<0.05). In contrast to synovial COX-1, RT-PCR revealed a significant induction of COX-2 through PGE 2. Conclusions With respect to the concentrations studied, the data suggest that in inflamed synovial tissue in OA, up to 30% of PGE 2 might be generated via the COX-1 pathway. In therapy of OA, the relative contribution of COX-1 in synovial inflammation should be considered, weighing the potency of COX-unspecific NSAID against the assumed superior gastrointestinal safety profile of selective COX-2 inhibitors.

Cyclooxygenase enzymes: regulation and function.

The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyze the formation of prostaglandins, thromboxane, and levuloglandins. The prostaglandins are autocoid mediators that affect virtually all known physiological and pathological processes via their reversible interaction with G-protein coupled membrane receptors. The levuloglandins are a newer class of products that appear to act via irreversible, covalent attachment to numerous proteins. COX enzymes are clinically important because they are inhibited by aspirin and numerous other non-steroidal anti-inflammatory drugs. This inhibition of COX confers relief from inflammatory, pyretic, thrombotic, neurodegenerative and oncological maladies. About one hundred years have elapsed since Hoffman designed and synthesized acetylsalicylic (aspirin) as an agent intended to lessen the gastrointestinal irritation of salicylates while maintaining their efficacy. During the past forty years systematic advances in our understanding of the structure, regulation and function of COX isoenzymes have enabled the design and synthesis of COX-2 selective inhibitors as agents intended to lessen the gastrointestinal irritation of aspirin and non-selective NSAIDs. This review discusses: 1) how two separate catalytic processes in COX - peroxidase and prostaglandin synthase - act in an integrated fashion manner to generate prostaglandins; 2) why irreversible inactivation of COX is important constitutively and pharmacologically; 3) how cells have managed to use two closely related, almost identical enzymes in ways that discriminate their physiological versus pathological roles; 4) how investigators have used these advances to formulate and test medically important uses for old drugs (i.e. aspirin) and create new ones that still seek to achieve Hoffman's original goal.

Different Mechanisms Lead to the Angiogenic Process Induced by Three Adenocarcinoma Cell Lines

Neoangiogenesis is essential for tumor and metastasis growth, but this complex process does not follow the same activation pathway, at least in tumor cell lines originated from different murine mammary adenocarcinomas. LMM3 cells were the most potent to stimulate new blood vessel formation. This response was significantly reduced by preincubating cells with indomethacin and NS-398, non-selective cyclooxygenase (COX) and COX-2 selective inhibitors, respectively. COX-1 and COX-2 isoenzymes were both highly expressed in LMM3 cells, and we observed that indomethacin was more effective than NS-398 to inhibit prostaglandin E2 (PGE2) synthesis. In addition, nitric oxide synthase (NOS) inhibitors, Nomega monomethyl L-arginine and aminoguanidine, also reduced LMM3-induced angiogenesis and nitric oxide (NO) synthesis as well. NOS2 > NOS3 proteins and arginase II isoform were detected in LMM3 cells by Western blot. The latter enzyme was also involved in the LMM3 neovascular response, since the arginase inhibitor, Nomega hydroxy L-arginine reduced the angiogenic cascade. On the other hand, parental LM3 cells were able to stimulate neovascularization via COX-1 and arginase products since only indomethacin and Nomega hydroxy L-arginine, which diminished PGE2 and urea synthesis, respectively, also reduced angiogenesis. In turn, LM2 cells angiogenic response could be due in fact to PGE2-induced VEGF liberation that stimulated neoangiogenesis at very low levels of NO.

Acute Pulmonary Oedema Induced by???COX-2 Inhibitors in a Patient with???Chronic Pain

Cyclo-oxygenase (COX) inhibitors are by far the changed her primary-care provider. The new primamost commonly used analgesics since they are efry-care specialist started the patient on celecoxib fective for the treatment of pain derived from com100mg twice a day. Since the patient felt that celemon causes and are available without prescription. coxib alone was not enough to control her pain, she They are well absorbed from the gastrointestinal used the refills on the prescription provided by the tract and, with occasional use, adverse effects are first primary-care provider, taking additional tablets minimal. There are two major classes of COX isoof rofecoxib (usually 25mg daily). enzymes: COX-1 is constitutively expressed and Her chronic low back pain improved over the COX-2 is induced in the inflammatory state. next month, but the patient started to complain of COX-2-selective drugs, which were recently introshortness of breath and bilateral leg oedema, and duced for the treatment of arthritis, have been assowas admitted to the emergency room with severe ciated with reductions in gastric irritation. Whether respiratory distress. On examination, she was in COX-2-selective drugs have analgesic efficacy acute respiratory failure with tachypnoea of 25 equivalent to that of other NSAIDs remains to be breaths/min, speech dyspnoea, use of accessory demonstrated. muscles and signs of peripheral cyanosis and bilaterNSAIDs, particularly COX-2 isoenzyme inhibial +3 pitting oedema. The pulse oximeter showed tors, are among the most frequently prescribed saturation of 86% and 90% with a rebreathing mask medications for the treatment of chronic noncancer on 100% oxygen. The blood gas analysis was conpain, and polypharmacy is a common problem in sistent with hypoxia and acute respiratory acidosis. recipients of these drugs. COX-2 inhibitors appear The chest x-ray was consistent with acute pulmonto have a better gastrointestinal, but not cardioary oedema. The patient was afebrile and her white vascular, adverse effect profile than COX-1 inhibicell count was within the normal limits. Cardiac tors. Furthermore, rofecoxib in particular is known enzymes were also within normal limits and no new to cause fluid overload.[1] ECG changes occurred. The ejection fraction was mildly reduced (by 35%) as per 2D ECG, without 1. Case Report significant change.

