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Inflammation is an essential body immune system response against various infections and tissue injuries and maintains normal homeostasis. Alterations in inflammatory responses lead to multiple disorders like heart diseases, obesity, diabetes, cancer, stroke, and neurodegenerative disorders. Cyclooxygenases (COXs), the enzymes, exist in two isoforms (COX‐1 and COX‐2) that catalyze the rate‐determining step of prostaglandin biogenesis and play a significant role in inflammation. COX‐2 inhibitors, although effective anti‐inflammatory agents are considered to be highly unsafe for long‐term usage due to their possible side and adversative effects. Recently, fused‐thienopyrimidines have emerged as a privileged scaffold with excellent anti‐inflammatory potential. In the present review, we have emphasized the recent developments in the design and synthetic strategies of fused‐thienopyrimidine derivatives and their detailed structure‐activity‐relationship (SAR) studies. The primary goal of this review is to provide restructuring knowledge about this template, which could prove beneficial and valuable for chemists working in the anti‐inflammatory area. [ABSTRACT FROM AUTHOR]

In the present study, the optimized geometrical parameters and vibrational frequencies of the Genkwanin (5- hydroxy-2-(4-hydroxyphenyl)-7-methoxychromen-4-one) were obtained by both hatree fock(HF) and density functional theory(DFT) methods. The experimental FT-IR, FT-Raman spectrum of the compound has been recorded in the region 4000-600 cm-1 and 50-4000 cm-1 respectively. The calculated structural parameters and vibrational frequencies were analyzed and compared with obtained experimental results. The frontier molecular orbital (FMO), molecular electrostatic potential (MEP) and UV-vis studies of the compound has been computed to elucidate the electronic properties. Moreover, molecular docking studies were also carried out to investigate the inhibitory effect of the compound against cyclooxygenase (COX) enzymes. Results of molecular docking study reveals that the chosen compound effectively inhibits the active sites of the human cyclooxygenase(COX-1 and COX-2) enzyme. The binding energy of the compound were studied and compared to standard drugs Ibuprofen, Nimesulide and Mefenamic acid. The investigated compound showed good binding affinity compared to standard drugs. Therefore, this study is an attempt to identify a safe and effective new drug from flavonoids for the treatment of inflammatory disease. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs ( NSAIDs) and the immunosuppressant drug cyclosporine ( CSA) are concurrently administered in arthritis. Here, we investigated whether diclofenac (non-selective inhibitor of cyclooxygenase-1 and 2, COX-1/ COX-2), celecoxib (selective COX-2 inhibitor) or SC560 (selective COX-1 inhibitor) interact variably with haemodynamic effects of CSA in conscious female rats. Changes caused by CSA (10 mg/kg i.v.) in blood pressure ( BP), heart rate ( HR), HR variability ( HRV) and myocardial contractility were assessed in the absence and presence of individual NSAIDs (10 mg/kg each). Compared with vehicle values, CSA caused immediate and sustained (i) increases in BP and decreases in pulse pressure index ( PPI) and HR, (ii) elevations in left ventricular ( LV) contractility (d P/d tmax) and isovolumic relaxation constant (Τau) and (iii) increases in the time- and frequency-domain indices of HRV and shifted the cardiac sympathovagal balance towards parasympathetic dominance. CSA hypertension was abolished in rats pre-treated with celecoxib and intensified in the presence of diclofenac or SC560. Alternatively, the CSA-evoked decreases in PPI, increases in HRV indices and cardiac parasympathetic dominance were blunted by celecoxib in contrast to no effect for diclofenac or SC560. Similarly, celecoxib, but not other NSAIDs, eliminated the elevated LV contractility (d P/d tmax) and isovolumic relaxation constant (Τau, τ), which reflect cardiac systolic and diastolic function, respectively, that accompanied the CSA-induced pressure load. The data underscore the preferential capacity of selective COX-2 inhibition by celecoxib to mitigate CSA hypertension and consequent alterations in cardiac performance and autonomic balance. By contrast, CSA effects are preserved or even exacerbated after COX-1 inhibition. [ABSTRACT FROM AUTHOR]

Introduction Individuals of African descent (AFD) are more susceptible to non-freezing cold injury (NFCI) compared with Caucasian individuals (CAU). Vasodilatation to acetylcholine (ACh) is lower in AFD compared with CAU in the non-glabrous foot and finger skin sites; the reason for this is unknown. Prostanoids are responsible, in part, for the vasodilator response to ACh, however it is not known whether the contribution differs between ethnicities. Methods 12 CAU and 12 AFD males received iontophoresis of ACh (1 w/v%) on non-glabrous foot and finger skin sites following placebo and then aspirin (600 mg, single blinded). Aspirin was utilised to inhibit prostanoid production by inhibiting the cyclooxygenase (COX) enzyme. Laser Doppler flowmetry was utilised to measure changes in skin blood flow. Results Not all participants could receive iontophoresis charge due to high skin resistance; these participants were therefore excluded from the analyses. Foot : ACh elicited greater maximal vasodilatation in CAU than AFD following placebo ( P = 0.003) and COX inhibition (COXib) ( P < 0.001). COXib did not affect blood flow responses in AFD, but caused a reduction in the area under the curve for CAU ( P = 0.031). Finger : ACh elicited a greater maximal vasodilatation in CAU than AFD following placebo ( P = 0.013) and COXib ( P = 0.001). COXib tended to reduce the area under the curve in AFD ( P = 0.053), but did not affect CAU. Conclusions CAU have a greater endothelial reactivity than AFD in both foot and finger skin sites irrespective of COXib. It is concluded that the lower ACh-induced vasodilatation in AFD is not due to a compromised COX pathway. [ABSTRACT FROM AUTHOR]

Meloxicam is a cyclooxygenase ( COX) inhibitor with a higher selectivity for cyclooxygenase-2 ( COX-2) than for cyclooxygenase-1 ( COX-1). In the laboratory setting, this nonsteroidal anti-inflammatory drug ( NSAID) is commonly selected for analgesia in mice and administered every 24 h. This study characterizes the plasma concentration achieved from a dose of 1.6 mg/kg of meloxicam administered once every 24 h subcutaneously for 72 h in male and female C57 BL/6 mice. These values were compared, over time, to reference COX-2 inhibition constants for meloxicam. No significant differences in trough plasma concentrations were noted between genders. The plasma concentrations were below the COX-2 IC50 after 12 h. To maintain a plasma concentration at or above the COX-2 whole blood IC50, the study results suggest an administration frequency of every 12 h when using a dose of 1.6 mg/kg in C57 BL/6 mice. [ABSTRACT FROM AUTHOR]

It is now recognised that the brain and the peripheral immune system have bidirectional communication in both health and neuronal diseases. Brain inflammation results after both acute injury and also with the appearance of mutated proteins or endogenous neurotoxic metabolites associated with slow neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and some psychiatric disorders. Microglia play a key role in brain inflammation by the release of pro-inflammatory cytokines and with ageing, microglia exhibit 'priming' leading to increased basal release of the pro-inflammatory cytokines. Neurochemical targets to reduce or slow chronic brain inflammation include cyclooxygenase enzymes, Nrf2 transcription factor, angiotensin AT1 receptors and sigma-1 receptors. Development of more selective drugs to act at these targets is occurring but large scale clinical trials to validate the drugs will take significant time. [ABSTRACT FROM AUTHOR]

