thromboxane-b2 and Edema

Pharmacokinetic and pharmacodynamic parameters were established for enantiomers of the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (KTP), each administered separately at a dose level of 1.1 mg/kg to a group of six New Forest geldings, in a three-period cross-over study using a tissue cage model of inflammation. For both S(+)-and R(-)-KTP, penetration into tissue cage fluid (transudate) and inflamed tissue cage fluid (exudate) was rapid, and clearances from exudate and transudate were much slower than from plasma. AUC values were, therefore, higher for exudate and, to a lesser degree, transudate than for plasma. Unidirectional chiral inversion of R(-)-to S(+)-KTP was demonstrated. Administration of both enantiomers produced marked, time-dependent inhibition of synthesis of serum thromboxane B2 and exudate prostaglandin E2, indicating non-selective inhibition of cyclo-oxygenase (COX) isoenzymes COX-1 and COX-2 respectively. Administration of both enantiomers also produced partial inhibition of beta-glucuronidase release into inflammatory exudate and of bradykinin-induced skin oedema. It is suggested that, although S(+)-KTP is generally regarded as the eutomer, R(-)-KTP was probably at least as active in inhibiting bradykinin swelling. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could not be undertaken following R(-)-KTP administration because of chiral inversion to S(+)-KTP, but pharmacodynamic parameters, Emax, EC50, N, keO and t1/2(keO). were determined for s(+)-KTP using the sigmoidal Emax equation. PK/DP modelling provided a novel means of comparing and quantifying several biological effects of KTP and of investigating its mechanisms of action.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Cross-Over Studies; Dinoprostone; Dose-Response Relationship, Drug; Edema; Extracellular Space; Glucuronidase; Horses; Injections, Intravenous; Ketoprofen; Male; Prostaglandin-Endoperoxide Synthases; Regression Analysis; Software; Stereoisomerism; Thromboxane B2

The pharmacodynamics of the non-steroidal anti-inflammatory drugs flunixin, tolfenamic acid and ketoprofen were studied in calves after intravenous administration. An acute inflammatory reaction was induced in tissue cages by the intracaveal injection of the mild irritant carrageenan, and the inhibition of inflammatory mediators and enzymes was investigated. The substances measured in the exudate included the enzymes (active and total metalloproteases, serine and cysteine proteases, acid phosphatase [AP], lactate dehydrogenase [LDH] and beta-glucuronidase) and the eicosanoids (prostaglandin [PG]E2 and leukotriene [LT]B4). Studies were also made of inhibition of the synthesis of serum thromboxane (Tx)B2 ex vivo, of bradykinin-induced oedema in vivo and of the generation of superoxide anions (O2-) in vitro. None of the drugs affected the concentration of LTB4, or the activities of metalloproteases, cysteine and serine proteases, AP or LDH in the exudate. All the drugs inhibited the synthesis of serum TxB2 and exudate PGE2 and inhibited the release of beta-glucuronidase. They also decreased the oedematous response to intradermally injected bradykinin and inhibited the generation of O2- ions by neutrophils in vitro. These actions may contribute to the anti-inflammatory effects of the drugs and hence to their clinical efficacy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Cattle Diseases; Clonixin; Cross-Over Studies; Dinoprostone; Edema; Glucuronidase; Ketoprofen; Neutrophils; ortho-Aminobenzoates; Superoxides; Thromboxane B2

The pharmacokinetics (PK) and pharmacodynamics (PD) of ketoprofen (KTP) were studied in calves following intravenous administration of the drug racemate at a dose rate of 3 mg/kg. To evaluate the anti-inflammatory properties of KTP, a model of acute inflammation, consisting of surgically implanted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. No differences were observed between disposition curves of KTP enantiomers in plasma, exudate or transudate. This indicates that in calves KTP pharmacokinetics is not enantioselective. S(+)- and R(-)- KTP each had a short elimination half-life (t1/2 beta) of 0.42 +/- 0.08 h and 0.42 +/- 0.09 h, respectively. The volume of distribution (Vd) was low, values of 0.20 +/- 0.06 L/kg and 0.22 +/- 0.06 L/kg being obtained for R(-) and S(+)KTP, respectively. Body clearance (ClB) was high, correlating with the short elimination half-life, 0.33 +/- 0.03 L/kg/h [R(-)KTP] and 0.32 +/- 0.04 L/kg/h [S(+)-KTP]. KTP pharmacodynamics was evaluated by determining the effects on serum thromboxane (TxB2), exudate prostaglandin (PGE2), leukotriene (LTB4) and beta-glucuronidase (beta-glu) and bradykinin (BK)-induced oedematous swelling. Effect-concentration inter-relationships were analysed by PK/PD modelling. KTP did not affect exudate LTB4, but inhibition of the other variables was statistically significant. The mean EC50 values for inhibition of serum TxB2, exudate PGE2 and beta-glu and BK-induced swelling were 0.118, 0.086, 0.06 and 0.00029 microgram/mL, respectively. These data indicate that KTP exerted an inhibitory action, not only as expected, on eicosanoid (TxB2 and PGE2) synthesis but also on exudate beta-glu and BK-induced oedema. The EC50 values for these actions indicate that they are likely to contribute to the overall anti-inflammatory effects of KTP in calves. However, claims that KTP inhibits 5-lipoxygenase and thereby blocks the production of inflammatory mediators such as LTB4 were not substantiated. PK/PD modelling has proved to be a useful tool for analysing the in vivo pharmacodynamics of KTP and for providing new approaches to elucidating its mechanism(s) of action.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Carrageenan; Cattle; Cattle Diseases; Cross-Over Studies; Diffusion Chambers, Culture; Dinoprostone; Dose-Response Relationship, Drug; Edema; Glucuronidase; Half-Life; Inflammation; Injections, Intravenous; Ketoprofen; Leukotriene B4; Male; Stereoisomerism; Thromboxane B2

