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      Different Actions of the Cyclooxygenase 2 Selective Inhibitor Flosulide in Rats with Passive Heymann Nephritis

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          The prostaglandin cyclooxygenase (Cox) exists in two isoforms with different genetic representation. The isoform, which is constitutively expressed (Cox 1), and mediates physiological functions of prostaglandins, and the inducible isoform (Cox 2) which is upregulated by inflammatory stimuli. This study attempts to determine whether a Cox 2 selective inhibitor, flosulide, differs from the mixed type Cox 1 and Cox 2 inhibitor aspirin in respect of renal function and eicosanoid excretion in experimental nephritis. The effects of flosulide and aspirin were studied during the autologous phase of passive Heymann nephritis (PHN) in rats. Female Wistar rats were injected i.v. with 1 ml of Fx1A antiserum at day 1. From day 7 to day 14 they received either aspirin (aspirin, 50 mg/day), flosulide, (0.75 mg/day) or vehicle p.o. The kidney function was evaluated and the animals sacrificed. The kidneys were removed and glomeruli isolated. The glomeruli were incubated in physiological buffer solution. Basal prostaglandin generation was determined in the supernatant. Treatment with flosulide significantly reduced proteinuria as compared to aspirin treatment (64±15 vs. 109±14 mg/24 h, p < 0.05). Plasma protein and albumin levels were significantly lower in the aspirin-treated group than in flosulide-treated animals (4.7±0.26 vs. 5.48±0.08 mg/dl, p < 0.05 and 0.96±0.04 vs. 1.25±0.10 mg/dl, p < 0.05). Glomerular prostaglandin production (6-keto-PGF<sub>1α</sub>, TxB<sub>2</sub>, Bicyclo-PGE<sub>2</sub>) was significantly reduced in aspirin-, but not in flosulide-treated animals. This was mainly due to a reduction of glomerular TxB<sub>2</sub> production by aspirin. Our data demonstrate that a Cox 2 selective inhibitor of prostaglandin formation, flosulide, has beneficial effects on preservation of kidney function in rats with PHN, whereas aspirin has not. These beneficial effects of flosulide possibly result from preservation of the physiological glomerular prostaglandin production. Thus, selective Cox 2 inhibitors might be interesting substances for treatment of nephrotic syndrome.

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          Most cited references 3

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          Cloning two isoforms of rat cyclooxygenase: differential regulation of their expression.

           P Chanmugam,  Y Xia,  L Feng (1993)
          Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: COX-1 encoded by a 2.8-kb mRNA, and a mitogen-inducible COX-2 encoded by a 4-kb mRNA. We have cloned the COX-1 and COX-2 cDNAs from the cDNA library constructed from lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages. The deduced amino acid sequence showed that COX-1 contained 602 amino acids, whereas COX-2 contained 604 amino acids. There is 95% conservation of the nucleotide sequence in the open reading frame of COX-1 between the rat and the mouse, while the homology of the 3' untranslated region is 68% except for a 150 bp segment adjacent to the stop codon which is nonhomologous with the mouse. Transfection of both COX cDNAs into Cos-7 cells resulted in increased COX activity. In rat vascular smooth muscle cells, interleukin-1 beta selectively increased the expression of COX-2, but not that of COX-1, as assessed by enzyme activity, immunoprecipitation of COX proteins, and mRNA analysis. Only the brain among tissues tested exhibits basal expression of COX-2 as the major form of the enzyme. However, COX-2 mRNA was expressed in vivo in the lung and kidney, but not in the heart, after systemic administration of LPS, suggesting that COX-2 but not COX-1 plays a major role in producing COX-derived products of arachidonic acid during endotoxic shock. Thus, the two COX isoforms were differentially expressed, and COX-2 was selectively induced in response to inflammatory stimuli in rats.
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            Selective inhibition of cyclooxygenase 2.

            Cyclooxygenase (COX), a key enzyme in the formation of prostanoids, is known to exist in two isoforms: an inducible enzyme (COX 2) and a constitutive from (COX 1). Both enzymes are inhibited by non-steroidal anti-inflammatory drugs (NSAID), but only marginal selectivity has thus far been reported. In this study, we report on a novel selective inhibitor of COX 2, CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanon e). Human washed platelets were used as a source of COX 1. For IL-1 stimulated rat mesangial cells we demonstrated the almost exclusive presence of COX 2 in western blot and mRNA analysis. Therefore these two model systems were chosen for selectivity testing. With an IC50 value of 15 nM, CGP 28238 blocked COX 2 activity in a similar concentration range to that of other potent NSAID such as indomethacin and diclofenac (IC50 = 1.17-8.9 nM). However, in contrast to these reference NSAIDs, CGP 28238 was at least 1000-fold less potent in inhibiting COX 1. Using other cell systems reported to express COX 1 or COX 2, we obtained a similar selectivity for COX 2. Thus, on the basis of our findings, CGP 28238 is a novel, highly potent and selective inhibitor of COX 2 and may be a lead compound for a new generation of potent anti-inflammatory drugs with an improved side-effect profile.
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              Influence of the anti-inflammatory compound flosulide on granulocyte function.

              Polymorphonuclear leukocytes (PMN) are involved in inflammatory reactions. It is thought that oxygen-derived free radicals released from activated PMN may participate in tissue damage during inflammation. We have shown that flosulide (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ), a novel highly potent anti-inflammatory compound, inhibits superoxide production induced by N-formyl-Met-Leu-Phe (FMLP), C5a and PMA without impairing bacterial killing or chemotaxis. Flosulide (10(-5)-10(-7) M) was more potent in inhibiting the FMLP-induced respiratory burst of PMN than the structurally related compound nimesulide. FMLP-induced superoxide generation was also inhibited by two human flosulide metabolites. A good correlation between this in vitro effect and in vivo anti-inflammatory potency in rat adjuvant arthritis was found for flosulide and its metabolites. Indomethacin, piroxicam and ibuprofen did not inhibit the respiratory burst at 10(-5) M. FMLP receptor number was decreased by 36% in the presence of 10(-5) M flosulide. However, a 250-fold molar excess of flosulide could not displace labeled FMLP from the receptor. Inhibition of degranulation of primary and secondary granules was a common effect of all anti-inflammatory compounds tested. At a concentration of 10(-5) M, all drugs inhibited degranulation to about the same degree, independent of their in vivo anti-inflammatory activity.

                Author and article information

                S. Karger AG
                October 1998
                23 September 1998
                : 80
                : 2
                : 220-226
                Departments of a Nephrology and Rheumatology and b Pharmacology, Heinrich Heine University, Düsseldorf, Germany
                45171 Nephron 1998;80:220–226
                © 1998 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 3, References: 32, Pages: 7
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/45171
                Original Paper


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