Melanogenesis plays an important role in the protection of skin against UV through production of melanin pigments, but abnormal accumulation of this pigment causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we show for the first time that a small library of mimosine dipeptide enantiomers (Mi-L/D-amino acid) inhibit the melanogenesis in B16F10 melanoma cells by down-regulating the cellular tyrosinase with little effect on their growth or viability. Two of them, Mi-D-Trp and Mi-D-Val, turned out to be the most potent inhibitors on melanin content and cellular tyrosinase in B16F10 melanoma cells. In addition, most of the mimosine dipeptides were more potent than mimosine for inhibiting cyclooxygenase 1 (COX-1) with IC50 of 18–26 μM. Among them, Mi-L-Val and Mi-L-Trp inhibited cyclooxygenase 2 (COX-2) more potently than indomethacin, with IC50 values of 22 and 19 μM, respectively. Taken together, our results suggest the possibility that mimosine dipeptides could be better candidates (than mimosine) for anti-melanogenic (skin hyperpigmentation treatment) and cyclooxygenase (COX) inhibition. [ABSTRACT FROM AUTHOR]

Cyclooxygenases (COX) are present in the body in two isoforms, namely: COX-1, constitutively expressed, and COX-2, induced in physiopathological conditions such as cancer or chronic inflammation. The inhibition of COX with non-steroideal anti-inflammatory drugs (NSAIDs) is the most widely used treatment for chronic inflammation despite the adverse effects associated to prolonged NSAIDs intake. Although selective COX-2 inhibition has been shown not to palliate all adverse effects (e.g. cardiotoxicity), there are still niche populations which can benefit from selective COX-2 inhibition. Thus, capitalizing on bioactivity data from both isoforms simultaneously would contribute to develop COX inhibitors with better safety profiles. We applied ensemble proteochemometric modeling (PCM) for the prediction of the potency of 3,228 distinct COX inhibitors on 11 mammalian cyclooxygenases. Ensemble PCM models (R20 test = 0.65, and RMSEtest = 0.71) outperformed models exclusively trained on compound (R20 test = 0.17, and RMSEtest = 1.09) or protein descriptors (R20 test = 0.16 and RMSEtest = 1.10) on the test set. Moreover, PCM predicted COX potency for 1,086 selective and non-selective COX inhibitors with R20 test = 0.59 and RMSEtest = 0.76. These values are in agreement with the maximum and minimum achievable R20 test and RMSEtest values of approximately 0.68 for both metrics. Confidence intervals for individual predictions were calculated from the standard deviation of the predictions from the individual models composing the ensembles. Finally, two substructure analysis pipelines singled out chemical substructures implicated in both potency and selectivity in agreement with the literature. [ABSTRACT FROM AUTHOR]

Cyclooxygenases (COX) are present in the body in two isoforms, namely: COX-1, constitutively expressed, and COX-2, induced in physiopathological conditions such as cancer or chronic inflammation. The inhibition of COX with non-steroideal anti-inflammatory drugs (NSAIDs) is the most widely used treatment for chronic inflammation despite the adverse effects associated to prolonged NSAIDs intake. Although selective COX-2 inhibition has been shown not to palliate all adverse effects (e.g. cardiotoxicity), there are still niche populations which can benefit from selective COX-2 inhibition. Thus, capitalizing on bioactivity data from both isoforms simultaneously would contribute to develop COX inhibitors with better safety profiles. We applied ensemble proteochemometric modeling (PCM) for the prediction of the potency of 3,228 distinct COX inhibitors on 11 mammalian cyclooxygenases. Ensemble PCM models (R02 test=0.65, and RMSEtest=0.71) outperformed models exclusively trained on compound (R02 test=0.17, and RMSEtest=1.09) or protein descriptors (R02 test=0.16 and RMSEtest=1.10) on the test set. Moreover, PCM predicted COX potency for 1,086 selective and non-selective COX inhibitors with R02 test=0.59 and RMSEtest=0.76. These values are in agreement with the maximum and minimum achievable R02 test and RMSEtest values of approximately 0.68 for both metrics. Confidence intervals for individual predictions were calculated from the standard deviation of the predictions from the individual models composing the ensembles. Finally, two substructure analysis pipelines singled out chemical substructures implicated in both potency and selectivity in agreement with the literature. Graphical abstract Prediction of uncorrelated bioactivity profiles for mammalian COX inhibitors with Ensemble Proteochemometric Modeling. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to investigate the effect of common single nucleotide genomic polymorphisms in the cyclooxygenase-1 (COX-1) gene on the thromboxane A2 (TxA2) metabolite concentrations in serum and urine, as well as on prostaglandin F2α (PGF2α) urinary excretion in the diabetic population on acetylsalicylic acid (ASA) therapy. Material and methods: The study cohort consisted of 284 Caucasians with diabetes type 2 who had been taking ASA tablets at the dose of 75 mg/day for at least 3 months. Genotyping for the 4 selected SNPs within the COX-1 gene (two nonsynonymous-coding variants, rs3842787 [C50T, P17L] and rs5789 [C174A, L237M]; and two other synonymous SNPs, rs3842788 [G128A, Q41Q] and rs5788 [C644A]) was performed using the Sequenom iPLEX platform. Results: No statistically significant results were observed for the investigated SNPs and measured metabolites in the investigated cohort of patients. Statistically significant differences in S-TxB2 could however be observed for rs5788 in the subgroup of patients with very high S-TxB2 concentrations. In particular, more patients who were carriers of the minor allele for this polymorphism were observed in the group with S-TxB2 levels > 95th percentile, when compared with similar carriers in the group with S-TxB2 < 95th percentile (20% vs. 1.1%, respectively, p < 0.001, Mann-Whitney test). Conclusions: The results of our study suggest that the four investigated common SNPs in the COX1 gene are not associated with obviously altered TxA2 metabolism and PGF2α synthesis in the investigated diabetic cohort treated with ASA. [ABSTRACT FROM AUTHOR]

Oxicams are a class of nonsteroidal anti-inflammatory drugs (NSAIDs) structurally related to the enolic acid class of 4-hydroxy-1,2-benzothiazine carboxamides. They are used clinically to treat both acute and chronic inflammation by inhibiting the activity of the two cyclooxygenase (COX) isoforms, COX-1 and COX-2. Oxicams are structurally distinct from all other NSAIDs, exhibiting a novel binding pose in the COX active site. The 4-hydroxyl group on the thiazine ring partners with Ser-530 via hydrogen bonding while two coordinated water molecules mediate a polar interaction between the oxicam and COX. The rotation of Leu-531 in the complex opens a new pocket, which is not used for binding other NSAIDs to the enzyme. This structure provides the basis for understanding documented structure-activity relationships within the oxicam class. In addition, from the oxicam template, a series of potent microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors represents a new direction for drug development. Here, we review the major route of oxicam synthesis and structure-activity for COX inhibition, as well as recent advances in oxicam-mediated mPGES-1 inhibition. © 2014 IUBMB Life, 66(12):803-811, 2014 [ABSTRACT FROM AUTHOR]