Chemical investigation of cyanobacterial strain HT-58-2, which most closely aligns with the genus

Topics: Animals; Anti-Inflammatory Agents; Cyanobacteria; Diterpenes; Ear Diseases; Edema; Escherichia coli; Lipopolysaccharides; Mice; Rats; Superoxides; Thromboxane B2

Bioassay-guided fractionation of the anti-inflammation fractions of the Red Sea sponges Scalarispongia aqabaensis and Callyspongia siphonella yielded two new sterols from chloroform fractions of methanol extracts, namely scalaristerol (5alpha,8alpha-dihydroxycholest-6-en-3beta-ol) (1) from Scalarispongia aqabaensis, and callysterol (ergosta-5,11-dien-3beta-ol) (2) from Callyspongia siphonella. Structure determination was based on extensive NMR studies and mass spectrometry. The antiinflammatory activity of compounds 1 and 2 was assessed using the rat-hind paw edema method and by study of their effect on the release of O2(-) and TXB2 from LPS-activated rat neonatal microglia.

Topics: Animals; Anti-Inflammatory Agents; Callyspongia; Edema; Microglia; Molecular Structure; Phytosterols; Rats; Superoxides; Thromboxane B2

Compound ZLJ-6 [(Z)-1-methyl-1,5-dihydro-2-amino-5-[4-(mesyl)benzylidene]-4H-imi-dazole-4-one mesilate] is a potent inhibitor of cyclooxygenase (IC(50)=0.73 and 0.31 microM, for cyclooxygenase-1 and cyclooxygenase-2 respectively) in human whole blood. It also inhibited the production of thromboxane B(2) and prostaglandin E(2) in calcium ionophore A23187-induced human (IC(50)=0.50 microM) and rat whole blood (IC(50)=0.93 microM), and rat peritoneal leukocytes (IC(50)=2.27 microM). ZLJ-6 suppressed the activity of 5-lipoxygenase in the rat basophilic leukemia (RBL-1) cell lysate (IC(50)=0.32 microM) and in intact cells (IC(50)=1.06 microM) and reduced the generation of leukotriene B(4) (LTB(4)) in A23187-stimulated human (IC(50)=1.61 microM) or rat whole blood (IC(50)=0.99 microM), and rat peritoneal leukocytes (IC(50)=2.59 microM). In vivo, ZLJ-6, administered orally, demonstrated potent anti-inflammatory activity in the carrageenin-induced paw oedema model in rats and showed analgesic activity in the acetic acid-induced abdominal construction model in mice. No gastrointestinal ulcers were found with the anti-inflammatory dose (30 mg/kg) in normal rats. These results indicated that ZLJ-6 potently inhibited 5-lipoxygenase and cyclooxygenase, and blocked the production of LTB(4), TXB(2) and PGE(2). Thus ZLJ-6 is an ideal substitute for classical non-steroidal anti-inflammatory therapy.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Edema; Female; Humans; Imidazoles; Inhibitory Concentration 50; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Rats; Rats, Sprague-Dawley; Sulfones; Thromboxane B2

1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Biological Availability; Blood Platelets; Cell Line; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Female; Fever; Fibroblasts; Humans; Hyperalgesia; Male; Membrane Proteins; Organic Chemicals; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Rats, Wistar; Skin; Thromboxane B2

We investigated the mechanism of inhibition of loxoprofen sodium, a non-steroidal anti-inflammatory drug (NSAID), and its active metabolite (loxoprofen-SRS) on cyclooxygenase (COX). In in vitro assays, loxoprofen sodium appeared inactive against recombinant human COX-1 and COX-2, whereas loxoprofen-SRS inhibited both. In the investigation of kinetic behavior, loxoprofen-SRS showed time-dependent inhibition for both isozymes. Human whole blood assay also showed that loxoprofen-SRS possesses the profile of a non-selective inhibitor for COX. In a rat air pouch model, oral administration of loxoprofen sodium lowered prostaglandin (PG) E2 in both fluid exudates of the inflammatory pouch and stomach tissue with ED50 values of 2.0 and 2.1 mg/kg, respectively. Additionally, platelet thromboxane B2 production was also inhibited by loxoprofen sodium (ED50 of 0.34 mg/kg). In a rat carrageenan-induced paw edema model, loxoprofen sodium dose-dependently reduced the paw edema, accompanied by a decrease in PGE2 content in inflamed paw exudates. These findings suggest that the COX inhibitory activity of loxoprofen sodium is attributable to its active metabolite, loxoprofen-SRS, and that loxoprofen-SRS shows non-selective inhibition for COX.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Edema; Enzyme-Linked Immunosorbent Assay; Foot; Male; Oxygen Consumption; Peroxidases; Phenylpropionates; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Thromboxane B2