Synthesis and Prostaglandin Synthase Inhibitory Activity of New Aromatic O‐Alkyloxime Ethers Substituted with Methylsulfonamido or Methylsulfonyl Groups on Their Aliphatic Portion.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cyclooxygenase-1 in the spinal cord is altered after peripheral nerve injury.

The mechanisms underlying neuropathic pain are incompletely understood and its treatment is often unsatisfactory. Spinal cyclooxygenase-2 (COX-2) expression is upregulated after peripheral inflammation, associated with spinal prostaglandin production leading to central sensitization, but the role of COX isoenzymes in sensitization after nerve injury is less well characterized. The current study was undertaken to determine whether COX-1 was altered in this model. Male rats underwent partial sciatic nerve transsection (PSNT) or L5-L6 spinal nerve ligation (SNL). Four weeks after PSNT and 4 h, 4 days, or 2 weeks after SNL, COX-1 immunohistochemistry was performed on the L2-S2 spinal cord. COX-1 immunoreactivity (COX-1-IR) was unaffected 4 h after SNL. In contrast, 4 days after SNL, the number of COX-1-IR cells increased in the ipsilateral spinal cord. COX-1-IR increased in cells with glial morphology in the superficial laminae, but decreased in the rest of the ipsilateral spinal cord 4 weeks after PSNT and 2 weeks after SNL. These changes in immunostaining were greatest at the L5 level. These data suggest that COX-1 expression in the spinal cord is not static, but changes in a time- and laminar-dependent manner after nerve injury. These anatomic data are consistent with observations by others that spinally administered specific COX-1 inhibitors may be useful to prevent and treat neuropathic pain.

The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs.

The regular intake of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with decreased incidence of certain types of cancer particularly those with an inflammatory component. The protective effects of these drugs in colorectal cancer are particularly marked, with a 40-50% reduction in risk. Research in this area has focussed on understanding and optimising these cytoprotective effects. NSAIDs are believed to operate by inhibiting COX-2, an enzyme that appears to be involved in a number of cancer promoting processes. This hypothesis is consistent with the observation that the COX-2 selective inhibitors dramatically decrease tumour formation in human and animal studies. Surprisingly aspirin, which is selective for COX-1 over COX-2, and sulindac, which is an equipotent inhibitor of the COX isoenzymes, appear to have a similar anticancer profile to the COX-2 selective NSAIDs. A number of mechanisms have been proposed to explain the anomalous effects of aspirin. The first of these relates to the unique mode of action of aspirin, which acetylates the COX-2 enzyme and generates the cancer-suppressing 15R-hydroxyeicosatetraenoic acid at the site of a potential tumour. The alternative rationale relates to the metabolism of aspirin to salicylic acid, which has a cyclooxygenase independent anti-inflammatory mechanism, preventing the inflammatory response at the gene transcription level. A new generation of drugs could evolve from approaches to improving the therapeutic index of aspirin or by modifications to known therapies such as sulindac and celecoxib.

Synthesis and prostaglandin synthase inhibitory activity of new aromatic O-alkyloxime ethers substituted with methylsulfonamido or methylsulfonyl groups on their aliphatic portion

Some aromatic O-alkyloxime ethers substituted with methylsulfonamido ( 7) or methylsulfonyl ( 8) groups on their aliphatic portions were prepared as analogues of structurally related cyclooxygenase (COX) inhibitors ( 6) bearing a carboxylic group typical of the classic non-steroidal anti-inflammatory drugs (NSAIDs) in the place of the sulfurated moiety. In addition, also analogues of compounds 8 in which the aliphatic chain is further lengthened by 1 ( 9), 2 ( 10), or 3 ( 11) carbon atoms were synthesized. All compounds ( 7– 11) were tested in vitro towards COX2, and compounds 7– 9 towards COX1, by measuring prostaglandin E2 (PGE 2) production in activated J774.2 macrophages and U937 cell lines, respectively. While all new compounds were found to possess little or no activity on the COX2 isoenzyme, some of these ( 7a– 7d, 8a, 8d, 9e and 9f) appeared to possess an appreciable activity on COX1, with % inhibition values at a concentration of 1 μM ranging from 30% of 8a to 76% of 9e. The COX1 selectivity of the new compounds was tentatively explained by means of a docking study of one of the more active compounds tested on both COX isoenzymes ( 7d), which indicated a different number of hydrogen bonding interactions with the Arg120 of the active sites of the two enzymes, and therefore, an energetically favored interaction (3.5 kcal/mol) with COX1, compared with COX2.