Objectives. To examine the effects of inhibition of cyclooxygenase (COX) on islet hormone secretion in vitro and on pancreatic islet blood flow in vivo. Methods. Insulin release was measured in a static incubation system of islets isolated from Wistar-F rats after inhibition of COX-1 and COX-2 with SC 560 (COX-1), FR 122047 (COX-1), rofecoxib (COX-2), or indomethacin (both COX-1 and COX-2). In other rats organ blood flow values were measured with a microsphere technique during both normo- and hyperglycemia after administration of these enzyme inhibitors. Results. Serum insulin values were lower after pretreatment with a COX-1 inhibitor or a non-selective COX inhibitor in both control and glucose-injected rats in vivo, whereas COX-2 inhibition had no such effects. However, inhibition of COX had only minor effects on insulin release in vitro. Inhibition of COX affected neither total pancreatic nor islet blood flow in normoglycemic rats. Hyperglycemia caused an increase in both these flow values and in the duodenum. The increase in total pancreatic and duodenal blood flow was prevented by inhibition of COX-2 or non-selective COX inhibition. However, no effects on islet blood flow were seen after COX inhibition. Conclusion. Inhibition of COX affects insulin release and blood glucose concentrations in vivo. However, COX inhibition has only minor effects on pancreatic islet blood flow, but prevents the glucose-induced increase in total pancreatic blood flow. [ABSTRACT FROM AUTHOR]

Recombinant human cyclooxygenase-1 (COX-1) was expressed from stably transfected Trichoplusia ni BTI TN-5B1-4 (TN-5B1-4) and Drosophila melanogaster S2 cells. Two kinds of recombinant COX-1 with molecular weights (MWs) of 68 and 74 kDa were expressed in the intracellular fractions of stably transfected TN-5B1-4/ COX-1 and S2/COX-1 cells, due to glycosylation. The recombinant COX-1 secreted to medium fractions has a MW of 72 kDa. Recombinant COX-1 in the intracellular fractions was purified to homogeneity using a one-step Ni-NTA affinity fractionation method. Recombinant COX-1 purified from TN-5B1-4/COX-1 and S2/COX-1 cells contained 11,389 and 33,850 Unit/mg of specific peroxidase activity, respectively. The maximum productions of intracellular recombinant COX-1 were 1.7 and 5.6 μg/10 cells in the T-flask cultures of TN-5B1-4/COX-1 and S2/COX-1 cells, respectively. Taken together, our findings indicate that S2 cells can be more suitable system to produce recombinant COX-1, compared to TN-5B1-4 cells. [ABSTRACT FROM AUTHOR]

Aims In various studies and also in traditional medicine, many properties for Nigella sativa, such as antioxidant effects and gastric mucosa protection have been reported. The aim of this study was to investigate the effect of hydro-alcoholic extract of Nigella sativa on acid and mucus secretion in cyclooxygenase inhibition conditions. Materials & Methods This interventional study was done using 40 Wistar rats. The rats were divided into 5 groups; positive control (distilled water), Ranitidine (50mg/kg) and three groups receiving Nigella sativa extract (100, 200 and 400mg/kg). The groups were treated by gavage for 5 days and on 6th day Indomethacin was gavaged to cyclooxygenase inhibition and 6 hours later acid and mucus secretion were examined. Findings No differences were observed in acid secretion between treated groups with Ranitidine, the extract and Indomethacin. But mucus secretion in groups of 100 and 200mg/ kg doses of the extract was higher than the group receiving Indomethacin significantly. Conclusion Nigella seed extract can protect the gastric mucosa against damages caused by cyclooxygenase inhibition, but is not able to reduce the acid secretion elevated by Indomethacin. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Intestinal inflammation alters colonic afferent nerve sensitivity which may contribute to patients'' perception of abdominal discomfort. We aimed to explore whether mast cells and the cyclooxygenase pathway are involved in altered afferent nerve sensitivity during colitis. Methods: C57Bl6 mice received 3% dextran-sulfate sodium (DSS) in drinking water for 7days to induce colitis. Control animals received regular water. On day 8 inflammation was assessed in the proximal colon by morphology and histology. Extracellular afferent nerve discharge was recorded from the mesenteric nerve of a 2cm colonic segment. Subgroups were treated in vitro with the mast cell stabilizer doxantrazole (10−4 M) or the cyclooxygenase inhibitor naproxen (10−5 M). Results: DSS colitis resulted in morphological and histological signs of inflammation. At baseline, peak firing was 11±2imps−1 in colitis segments and 5±1imps−1 in uninflamed control segments (p<0.05; mean±SEM; each n=6). In colitis segments, afferent nerve discharge to bradykinin (0.5μM) was increased to 47±7 compared to 23±6imps−1 in recordings from non-inflamed control tissue (p<0.05). Mechanosensitivity during luminal ramp distension (0–80cmH2O) was increased reaching 24±5imps−1 at 80cmH2O during colitis compared to 14±2 in non-inflamed controls (p<0.05). Doxantrazole or naproxen reduced afferent discharge to bradykinin and luminal ramp distension in colitis segments to control levels. Conclusion: Intestinal inflammation sensitizes mesenteric afferent nerve fibers to bradykinin and mechanical stimuli. The underlying mechanism responsible for this sensitization seems to involve mast cells and prostaglandins. [Copyright &y& Elsevier]

Cyclooxygenase-2 (COX-2) expression and prostaglandin production are suggested to play important, complex roles in the pathogenesis of various liver diseases. Studies on the effects of COX-2 inhibitors on the progression of liver fibrosis present controversial results, and the proposed therapeutic potential of these agents in chronic liver disease is predicated largely on their effectiveness in modulating hepatic stellate cell activation in vitro. This study investigated the modulatory effect of celecoxib, a selective COX-2 inhibitor, in CCl4-mediated hepatotoxicity in rats. Thirty Wistar albino rats, weighing 120-180 g, were assigned into five groups of 6 rats/group. Groups 1 and 2 received saline (10 mL/kg) and CCl4 (80 mg/kg), respectively. Group 3 was given celecoxib (5.7 mg/kg), whereas groups 4 and 5 were pretreated with 2.9 and 5.7 mg/kg/day of celecoxib, respectively, 1 hour before CCl4 treatment. Plasma aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities increased significantly by 118.5, 150.0, and 51.3%, respectively, with an accompanying decrease ( P < 0.05) in total protein and albumin after CCl4 treatment. Hepatotoxicity was associated with a significant increase in plasma cholesterol, hepatic lipid peroxidation (LPO), and severe hepatic necrosis with marked fatty and cellular (i.e., mononuclear cells) infiltration. Although celecoxib neither reduced CCl4-induced increases in marker enzymes of hepatotoxicity nor significantly attenuated hepatic necrosis, it, however, was effective in reducing elevated cholesterol by 16.5 and 20.8% and LPO by 12.9 and 35.5% at 2.9 and 5.7 mg/kg, respectively. Data suggest that COX-2 inhibitors may be effective in controlling hypercholesterolemia and peroxidative changes associated with liver injury. [ABSTRACT FROM AUTHOR]