Peripheral inflammation involves an increase in cyclooxygenase-2 (COX-2)-mediated prostaglandin (PG) synthesis in the central nervous system (CNS), which contributes to allodynia and hyperalgesia. In the present study we have determined the changes in prostanoid tissue levels and in expression of terminal prostanoid synthases in both the CNS and inflamed peripheral tissue during carrageenan-induced paw inflammation in the rat. Prostanoid levels were measured by liquid chromatography-mass spectrometry and enzyme expression at the RNA level by quantitative PCR analysis during both the early (1-6 h) and late (12 and 24 h) phases of the inflammatory response. In the paw, the early phase was associated with increases in PGE(2) and thromboxane (TX)B(2) levels and with a peak of COX-2 expression that preceded that of microsomal prostaglandin-E(2) synthase-1 (mPGES-1). COX-2 and mPGES-1 remained elevated during the late phase, and PGE(2) continued to further increase through 24 h. The cytosolic PGE(2) synthase (cPGES) showed a small transient increase during the early phase, whereas mPGES-2 expression was not affected by inflammation. In the cerebrospinal fluid, elevated levels of PGE(2), 6-keto-PGF(1alpha), PGD(2), and TXB(2) were detected during the early phase. PGE(2) levels also increased in the spinal cord and, to a lesser extent, in the brain and remained elevated in both the cerebrospinal fluid and the spinal cord during the late phase. The expression of mPGES-1 was strongly up-regulated in the brain and spinal cord during inflammation, whereas no change was detected for the expression of cPGES, mPGES-2, COX-1, and terminal PGD, TX, or PGI synthases. The results show that the carrageenan-induced edema in the paw elicits an early phase of COX-2 induction in the CNS leading to an increase synthesis in PGD(2), 6-keto-PGF(1alpha), and TXB(2) in addition to the major PGE(2) response. The data also indicate that the up-regulation of mPGES-1 contributes to COX-2-mediated PGE(2) production in the CNS during peripheral inflammation.

Topics: Animals; Blotting, Western; Brain; Carrageenan; Central Nervous System; Chromatography, Liquid; Cytosol; Dinoprostone; Edema; Extremities; Inflammation; Intramolecular Oxidoreductases; Microsomes; Polymerase Chain Reaction; Prostaglandin-E Synthases; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Spinal Cord; Thromboxane B2; Time Factors; Up-Regulation

Hwaotang, a traditional Korean medicinal formulation, is a dried decoctum of a mixture of 7 herbal medicines, consisting of Angelica gigantis Radix, Rehmanniae radix, Paeoniae radix, Ciniamomi cortex, Cnidii rhizoma, Persicae semen and Carthami flos. We have investigated that Hwaotang water extract (HOT) has various effects on stimulus-induced superoxide generation in human neutrophils. The effects of HOT on superoxide generation in human neutrophils were investigated. HOT significantly inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide generation in a concentration-dependent manner, but not that induced by arachidonic acid (AA). On the other hand, HOT enhanced superoxide generation induced by phorbol 12-myristate 13-acetate (PMA) in a concentration-dependent manner. The superoxide generation induced by PMA with HOT was suppressed by staurosporine, an inhibitor of protein kinase C, but was not suppressed by genistein, an inhibitor of protein tyrosine kinase. Tyrosyl phosphorylation of a 58 kDa protein, which was increased by fMLP, was inhibited by HOT. HOT also inhibited the generation of a 47 kDa protein and platelet aggregation in human blood. The results suggest that protein tyrosine kinase participates in fMLP-mediated superoxide generation by HOT-treated human neutrophils. HOT inhibited neutrophil functions, including degranulation, superoxide generation, and leukotriene B4 production, without any effect on 5-lipoxygenase activity. HOT reduced nitric oxide (NO) and prostaglandin E2 production in mouse peritoneal macrophages stimulated with lipopolysaccharide, whereas no influence on the activity of iNOS, COX-2 or COX-1 was observed. HOT significantly reduced mouse paw oedema induced by carrageenan. Western blot analysis showed that HOT reduced the expression of iNOS and COX-2. The results indicate that HOT exerts anti-inflammatory effects related to the inhibition of neutrophil functions and of NO and prostaglandin E2 production, which could be due to a decreased expression of iNOS and COX-2.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Carrageenan; Cell Degranulation; Cyclooxygenase 1; Cyclooxygenase 2; Cytochalasin B; Dinoprostone; Edema; Female; Gastric Mucosa; Gene Expression; Genistein; Hindlimb; Humans; Indomethacin; Isoenzymes; Korea; Leukotriene B4; Lipopolysaccharides; Macrophages, Peritoneal; Medicine, East Asian Traditional; Membrane Proteins; Mice; N-Formylmethionine Leucyl-Phenylalanine; NADPH Oxidases; Neutrophils; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pancreatic Elastase; Phosphoproteins; Phosphorylation; Phosphotyrosine; Plant Extracts; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Protein Kinase Inhibitors; Staurosporine; Stomach; Superoxides; Tetradecanoylphorbol Acetate; Thromboxane B2