Structure-activity characterization of molecular databases plays a central role in drug discovery. However, the characterization of large databases containing structurally diverse molecules with several end-points represents a major challenge. For this purpose, the use of chemoinformatic methods plays an important role to elucidate structure-activity relationships. Herein, a general methodology, namely Chemotype Activity and Selectivity Enrichment plots, is presented. Chemotype Activity and Selectivity Enrichment plots provide graphical information concerning the activity and selectivity patterns of particular chemotypes contained in structurally diverse databases. As a case study, we analyzed a set of 658 compounds screened against cyclooxygenase-1 and cyclooxygenase-2. Chemotype Activity and Selectivity Enrichment plots analysis highlighted chemotypes enriched with active and selective molecules against cyclooxygenase-2; all this in a simple 2D graphical representation. Additionally, the most active and selective chemotypes detected in Chemotype Activity and Selectivity Enrichment plots were analyzed separately using the previously reported dual activity-difference maps. These findings indicate that Chemotype Activity and Selectivity Enrichment plots and dual activity-difference maps are complementary chemoinformatic tools to explore the structure-activity relationships of structurally diverse databases screened against two biological end-points. [ABSTRACT FROM AUTHOR]

Flurbiprofen acts as a nonselective inhibitor for cyclooxygenases (COX-1 and COX-2), but its impact on hepatic ischemia/ reperfusion (I/R) injury remains unclear. Mice were randomized into sham, I/R and flurbiprofen (Flurb) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 90 min and unclamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with flurbiprofen prior to I/R insult significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and prevented hepatocytes from I/R-induced apoptosis/necrosis. Moreover, flurbiprofen dramatically inhibited mitochondrial permeability transition (MPT) pore opening, and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that flurbiprofen markedly inhibited glycogen synthase kinase (GSK)-3β activity and increased phosphorylation of GSK-3β at Ser9, which, consequently, could modulate the adenine nucleotide translocase (ANT)-cyclophilin D (CyP-D) complex and the susceptibility to MPT induction. Therefore, administration of flurbiprofen prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through inhibition of MPT and inactivation of GSK-3β, and provides experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings in addition to its conventional use for pain relief. [ABSTRACT FROM AUTHOR]

Abstract: The α2-adrenergic system is involved in pain processing and inflammation-induced sensitization. α2-adrenoceptor agonists induce analgesia, and this effect is greater when administered in combination with other analgesics. In the present study, we assessed a possible enhancement of antinociception combining the α2-adrenoceptor agonist medetomidine with subeffective doses of NCX701 (nitroparacetamol). The effects of the drugs were studied in spinal cord neuronal responses from adult male Wistar rats with carrageenan-induced inflammation, using the recording of single motor unit technique. The experiments showed that the i.v. administration of medetomidine and NCX701 induced a more potent and effective antinociceptive effect than medetomidine when given alone (ID50: 0.47±0.1 vs. 1.1±0.1μg/kg) or in the presence of paracetamol, in naturally-evoked nociceptive responses. In addition, the duration of antinociception was significantly longer (P<0.001, 100min after administration). The use of low doses of NCX701 and α2-adrenoceptor agonists might open new perspectives in the treatment of inflammatory pain. [Copyright &y& Elsevier]

Abstract: A series of novel acrylic acid derivatives bearing at the 3 position thienyl, furfuryl and 3,5-ditert-butyl-4-hydroxyphenyl substituents have been designed, synthesized and tested as potential dual lipoxygenase/cyclooxygenase-1 (LOX/COX-1) inhibitors and as antioxidant and anti-inflammatory agents. Some compounds have shown moderate antioxidant and COX-1 inhibitory activities, very good anti-inflammatory activity and an inhibition of soybean lipoxygenase (LOX) higher than caffeic acid. In particular, compound 4I disclosed a moderate in vitro LOX inhibition with an IC50 = 100 μM whereas compounds 1I and 2II exhibited the best, albeit poor, activity as COX-1 inhibition (75% inhibition at 100 μM). Good radical scavenging properties were shown by compounds 4I, 3I and 1II. Docking simulations performed on LOX inhibitor 4I and COX-1 inhibitor 1I indicated that hydrophobic key interactions may govern the enzyme-inhibitor binding. [Copyright &y& Elsevier]

Abstract: Recent evidence suggests that P2X3 receptors express abundantly in nociceptive sensory neurons and play an important role in neuropathic pain. Upregulation of prostaglandin E2 (PGE2) after nerve injure is involved in the pathogenesis of neuropathic pain. An increase of P2X3 receptors after chronic constriction injury (CCI) to the sciatic nerve has also been reported, the mechanisms are not known clearly. In this study, we examined the effects of systemic administration of cyclooxygenase (COX) inhibitors on analgesia and the expression of P2X3 receptors in the dorsal root ganglia (DRG) in CCI rats. Rats received 0.9% saline, the nonselective COX inhibitor ibuprofen (40mgkg−1 day−1) or the selective COX-2 inhibitor celecoxib (30mgkg−1 day−1) by gavage twice daily from 3 to 14 days after surgery. Mechanical allodynia and thermal hyperalgesia induced by CCI were markedly attenuated by celecoxib from 5 to 14 days after surgery, and relieved by ibuprofen treatment from 7 to 10 days after surgery. The increase of P2X3 receptors in the DRG in CCI rats on day 14 after surgery was also significantly inhibited; the effect of ibuprofen was stronger than that of celecoxib. These results demonstrate that up-regulated COX/PGE2 after nerve damage may play an important role in neuropathic pain. They are highly involved in the expression of P2X3 receptors in the DRG in CCI rats. [Copyright &y& Elsevier]

Background. Among dialysis patients, acute mesenteric ischemia is mostly caused by non-occlusive mesenteric ischemia (NOMI). There is a very high mortality rate associated with this complication, but prognostic factors associated with NOMI are not well-known. Method. In this study, we retrospectively reviewed the records of dialysis patients to identify prognostic factors associated with mortality from NOMI. Overall, there were 541 patients on hemodialysis (HD) and 158 patients on peritoneal dialysis (PD) in our hospital from January 2007 to December 2008. Among these 699 patients, we diagnosed NOMI by surgical and/or radiological criteria. A total of 12 dialysis patients (9 on HD and 3 on PD) developed NOMI during the study period. Result. The incidence of NOMI was 1.04% per patient-year for all dialysis patients (0.95% for HD and 1.35% for PD patients). Most of the 12 patients had chronic hypotension (83.3%, 10/12). Four patients expired following development of NOMI. Our results showed that mortality was significantly higher in patients who were administered a cyclooxygenase ( COX) inhibitor prior to ischemia. Hypobicarbonemia during NOMI, which might indicate the severity of hypoperfusion, is also associated with higher mortality. Conclusion. NOMI is rare in dialysis patients. COX inhibitor administration should be given with caution in long-term hypotensive dialysis patients. [ABSTRACT FROM AUTHOR]