Silsosangami is a dried decoctum of a mixture of seven Korean herbal medicine, which is consisted of seven herbs (indicated as concentrations) of Typhae Pollen, Pteropi Faeces, Paeoniae Radicis rubra, Cnidii Rhizoma, Persicae Semen, Carthami Flos and Curcumae Tuber. In the present study, the effects of Silsosangami water extract (SSG) on hemolysis in human blood were studied. Using an in vitro system, only Curcumae Tuber, Persicae Semen and Paeoniae Radicis rubra had the strongest effects on hemolysis; Typhae Pollen and Pteropi Faeces had the slight effects; and Cnidii Rhizoma and Carthami Flos had no effect. On the other hand, the SSG inhibited neutrophil functions, including degranulation, superoxide generation, and leukotriene B4 production, without any effect on 5-lipoxygenase activity. This SSG reduced nitric oxide (NO) and prostaglanin E2 (PGE2) production in mouse peritoneal macrophages stimulated with lipopolysaccharide, without the influence on the activity of inducible NO synthase (iNOS), cyclooxygenase COX-2 and COX-1 being observed. SSG significantly reduced mouse paw oedema induced by carrageenan. Western blot analysis showed that SSG reduced the expression of iNOS and COX-2. These results suggested that SSG might be used as a novel antithrombotic therapeutic agents in post-myocardial infarction and also, indicated that SSG exerts anti-inflammatory effects related to the inhibition of neutrophil functions and of NO and PGE2 production, which could be due to a decreased expression of iNOS and COX-2.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Edema; Erythrocytes; Gene Expression; Hemolysis; Herbal Medicine; Humans; Korea; Leukotriene B4; Macrophages, Peritoneal; Medicine, East Asian Traditional; Membrane Proteins; Mice; Neutrophils; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pancreatic Elastase; Phytotherapy; Plant Extracts; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

This study evaluates the action of celecoxib and rofecoxib, two selective cyclooxygenase-2 (COX-2) inhibitors in two acute models of inflammation, carrageenan (Cg)-induced rat pleurisy, and paw oedema formation.. Male Wistar rats (N = 4-10 per group) were used. A fixed volume of PBS or carrageenan was injected into the pleural cavity or into the paw. Furthermore, the myeloperoxidase (MPO) activity and the levels of nitrite/nitrate (NOx), interleukin-1beta (IL-1beta), tumor necrosis factor-a (TNF-a) and PGE2 were also assessed in the paw tissue or in pleural exudate.. Dexamethasone (DEX, 0.5 mg kg(-1), s.c., -4 h) and indomethacin (INDO, 3 mg kg(-1), p.o., -1 h) suppressed Cg-induced pleural exudate accumulation by 84 and 77% and inflammatory cell influx by 66 and 47%, respectively. In contrast, celecoxib (CLX, 10 mg kg(-1), p.o., -1 h) or rofecoxib (RFX, 10 mg kg(-1) , p.o., -1 h) only reduced the Cg-induced pleural exudate volume by 44 and 40%, respectively, but had no significant effect over inflammatory cell influx. At the same doses used for pleurisy, DEX, INDO, CLX, RFX and SC-560 (a selective COX-1 inhibitor, 40 mg kg(-1), p.o., -1 h), inhibited the Cg-induced paw oedema by 49, 31, 21, 21 and 17%. DEX, INDO or SC-560 reduced the level of MPO by 71, 78 and 59%, while CLX or RFX produced a small, but significant increase (28 or 16%) in MPO activity. In the rat model of pleurisy, PGE2 levels in cell-free exudates were significantly attenuated by 91, 89, 57 and 65% in animals treated with DEX, INDO, CLX or RFX. In contrast, INDO reduced significantly the whole bloodTXB, synthesis (59%) while DEX and INDO reduced the pleural content of NOx significantly. Treatment of animals with CLX or RFX did not alter the content of pro-inflammatory cytokines IL-1beta or TNF-alpha in the pleural exudate, but CLX reduced IL-1beta levels in the rat paw tissue and RFX increased TNF-alpha in this tissue.. Together these results provide consistent evidence indicating that the selective COX-2 inhibitors CLX and RFX, in contrast to DEX, INDO or SC-560, despite reducing greatly the Cg-induced pleural exudation, PGE2 content and paw oedema have only partial acute anti-inflammatory properties in two different rat acute models of inflammation.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dexamethasone; Dinoprostone; Edema; Indomethacin; Inflammation; Interleukin-1; Isoenzymes; Lactones; Male; Nitric Oxide; Peroxidase; Pleurisy; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Sulfones; Thromboxane B2; Tumor Necrosis Factor-alpha

We investigated the effects of FR122047 (1-[(4,5-bis(4-methoxyphenyl)-2-thiazoyl)carbonyl]-4-methylpiperazine hydrochloride), a selective cyclo-oxygenase (COX)-1 inhibitor, in rat type II collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). Using an ex vivo rat whole blood assay, FR122047 (0.032 - 3.2 mg kg(-1)) inhibited COX-1-derived thromboxane (TX) B(2) production with ED(50) value of 0.059 mg kg(-1), indicating that it was orally active, but did not inhibit lipopolysaccharide-induced prostaglandin (PG) E(2) production derived by COX-2. Oral administration of FR122047 showed a dose-dependent anti-inflammatory effect in rat CIA with ED(50) value of 0.56 mg kg(-1). This drug also dose dependently suppressed the levels of PGE(2) and TXB(2) in CIA rat paws with ED(50) values of 0.24 and 0.13 mg kg(-1), respectively. FR122047 had no effect in rat AIA model. In contrast, indomethacin, a non-selective COX inhibitor, was anti-inflammatory and reduced the formation of PGs in AIA rat paws. Unlike indomethacin, chronic treatment of FR122047 did not damage the stomach mucosa in CIA rats. These results demonstrate that COX-1 contributes to the oedema and the formation of PGE(2) and TXB(2) in rat CIA model, but not in rat AIA model. We conclude that FR122047 has an orally active and anti-inflammatory effect mediated by inhibition of PGE(2) and TXB(2) produced by COX-1 at a site of inflammation induced by type II collagen and it may be a useful tool for studying the involvement of COX-1 in various in vivo models of inflammation.

Topics: Adjuvants, Immunologic; Animals; Arthritis, Experimental; Chronic Disease; Collagen; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Edema; Female; Hindlimb; Isoenzymes; Membrane Proteins; Piperazines; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Lew; Thiazoles; Thromboxane B2

We examined the effects of ML3000 and several non-steroidal antiinflammatory drugs (NSAIDs) on the synthesis of products of 5-LOX (LTB4, LTC4) and COX-1/2 (TXB2, PGE2) in vitro and ex vivo in order to further elucidate the mechanism of action of ML3000.. Using a human whole blood assay the effect of ML3000 on the shunt of arachidonic acid to the lipoxygenase pathway when COX is blocked was studied. ML3000 (0.3, 1, 3, 10, 30 microg/ml) and indomethacin (0.3, 1, 3, 10, 30 microg/ml) concentration-dependently inhibited the synthesis of PGE2 (IC50 = 3.9 and 4.5 microM). In contrast to ML3000, indomethacin produced an increase of LTC4 of up to 155.5% of control. 5-lipoxygenase inhibition was further tested in a basophilic leukemia cell assay using RBL-1 cells. ML3000 (1-10 microM) inhibited the synthesis of LTB4 in a concentration related manner (IC50: 3.6 microM). In carrageenan induced rat paw edema, ML3000 and indomethacin completely blocked the formation of PGE2 in the inflamed tissue. The LTB4 production in the inflamed paw was reduced to basal levels by ML3000 (10 +/- 1.4 pg/paw saline control and 7.5 +/- 1.3-5.9 +/- 3.2 pg/paw ML3000), whereas LTB4 levels remained markedly elevated as compared to saline control by indomethacin (30.7 pg/paw). 5-LOX inhibition in the inflamed rat colon was investigated by measuring LTB4 synthesis. MK-886 and ML3000 at 10 mg/kg p.o. reduced LTB4 production to 29.8 +/- 4.9 and 30.1 +/- 2.8 pg/mg tissue as compared to control (54.2 +/- 7.4 mg/kg tissue). LTB4 levels in the rat stomach were comparable to control (2.5 +/- 0.4 pg/mg protein) after oral administration of ML3000 (10, 30, 100 mg/kg), whereas oral treatment with indomethacin (0.3, 1, 3 mg/kg) or diclofenac (1, 3 mg/kg) increased LTB4 up to 9.2 +/- 2.3 or 8.9 +/- 1.6 pg/mg protein. This effect was significant at 1 mg/kg diclofenac and 0.3 mg/kg indomethacin.. These results provide further evidence, that ML3000 inhibits 5-LOX as well as COX-1 and COX-2 in vitro and in animal experiments. The favourable gastrointestinal (GI) tolerability of the compound is believed to be linked to the mechanism of combined 5-LOX and COX-1/2 inhibition of ML3000.

Topics: Acetates; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colon; Cyclooxygenase Inhibitors; Edema; Gastric Mucosa; Humans; Leukotriene B4; Leukotriene C4; Lipoxygenase Inhibitors; Male; Pyrroles; Rats; Rats, Sprague-Dawley; Rats, Wistar; Stomach; Thromboxane B2

To assess anti-inflammatory effects of carprofen (CPF), CPF enantiomers, and N(G)-nitro-L-arginine methyl ester (LNAME) in sheep.. 8 sheep.. Sheep with SC tissue cages were used. After intracaveal injection of 1% carrageenan, sheep were given single doses of racemic (Rac; 50:50 mixture of S[+] and R[-] enantiomers)-CPF (4.0 mg/kg), R(-)CPF (2.0 mg/kg), S(+)CPF (2.0 mg/kg), LNAME (25 mg/kg), and placebo (PLB) IV in a crossover design.. Rac-CPF and S(+)CPF inhibited serum thromboxane2 (TXB2) and exudate prostaglandin (PG)E2 generation significantly for 32 hours. Maximal inhibitory effect for serum TXB2 was 79+/-3% for Rac-CPF and 68+/-6% for S(+)CPF. The Rac-CPF and S(+)CPF induced 50 to 98% reversible inhibitory effect for exudate PGE2 generation during a 4- to 32-hour period. The R(-)CPF and LNAME attenuated serum TXB2 generation significantly. The R(-)CPF did not affect exudate PGE2 production, whereas L-NAME potentiated exudate, PGE2 generation by 30% during 4 to 32 hours. The S(+)CPF and LNAME increased leukotriene B4 generation and WBC recruitment in exudate although significance was achieved only at a few time points. Increase in skin temperature over inflammatory cages was effectively inhibited by Rac-CPF and S(+)CPF but not by R(-)CPF CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen is a potent cyclooxygenase inhibitor in vivo in sheep, and its anti-inflammatory effects are attributable only to S(+)CPF in Rac-CPF. Nitric oxide may enhance eicosanoid production and accelerate the acute inflammatory process.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Carrageenan; Cross-Over Studies; Dinoprostone; Edema; Enzyme Inhibitors; Exudates and Transudates; Leukotriene B4; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Sheep; Stereoisomerism; Thromboxane B2