Abstract: Leukotriene D4 (LTD4)-induced bronchoconstriction in guinea-pig airways has a cyclooxygenase (COX)-dependent component. The main objective of this study was to establish if prostaglandin (PG) D2-induced bronchoconstriction also was modulated by COX products. The effects of non-selective and selective COX-1 and COX-2 inhibitors on bronchoconstriction induced by LTD4 and PGD2 were investigated in the perfused and ventilated guinea-pig lung (IPL). Both LTD4-induced bronchoconstriction and thromboxane (TX) A2 release was suppressed by COX inhibitors or by TX synthesis inhibition. The release of additional COX products following CysLT1 receptor activation by LTD4 was established by measurements of immunoreactive 6-keto PGF1α (a stable metabolite of PGI2) and PGE2. In contrast, TP receptor-mediated bronchoconstriction by PGD2 was somewhat enhanced by COX inhibitors, and there was no measurable release of COX products after TP receptor activation with U-46619. PGE2 was bronchoprotective in IPL as it inhibited the histamine-induced bronchoconstriction. In the isolated guinea-pig trachea, neither PGD2 nor U-46619 actively released PGE2, but continuous production of PGE2 and PGI2 was established, and the response to PGD2 was enhanced also in the trachea by COX inhibition. The study documented that bronchoconstriction induced by LTD4 and PGD2 in IPL was modulated differently by COX products. Whereas bronchoconstriction induced by LTD4 was amplified predominantly by secondarily released TXA2, that induced by PGD2 was attenuated by bronchoprotective PGE2 and PGI2, presumably tonically produced in the airways. [Copyright &y& Elsevier]

Background and Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesic and anti-inflammatory by virtue of inhibition of the cyclooxygenase (COX) reaction that initiates biosynthesis of prostaglandins. Findings in a pulmonary pharmacology project gave rise to the hypothesis that certain members of the NSAID class might also be antagonists of the thromboxane (TP) receptor.Experimental Approach: Functional responses due to activation of the TP receptor were studied in isolated airway and vascular smooth muscle preparations from guinea pigs and rats as well as in human platelets. Receptor binding and activation of the TP receptor was studied in HEK293 cells.Key Results: Diclofenac concentration-dependently and selectively inhibited the contraction responses to TP receptor agonists such as prostaglandin D2 and U-46619 in the tested smooth muscle preparations and the aggregation of human platelets. The competitive antagonism of the TP receptor was confirmed by binding studies and at the level of signal transduction. The selective COX-2 inhibitor lumiracoxib shared this activity profile, whereas a number of standard NSAIDs and other selective COX-2 inhibitors did not.Conclusions and Implications: Diclofenac and lumiracoxib, in addition to being COX unselective and highly COX-2 selective inhibitors, respectively, displayed a previously unknown pharmacological activity, namely TP receptor antagonism. Development of COX-2 selective inhibitors with dual activity as potent TP antagonists may lead to coxibs with improved cardiovascular safety, as the TP receptor mediates cardiovascular effects of thromboxane A2 and isoprostanes. [ABSTRACT FROM AUTHOR]

Aspirin and other cyclooxygenase inhibitors can increase levels of tumor necrosis factor-alpha and engage pro-apoptosis paths and/or anti-apoptosis paths. Seemingly conflicting data are briefly reviewed. Aspirin has been shown to slightly increase survival duration in multiple myeloma. In this brief note caution is raised about use of aspirin and COX inhibitors generally in inflammatory states and specifically in myeloma. Should they increase tumor necrosis factor-alpha they could exacerbate disease. A figure is presented showing the tendency for interleukin-6 and tumor necrosis factor-alpha, both demonstrated to be growth factors in myeloma, to be counter-regulated. Since both are now easily measured by specialty labs, it would be reasonable to monitor these during myeloma treatment generally, and particularly when using aspirin, COX inhibitors, or any other drug with potential to increase these growth factors. [ABSTRACT FROM AUTHOR]

Abstract: Endotoxic fever is regulated by endogenous factors that provide pro- and anti-pyretic signals at different points along the febrigenic pathway, from the periphery to the brain. Current evidence indicates that the febrile response to invading Gram-negative bacteria and their products is initiated upon their arrival in the liver via the circulation and their uptake by Kupffer cells (Kc). These pathogens activate the complement cascade on contact, hence generating complement component 5a. It, in turn, very rapidly stimulates Kc to release prostaglandin (PG)E2. Pyrogenic cytokines (TNF-α, etc.) are produced later and are no longer considered to be the immediate triggers of fever. The Kc-generated PGE2 either (1) may be transported by the bloodstream to the ventromedial preoptic-anterior hypothalamus (POA, the locus of the temperature-regulating center), presumptively diffusing into it and acting on thermoregulatory neurons; PGE2 is thus taken to be the final, central fever mediator. Or (2) it may activate hepatic vagal afferents projecting to the medulla oblongata, thence to the POA via the ventral noradrenergic bundle. Norepinephrine consequently secreted stimulates α1-adrenoceptors on thermoregulatory neurons, rapidly evoking an initial rise in core temperature (Tc) not associated with any change in POA PGE2; this neural, PGE2-independent signaling pathway is quicker than the blood-borne route. Elevated POA PGE2 and a secondary Tc rise occur later, consequent to α2 stimulation. Endogenous counter-regulatory factors are also elaborated peripherally and centrally at different points during the course of the febrile response; they are, therefore, anti-pyretic. These multiple interacting pathways are the subject of this review. [Copyright &y& Elsevier]

OBJECTIVE To investigate the role of cyclooxygenase (COX) isozymes (COX-1 and -2) in the regulation of bladder volume capacity (BVC) in several rat urodynamic models, using a selection of nonsteroidal anti-inflammatory drugs (NSAIDs), some selective for COX-2, correlating the potency of the tested compounds in the urodynamic models and their in vitro potency as inhibitors of COX isozymes, to verify the relative importance of the different isozymes. MATERIALS AND METHODS The effects of an i.v. administration of several nonselective and selective COX-2 inhibitors (indomethacin, meloxicam, naproxen, aspirin, paracetamol, flurbiprofen, nimesulide, NS-398, celecoxib, rofecoxib and L 745337) on bladder filling and voiding were evaluated in conscious and anaesthetized rats by cystometry. The cystometry was done in conscious rats 1 day after catheter implantation, by filling the bladder with dilute acetic acid (0.2%) or saline, and again with saline 5 days after catheterization. Effects on isovolumic bladder contractions in anaesthetized rats were also evaluated. RESULTS All the NSAIDs tested dose-dependently increased BVC; their potency at increasing BVC during infusion of the bladder with acetic acid was similar to that evaluated with saline on cystometry 1 day after catheterization. When a nonselective (naproxen) and a selective (nimesulide) COX-2 inhibitor were tested in rats with bladders infused with saline 5 days after catheterization, their effects on BVC were significantly lower than those evaluated at 1 day. All tested compounds dose-dependently inhibited isovolumic bladder contractions in anaesthetized rats. There was a good correlation between the potency in inhibiting the isovolumic bladder contractions in anaesthetized rats and in increasing BVC during cystometry in conscious rats with the bladder infused with acetic acid. The potency of the compounds in the cystometry model with bladders infused with acetic and in the isovolumic bladder voiding contractions correlated well with COX-2 inhibition, but not COX-1. CONCLUSIONS Both nonselective and COX-2 selective inhibitors are more active in inhibiting the micturition reflex in rats with bladder overactivity caused by bladder irritation than in normal rats. The potency of the anti-inflammatory compounds in inhibiting bladder overactivity induced by chemical or surgical irritation, and their activity in a cystometrographic model practically independent of bladder irritation (isovolumic bladder contractions in anaesthetized rats), was related to the potency as inhibitors of COX-2 isozyme. This suggests that the involvement of prostaglandins in the micturition reflex in rats is mainly mediated by this isozyme. [ABSTRACT FROM AUTHOR]