The mechanism of action of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)-phenyl]pyrazole), a novel and selective cyclooxygenase (COX)-2 inhibitor, in rat type II collagen-induced arthritis was investigated and compared with that of indomethacin. We tested the inhibitory effects of FR140423 on paw edema and the formation of arachidonic acid metabolites in inflamed paws immunized with type II collagen. Oral administration of FR 140423 showed a dose-dependent anti-inflammatory effect and was two-fold more potent than indomethacin. The increase of prostaglandin (PG) E2 and thromboxane (TX) B2 but not leukotriene B4 in inflamed paws was associated with the development of paw edema. FR140423 and indomethacin dose-dependently suppressed the levels of PGE2 and TXB2 in arthritic rat paws. Unlike indomethacin, FR140423 did not induce gastric lesions in arthritic rats. These results suggest that FR140423 shows a potent anti-inflammatory effect mediated by inhibition of prostanoids produced by COX-2 in inflamed tissues immunized with type II collagen, with a greatly improved safety profile compared to indomethacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arthritis; Collagen; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Edema; Female; Gastric Mucosa; Indomethacin; Isoenzymes; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Lew; Sulfoxides; Thromboxane B2

To investigate the effect of JTE-522, a selective cyclooxygenase (COX)-2 inhibitor, on prostaglandin (PG) production and COX expression in rats.. Male rats (4-8 weeks old) were used for in vivo experiments, while for in vitro assay, rat peritoneal macrophages were used.. JTE-522 (1-100 mg/kg) and indomethacin (0.03-10 mg/kg) were administered orally. JTE-522 and reference compounds (0.01-10 microM) were subjected to COX expression.. JTE-522 inhibited the development of carrageenin-induced paw edema and PGE2 production in inflammatory paws at a dose of 10 mg/kg. On the other hand, JTE-522 (1-100 mg/kg) did not affect A23187-stimulated thromboxane B2 release from whole blood or the PGE2 level in gastric mucosa. JTE-522 did not suppress lipopolysaccharide-induced COX-2 expression in peritoneal macrophages.. These results indicate that JTE-522 selectively inhibits PG production mediated by COX-2 in inflammatory tissues. JTE-522 may thus represent a novel type of anti-inflammatory drug without adverse effects on the gastro-intestinal tract.

Topics: Animals; Benzenesulfonates; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Edema; Foot; Gastric Mucosa; Inflammation; Isoenzymes; Macrophages, Peritoneal; Male; Oxazoles; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Sprague-Dawley; Thromboxane B2

A ditriazine derivative (4,10-dichloropyrido[5,6:4,5]thieno[3,2-d':3, 2-d]-1,2,3-ditriazine (DTD)) inhibited neutrophil functions, including degranulation, superoxide generation, and leukotriene B(4) production, without any effect on 5-lipoxygenase activity. This compound reduced nitric oxide (NO) and prostaglandin E(2) production in mouse peritoneal macrophages stimulated with lipopolysaccharide, whereas no influence on the activity of inducible NO synthase, cyclo-oxygenase-2 or cyclo-oxygenase-1 was observed. DTD significantly reduced mouse paw oedema induced by carrageenan and also markedly reduced NO and prostaglandin E(2) levels in exudates from 24-h zymosan-stimulated mouse air pouch. Western blot analysis showed that DTD reduced the expression of inducible NO synthase and cyclo-oxygenase-2. Our results indicate that DTD exerts anti-inflammatory effects related to the inhibition of neutrophil functions and of NO and prostaglandin E(2) production, which could be due to a decreased expression of inducible NO synthase and cyclo-oxygenase-2.

Topics: Animals; Anti-Inflammatory Agents; Blood Platelets; Carrageenan; Cell-Free System; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Edema; Female; Hindlimb; Humans; Inflammation; Isoenzymes; Leukocytes; Leukotriene B4; Luminescent Measurements; Macrophages, Peritoneal; Membrane Proteins; Mice; Microsomes; Neutrophil Activation; Neutrophils; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Pancreatic Elastase; Phospholipases A; Prostaglandin-Endoperoxide Synthases; Thromboxane B2; Triazines; Zymosan

The pathophysiologic sequence leading to respiratory failure after chest trauma can be an inevitable consequence of the primary injury or a secondary, mediator-driven inflammatory process. To distinguish between these alternatives, a simple cross-transfusion experiment was performed. A captive bolt gun injured the chest of anesthetized pigs that were mechanically ventilated with FiO2 = .21, .50, or .50 plus indomethacin (5 mg/kg intravenous; 15 min before injury). Tube thoracostomy immediately followed. After 30 min, blood from these injured donors was transfused into three matched groups of naive recipients (n = 8, 6, and 4, respectively) for a 33% exchange transfusion. Two control groups received blood from uninjured donors with tube thoracostomies only (FiO2 = .21, n = 7; FiO2 = .50, n = 10). Within 15-30 min after transfusion, in recipients from injured donors versus controls, lung compliance was decreased 20%, stroke volume and cardiac output were decreased 50%, and pulmonary vascular resistance was increased >300% (all p < .05). These changes recovered to baseline within 60-90 min. The stable metabolite of thromboxane A2, thromboxane B2, increased >500% in plasma within 15 min and remained elevated for >120 min. All responses were similar at 21 % or 50% O2, which suggests that hypoxia per se is not a cause of mediator production. All responses were eliminated by indomethacin. By 24 h, histologic changes included atelectasis in 3/3 recipients from injured donors versus 0/3 recipients from uninjured donors. We conclude that 1) blunt chest trauma releases blood borne mediators, including prostanoids; 2) these mediators can cause secondary cardiopulmonary changes in naive recipients similar to those produced by chest trauma; 3) the progression to trauma-induced respiratory failure is multifactorial; 4) early pharmacologic intervention, rather than supportive care alone, may benefit some victims of severe chest trauma.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Transfusion; Cerebrovascular Disorders; Contusions; Edema; Female; Hemodynamics; Indomethacin; Male; Oxygen Consumption; Pneumonia; Pulmonary Artery; Swine; Thoracic Injuries; Thromboxane B2; Vascular Resistance

The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.

Topics: Animals; Arthritis, Experimental; Blood Platelets; Carrageenan; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Edema; Hyperalgesia; Indomethacin; Inflammation; Isoenzymes; Male; Membrane Proteins; Models, Biological; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sulfonamides; Thromboxane B2

Several reports have shown peritumoral edema accompanying primary bone tumors demonstrated by magnetic resonance imaging (MRI). However, the mechanism of this inflammatory reaction is still unclear. The authors postulated that the reaction was caused by some chemical mediators including prostanoids, because several investigators have observed that some types of bone tumors synthesize prostanoids. Therefore, the authors compared MRI findings and tumor prostaglandin (PG) levels.. The subjects were 29 patients with primary bone tumor or tumor-like conditions: chondroblastoma (n = 5); chondrosarcoma, including rare variants (n = 8); giant cell tumor (n = 6); osteochondroma (n = 5); osteoblastoma (n = 2); Ewing's sarcoma (n = 2); and eosinophilic granuloma (n = 1). T1- and T2-weighted spin echo images were obtained in all but one patient before surgery. The tumor concentration of prostaglandin E2, 6-keto-PGF1 alpha, and thromboxane B2 were measured by radioimmunoassay.. MRI distinctly showed bone marrow edema in 9 and soft tissue edema in 12 of the 28 patients examined. These findings were significantly correlated with the PG levels. Moreover, the PG levels were correlated with the histologic classifications (P < 0.001). In particular, the chondroblastomas showed prominent concentrations of PGs compared with other cartilaginous tumors or giant cell tumors.. Although peritumoral edema accompanying benign and malignant bone tumors is not necessarily related to one single pathophysiologic mechanism, these results suggest that PG production was an important cause of the inflammatory reaction that was revealed by MRI. Recognition of this phenomenon is advantageous not only for strict diagnostic purposes but also for understanding the characteristic features of individual primary bone tumors.

Topics: 6-Ketoprostaglandin F1 alpha; Bone Neoplasms; Chondroblastoma; Dinoprostone; Edema; Eosinophilic Granuloma; Humans; Magnetic Resonance Imaging; Neoplasm Proteins; Osteoblastoma; Osteosarcoma; Thromboxane B2

1. DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furan one) was identified as a novel orally active and highly selective cyclo-oxygenase-2 (COX-2) inhibitor. 2. In CHO cells stably transfected with human COX isozymes, DFU inhibited the arachidonic acid-dependent production of prostaglandin E2 (PGE2) with at least a 1,000 fold selectivity for COX-2 (IC50 = 41 +/- 14 nM) over COX-1 (IC50 > 50 microM). Indomethacin was a potent inhibitor of both COX-1 (IC50 = 18 +/- 3 nM) and COX-2 (IC50 = 26 +/- 6 nM) under the same assay conditions. The large increase in selectivity of DFU over indomethacin was also observed in COX-1 mediated production of thromboxane B2 (TXB2) by Ca2+ ionophore-challenged human platelets (IC50 > 50 microM and 4.1 +/- 1.7 nM, respectively). 3. DFU caused a time-dependent inhibition of purified recombinant human COX-2 with a Ki, value of 140 +/- 68 microM for the initial reversible binding to enzyme and a kappa 2 value of 0.11 +/- 0.06 s-1 for the first order rate constant for formation of a tightly bound enzyme-inhibitor complex. Comparable values of 62 +/- 26 microM and 0.06 +/- 0.01 s-1, respectively, were obtained for indomethacin. The enzyme-inhibitor complex was found to have a 1:1 stoichiometry and to dissociate only very slowly (t1/2 = 1-3 h) with recovery of intact inhibitor and active enzyme. The time-dependent inhibition by DFU was decreased by co-incubation with arachidonic acid under non-turnover conditions, consistent with reversible competitive inhibition at the COX active site. 4. Inhibition of purified recombinant human COX-1 by DFU was very weak and observed only at low concentrations of substrate (IC50 = 63 +/- 5 microM at 0.1 microM arachidonic acid). In contrast to COX-2, inhibition was time-independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX-1. 5. DFU inhibited lipopolysaccharide (LPS)-induced PGE2 production (COX-2) in a human whole blood assay with a potency (IC50 = 0.28 +/- 0.04 microM) similar to indomethacin (IC50 = 0.68 +/- 0.17 microM). In contrast, DFU was at least 500 times less potent (IC50 > 97 microM) than indomethacin at inhibiting coagulation-induced TXB2 production (COX-1) (IC50 = 0.19 +/- 0.02 microM). 6. In a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 microM), DFU inhibited COX-1 with an IC50 value of 13 +/- 2 microM as compared to 20 +/- 1 nM for indomethacin. CGP 28238, etodo