Cyclooxygenase (COX) inhibitors have demonstrated efficacy in models of human cancer but the relevant mechanisms have not all been elucidated. Both Cox-dependent as well as Cox-independent mechanisms have been implicated. Using a syngeneic model of metastatic breast cancer, we have investigated the effect of Cox inhibitors on NK functions that are critical to the control of metastatic disease. NK recognition of target cells is governed by a balance of activating and inhibiting receptors that bind ligands including MHC class I. We now show that treatment of tumor cells with the nonselective COX-1/COX-2 inhibitor indomethacin or the selective COX-2 inhibitor celecoxib leads to decreased expression of the MHC class I molecules Ld and Kd . Downregulated class I expression is associated with concomitant increased sensitivity to NK cell-mediated lysis. Both COX inhibitors limit tumor metastasis and this therapeutic effect is dependent on NK but not T cell function. Antimetastatic activity is also lost in the absence of interferon- γ (IFN-γ). Both COX inhibitors also suppress local tumor growth of subcutaneously implanted mammary tumor cells in immune competent Balb/cByJ mice. This therapeutic activity is lost in the absence of either CD4+ or CD8+ T cells, but is not compromised by the loss of NK activity. Thus, the mechanism of tumor inhibition differs in the context of local versus metastatic disease. Taken together, these findings are consistent with a mechanism not previously described, whereby COX inhibitors may relieve MHC-mediated inhibition of NK cytotoxicity leading to recognition and lysis of metastatic tumor cells. [ABSTRACT FROM AUTHOR]

A number of drugs were assessed for their ability to inhibit stimulus-evoked prostanoid synthesis in cultured glia. These drugs included non-selective cyclooxygenase (COX) inhibitors and those considered to be selective for the inducible isoform of this enzyme (COX-2). Experiments were carried out on normal cultures and those which had been maintained in serum-free growth medium for four days then re-exposed to serum for a further seven days. All of the drugs tested elicited concentration-dependent inhibitions of arachidonic acid (AA)-stimulated thromboxane B2 (TXB2) accumulation in normal cultures with the following rank order of potency: indomethacin > piroxicam > nimesulide = NS398 > ibuprofen ≫ aspirin > paracetamol. In cultures which had been deprived of serum for four days, basal and AA-stimulated TXB2 production was considerably reduced, as was the amount of COX immunoreactivity determined by Western blotting. Basal and AA-stimulated TXB2 production together with COX immunoreactivity were restored to control levels by the re-addition of serum to serum-deprived cultures for 7 days. In these cultures, the rank order of potency was: indomethacin > piroxicam ≫ ibuprofen > nimesulide = NS398 ≫ aspirin > paracetamol; however, there were marked charges in the apparent IC50 values for particular drugs. Indomethacin, piroxicam and aspirin were very similar to control, but the potencies of ibuprofen (3-fold), NS398 (30-fold) and nimesulide (40-fold) were found to be decreased when compared to control. Paracetamol, on the other hand, was found to be almost 3-fold more potent under these conditions. Glia appear to express a COX with a novel sensitivity to particular inhibitors following serum deprivation and re-addition. [ABSTRACT FROM AUTHOR]

In this study ibuprofen (50.0 mg/kg, i.p.), rofecoxib (10.0 mg/kg, i.p.) and thalidomide (50.0 mg/kg, oral) were shown to prevent vincristine-induced mechanical hyperalgesia. Sprague-Dawley rats were injected every other day with vincristine (0.1 mg/kg) over 13 days. The animals were cotreated daily with vehicle (saline), ibuprofen, rofecoxib or thalidomide throughout the period of vincristine treatment. Mechanical withdrawal threshold to punctuate and radiant heat stimuli were determined prior to and then on alternate days throughout the treatment period. Vincristine vehicle-treated animals developed marked mechanical hyperalgesia from day 5 of chemotherapy and this lasted until the end of the experiment. Thermal thresholds were not altered by the administration of vincristine vehicle. Animals in the vincristine vehicle group neither gained nor lost weight during the treatment period. All three active drugs showed an antihyperalgesic effect on the responses to mechanical stimulation of the hind paw that was significant from day 5 for ibuprofen and thalidomide and from day 7 for rofecoxib. Thermal thresholds increased after the administration of both the NSAIDs and thalidomide. Rofecoxib was the only drug to show any beneficial effect in protecting the animals from failure to gain body weight. [ABSTRACT FROM AUTHOR]

(1) It is generally considered that fever is modulated in the preoptic-anterior hypothalamic area (POA) in response to signaling by pyrogenic cytokines elaborated in the periphery by mononuclear phagocytes and the consequent induction of prostaglandin (PG)E2 in the POA. The mechanism of the centripetal transmission of this pyrogenic signal, however, is controversial. One hypothesis suggests that it is conveyed via the vagus to the nucleus tractus solitarius and from there to the POA via the ventral noradrenergic bundle, causing the intraPOA release of norepinephrine (NE) which then stimulates the production of PGE2. (2) In this article, we review recent data from our laboratory showing that NE microdialyzed into the POA of conscious guinea pigs or injected intracerebroventricularly into conscious mice indeed evokes two distinct core temperature (Tc) rises, viz., one (AR)-mediated, rapid in onset and PGE2-independent, and the other , delayed and COX-2/PGE2-dependent. (3) We further present new data suggesting that the febrile response of conscious guinea pigs to intraperitoneally injected lipopolysaccharide (LPS) is mediated by intraPOA NE in accord with the above sequence, i.e., via to initiate the first, PGE2-independent elevation of Tc, and via to induce the delayed production of COX-2-dependent PGE2 and the continued rise of Tc. (4) These results thus validate the presumptive involvement of NE in LPS fever induction in guinea pigs. [Copyright &y& Elsevier]

Quantitative structure–activity relationship (QSAR) models of inhibiting action of some diarylimidazole derivatives on cylcooxygenase (COX) enzyme were constructed using modified particle swarm optimization (PSO) method. As a comparison to this method, the genetic algorithm (GA) was also tested. It has been demonstrated that the modified PSO is a useful tool for variable selection comparable to GA and even superior to GA. QSAR models are constructed separately for COX-2 inhibitory activity and selectivity of COX-2 inhibition over COX-1. The spatial descriptors play a key role in the compounds’ activity and selectivity to COX-2, especially Jurs descriptors. Polar interactions are the principal binding strength between compounds and COX-2 enzyme. In addition, the aqueous desolvation free energy (FH2O) value of substituent will affect the COX-2 inhibitory activity, while the charge distribution can affect the selectivity to COX-2. [Copyright &y& Elsevier]

We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area (POA) of conscious guinea pigs stimulates local PGE2 release. To identify the cyclooxygenase (COX) isozyme that catalyzes the production of this PGE2 and the adrenoceptor (AR) subtype that mediates this effect, we microdialyzed for 6 h NE, cirazoline (α1-AR agonist), and clonidine (α2-AR agonist) into the POA of conscious guinea pigs pretreated intrapreoptically (intra-POA) with SC-560 (COX-1 inhibitor) or nimesulide or MK-0663 (COX-2 inhibitors) and measured the animals' core temperature (T,.) and intra-POA PGE2 responses. Cirazoline induced Tc rises promptly after the onset of its dialysis without altering PGE2 levels. NE and clonidine caused early falls followed by late rises of Tc; intra-POA PGE2 levels were closely correlated with this thermal course. COX-1 inhibition attenuated the clonidine-induced Tc and PGE2 falls but not the NE-elicited hyperthermia, but COX-2 inhibition suppressed both the clonidine- and NE-induced Tc and PGE2 rises. Coinfused cirazoline and clonidine reproduced the late Tc rise of clonidine but not its early fall and also not the early rise produced by cirazoline; on the other hand, the PGE2 responses were similar to those to NE. Prazosin (α1-AR antagonist) and yohimbine (α2-AR antagonist) blocked the effects of their respective agonists. These results indicate that α1- and α2-AR agonists microdialyzed into the POA of conscious guinea pigs evoke distinct Tc. responses: α1-AR activation produces quick, PGE2-independent Tc. rises, and α2-AR stimulation causes an early Tc fall and a late, COX-2/PGE2,-dependent Tc rise. [ABSTRACT FROM AUTHOR]

Objective: We report fatal cases of multifocal ischemic injuries occurring in patients awaiting liver transplantation after severe concomitant paracetamol and cyclooygenase inhibitors self-poisoning.Design and Setting: Case report in an intensive care unit.Patients: In addition to signs of acute liver failure with a systemic inflammatory response syndrome, these three previously healthy young women demonstrated cutaneous vasoconstriction. One patient displayed a sudden ST-segment elevation with ventricular fibrillation.Interventions: Angiography, plasma endothelin concentrations measurements, and autopsy.Results: Radiography showed diffuse vasospasm on mesenteric and renal arteries, transiently reversed by vasodilators. We measured tenfold higher plasma endothelin concentrations than in healthy controls. Autopsy revealed no atherosis (including coronary arteries); organs showed multifocal ischemic injuries without thrombosis.Conclusions: Such injuries subsequent to dramatic vasoconstriction suggest that cyclooygenase inhibition has specific deleterious vascular side effects once systemic inflammatory response syndrome is in progress during paracetamol poisoning. [ABSTRACT FROM AUTHOR]

Objective: Recently, human β-defensin-2 (hBD-2), an inducible defensin, has been reported to be involved in innate immunity and host defence. To examine the exact roles of hBD-2 in the respiratory system, we examined the molecular mechanisms of hBD-2 gene expression in vitro . Methodology: Using a human airway cell line (LC-2/ad), lipopolysaccharide (LPS)-induced gene expression of hBD-2 was studied in the absence or the presence of (i) dexamethasone, (ii) inhibition of NF-κB and AP-1, (iii) intracellular calcium chelator, and (iv) cyclooxygenase (COX) inhibitors. Results: Lipopolysaccharide-induced gene expression of hBD-2 was down-regulated by (i) dexamethasone, (ii) inhibition of NF-κB and AP-1, and (iii) intracellular calcium chelator. However, COX inhibitors had no effect on LPS-induced mRNA expression of hBD-2. Conclusion: These findings suggest that glucocorticoids (GC), but not COX inhibitors, reduce hBD-2 gene expression, while NF-κB, AP-1 and intracellular calcium are essential for hBD-2 expression. Glucocorticoid-induced down-regulation of hBD-2 might be involved in the GC-induced suppression of respiratory host defence associated with hBD-2. [ABSTRACT FROM AUTHOR]

Summary The prospect that simple medications such as non-steroidal anti-inflammatory drugs (NSAIDs) could be recruited into the physician's armamentarium of anticancer drugs is intriguing, especially in the context of breast cancer, one of the leading causes of mortality in the Western world. There has consequently been a wider exploration of the role of cyclooxygenase (COX) in breast cancer, and we now accept that COX-2, one of its isoenzymes, is clearly implicated in the pathogenesis of the disease. This would seem to translate into a viable role for cyclooxygenase inhibitors in the treatment and prevention of breast cancer, but also raises issues regarding safety and tolerability of these drugs. In this article we discuss the theoretical consequences of cyclooxygenase inhibition, the significance of findings from experimental studies, large scale epidermiological investigations, and the relevance of large population studies of COX-2 inhibitors such as CLASS and VIGOR. [ABSTRACT FROM AUTHOR]

Purpose: On the basis of our anecdotal clinical observations that nonsteroidal anti-inflammatory agents relieved dysuria during radiotherapy for patients with prostate cancer, we conducted a Phase III randomized trial of ibuprofen vs. placebo for patients who had an increase in acute urinary symptoms. Our in vitro and in vivo laboratory data with a higher concentration of ibuprofen than achievable in this study demonstrated radiosensitization. This study examined whether the inflammatory response within the prostate during radiotherapy would respond to the standard dose of ibuprofen as assessed by a symptom score.Methods and Materials: Patients were registered to the study and were followed weekly with a formal symptom assessment. A double-blind randomization to ibuprofen, 400 mg q.i.d., vs. placebo for 7 days was done at a time when the severity score increased. The symptom response was evaluated at the end of the week.Results: Between 1995 and 1998, 100 patients were entered, 28 did not have a sufficient change in symptom score to be randomized, and 19 were either unable to take ibuprofen or withdrew before randomization. Of the 53 patients randomized, 27 received placebo and 26 ibuprofen. No statistically significant differences were found between the placebo and ibuprofen groups between baseline and randomization or between randomization and the 1-week posttreatment assessment. Neither group had a change in symptom severity between randomization and the 1-week posttreatment evaluation.Conclusion: The standard anti-inflammatory dose of ibuprofen did not relieve the acute urinary or rectal symptoms during radiotherapy for prostate cancer. The nonsteroidal anti-inflammatory drugs are potential radiation sensitizers with the mechanism of action as yet unknown. Clinical trials of the cyclooxygenase inhibitors as radiation sensitizers should explore a range of doses and evaluate potential mechanisms of action, including cyclooxygenase inhibition and other non-cyclooxygenase mechanisms. [Copyright &y& Elsevier]

Cyclooxygenase (COX) inhibitors could produce cartilage toxicity as well as delayed skeleton formation when administrated during pregnancy. The purpose of this experiment was to determine the effect of a nonselective COX inhibitor, propyphenazone (isopropylantipyrine), on the development of the knee joint in rats. The drug was administered orally in Tween 80 water suspension once a day on days 8–14 of gestation in three doses: R1: 2.1 mg/kg, R2: 21.0 mg/kg and R3: 210.0 mg/kg. Two control groups were formed: untreated control (K) and Tween 80-treated (T) animals. Fetuses were delivered by cesarean section on day 21 of gestation and examined macroscopically for external malformations. The knee joints of two fetuses of each litter were sectioned in situ or paraffin-embedded. The slides were examined microscopically. The remaining fetuses were stained using the Alcian blue and red S alizarin skeleton double-staining method. Reduced alizarin staining in bones from the knee joint, and wider epiphysial cartilage was seen in 2 of 53 examined fetuses (3.77%) exposed prenatally to the highest dose of propyphenazone. The extra sesamoid cartilage, located close to the lateral epicondyle of the femur, was absent in 10 cases in group T (15.87%), 9 cases in group K (15.00%), 8 cases in group R1 (12.50%), 9 cases in group R2 (14.75%) and 9 cases in group R3 (14.28%). Similarly sesamoid cartilage close to the middle epicondyle was seen in one fetus from group K (1.66%) and in one fetus from group R2 (1.63%). No histological changes were observed. Based on obtained results, it could be concluded that propyphenazone did not delay the formation of the knee joint.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

LIPOPOLYSACCHARIDE is an inflammatory agent and interleukin-1 is a cytokine. Their pro-inflammatory effects may be mediated by prostanoids produced by inducible cyclooxygenase-2. The aim of this study was to determine the prostanoids produced by lipopolysaccharide and interleukin-1 stimulated enterocytes through the cyclooxygenase-1 and 2 pathways. Cultured enterocytes were stimulated with lipopolysaccharide or interleukin-1 beta with and without cyclooxygenase inhibitors. Low concentrations of indomethacin and valerylsalicylic acid (VSA) were evaluated as cyclooxygenase-1 inhibitors and their effects compared with the effects of a specific cyclooxygenase-2 inhibitor, SC-58125. Prostaglandin E , 6-keto prostaglandin F , prostaglandin D and 2 1 alpha 2 leukotriene B levels were determined by radio4 immunoassay. Immunoblot analysis using isoformspecific antibodies showed that the inducible cyclooxygenase enzyme (COX-2) was expressed by 4 h in LPS and IL-1 beta treated cells while the constitutive COX-1 remained unaltered in its expression. Interleukin-1 beta and lipopolysaccharide stimulated the formation of all prostanoids compared with untreated cells, but failed to stimulate leukotriene B4. Indomethacin at 20 mu M concentration, and VSA inhibited lipopolysaccharide and interleukin 1 beta stimulated prostaglandin E , but not 6-keto prostaglandin F 2 1 alpha formation. SC-58125 inhibited lipopolysaccharide and interleukin-1 beta stimulated 6-keto prostaglandin F but not prostaglandin E release. The specific 1 alpha 2 cyclooxygenase-2 inhibitor also inhibited lipopolysaccharide produced prostaglandin D but not inter2 leukin-1 beta stimulated prostaglandin D While SC2 58125 inhibited basal 6-keto prostaglandin-F 1 alpha formation it significantly increased basal prostaglandin E and prostaglandin D formation. As SC2 2 58125 inhibited lipopolysaccharide and interleukin1 beta induced 6-keto prostaglandin F production but 1 alpha not prostaglandin E production, it suggests that 2 these agents stimulate prostacyclin production through a cyclooxygenase-2 mediated mechanism and prostaglandin E production occurs through a 2 cyclooxygenase-1 mediated mechanism. Prostaglandin D production appeared to be variably produced 2 by cyclooxygenase-1 or cyclooxygenase-2, depending on the stimulus. [ABSTRACT FROM AUTHOR]

Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless (Wnt) signaling pathway has emerged as the key regulator of cardiomyogenesis. In this study, we evaluated the effects of cyclooxygenase inhibitors on cardiac differentiation of hPSCs. Cardiac differentiation was performed by adherent monolayer based method using 4 hPSC lines (HES3, H9, IMR90, and ES4SKIN). The efficiency of cardiac differentiation was evaluated by flow cytometry and RT-qPCR. Generated hPSC-CMs were characterised using immunocytochemistry, electrophysiology, electron microscopy, and calcium transient measurements. Our data show that the COX inhibitors Sulindac and Diclofenac in combination with CHIR99021 (GSK-3 inhibitor) efficiently induce cardiac differentiation of hPSCs. In addition, inhibition of COX using siRNAs targeted towards COX-1 and/or COX-2 showed that inhibition of COX-2 alone or COX-1 and COX-2 in combination induce cardiomyogenesis in hPSCs within 12 days. Using IMR90-Wnt reporter line, we showed that inhibition of COX-2 led to downregulation of Wnt signalling activity in hPSCs. In conclusion, this study demonstrates that COX inhibition efficiently induced cardiogenesis via modulation of COX and Wnt pathway and the generated cardiomyocytes express cardiac-specific structural markers as well as exhibit typical calcium transients and action potentials. These cardiomyocytes also responded to cardiotoxicants and can be relevant as an in vitro cardiotoxicity screening model. [ABSTRACT FROM AUTHOR]

The article discusses a report within the issue by Y. Yu and team on the potential hazardous effects of cyclooxygenase (COX) enzyme inhibitor nonsteroidal anti-inflammatory drugs (NSAIDs) on the cardiovascular system, such as stroke or myocardial infarction. Yu and colleagues looked at the platelet aggregation, vasoconstriction, and vasodilation pathways in blood vessels caused by interactions between arachidonic acid products, prostaglandin E2 (PGE2), prostacyclin (PGI2), and thromboxane A2 (TxA2). They found that COX-2 inhibitors prompted the development of thrombosis and hypertension by blocking the vasodilation functions of PGE2 and PGI2, but not the vasoconstrictive effects of TxA2.

The economic evaluation of health care programs is undertaken to assess health care costs and benefits. Part of the goal of cost-effectiveness analysis is to maximize health benefits given the constraint of limited health care resources. The identification of costs is critical in a cost-effectiveness analysis of clinical interventions. The recent introduction of the cyclooxygenase (COX)-2-selective inhibitors, coxibs, for treatment of rheumatoid arthritis, osteoarthritis, and acute pain gives rise to cost-effectiveness issues. These new agents provide similar efficacy with fewer gastrointestinal events compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), but are more expensive on a per-dose basis. However, several modeled cost analyses have suggested that COX-2 inhibitors are cost effective in subsets of patients because they are associated with fewer downstream costs, particularly medical and surgical treatment of gastrointestinal adverse effects. Three cost-effectiveness models of interventions for rheumatoid arthritis and osteoarthritis, including COX-2 inhibitors, are reviewed. Prospective clinical investigation of the potential costs and benefits of these new agents is necessary to further support these findings. [Copyright &y& Elsevier]