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; CHO Cells; Cricetinae; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Digestive System; Dinoprostone; Dose-Response Relationship, Drug; Edema; Fever; Furans; Humans; Hyperalgesia; Indomethacin; Isoenzymes; Lipopolysaccharides; Male; Membrane Proteins; Peroxidases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Saimiri; Structure-Activity Relationship; Thromboxane B2; Transfection

The non-steroidal anti-inflammatory drug, carprofen, was administered intravenously as the racemate at a dose rate of 0.7 mg kg-1 to six Friesian bull calves aged 8-10 weeks. Anti-inflammatory properties were indicated by attenuation of temperature rise at sites of intradermal injection of the irritants, carrageenin and dextran, but responses were not statistically significant at most recording times. Carrageenin- and dextran-induced swelling were not significantly reduced by carprofen. Carprofen reduced ex vivo serum thromboxane B2 synthesis but this effect was also not significant at most sampling times. Enantioselective pharmacokinetics of carprofen was demonstrated, plasma concentrations of the R(-) enantiomer predominating at all sampling times. It is concluded that inhibition of cyclo-oxygenase is unlikely to be the sole mechanism of action of carprofen in calves.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Carrageenan; Cattle; Dextrans; Edema; Injections, Intradermal; Injections, Intravenous; Male; Skin Temperature; Thromboxane B2; Time Factors

The effects of bakuchiol, a meroterpenoid isolated from the leaves of Psoralea glandulosa L., on phospholipase A2 (PLA2) activity from different sources, human neutrophil responses, zymosan air pouch and topical inflammation in mice, were investigated. This natural product was a weak inhibitor of secretory and intracellular PLA2 but dose-dependently reduced the formation of LTB4 and TXB2 by human neutrophils and platelet microsomes, respectively. In addition, bakuchiol inhibited degranulation in human neutrophils, whereas superoxide generation was not affected. In mice, bakuchiol decreased cell migration, myeloperoxidase activity and eicosanoid levels in the air pouch inflammation induced by zymosan. After topical administration, this compound was effective as an inhibitor of oedema and myeloperoxidase activity in the 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear oedema and significantly reduced the PGE2 content and ear oedema in the arachidonic acid-induced response. Bakuchiol is a natural anti-inflammatory agent able to control leukocytic functions such as eicosanoid production, migration and degranulation in the inflammatory site.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Survival; Dinoprostone; Edema; Humans; In Vitro Techniques; Inflammation; Leukocyte Elastase; Leukocytes; Leukotriene B4; Male; Mice; Neutrophils; Peroxidase; Phenols; Phospholipases A; Phospholipases A2; Superoxides; Thromboxane B2; Zymosan

Ketoprofen creams were evaluated for the treatment of periodontal disease in a placebo-controlled, double-blind study in the rhesus monkeys, Macaca mulatta. Two formulations containing ketoprofen (1%), with or without vitamin E, were evaluated against appropriate controls (8 monkeys per group). Two weeks prior to treatment, the animals received prophylaxis on only the left side of the mouth (spontaneous model). Selected teeth on the right side of the mouth were ligated (ligature model). The creams were administered to the gingiva once daily at a standard dose of 1.8 ml per monkey for 6 months. Clinical assessments were made 2 wk before initiation, at baseline and 1, 2, 3 and 6 months post-treatment. The clinical parameters included plaque formation, gingival redness, edema, bleeding on probing and Ramfjord Attachment Level measurements (RAL). Radiographs were taken at 2 wk before initiation, baseline and at 3 and 6 months post-treatment. Digital, subtraction radiography was used to measure vertical linear bone loss along the interproximal root surfaces of the left and right mandibular first molars. Gingival crevicular fluid (GCF) was collected for biochemical assays on PGE2, TxB2, LTB4, IL-1 beta and TNF alpha. There were no significant differences among groups with respect to gingival indices. Radiographic data demonstrated significant positive effects on bone activity in both groups treated with ketoprofen formulations with improvement over time in the ligature model (0.01 < or = p < or = 0.04). The placebo group exhibited bone loss of 1.96 +/- 0.48 and 1.40 +/- 0.56 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream showed an apparent bone gain of 0.28 +/- 0.41 and 0.78 +/- 0.47 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream containing vitamin E showed a mean bone loss of 0.41-0.48 mm per site at 3 months with improvement to an apparent bone gain of 0.31 +/- 0.44 mm per site at 6 months. The biochemical data demonstrated early and significant suppression of GCF-LTB4 by both ketoprofen formulations at 1 month, which preceded the significant suppression of GCF-PGE2 at 2 and 3 months in the ligature model (p < 0.003) and at 2 to 6 months in the spontaneous model (p < 0.02). We conclude that ketoprofen at 1% level in suitable topical vehicles can effectively inhibit GCF-LTB4 and GCF-PGE2 and positively alter alveolar bone activity in the ligature-induced model of periodontitis in the m

Topics: Administration, Topical; Alveolar Bone Loss; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dental Plaque; Dinoprostone; Double-Blind Method; Edema; Emollients; Female; Follow-Up Studies; Gingival Crevicular Fluid; Gingival Hemorrhage; Gingivitis; Interleukin-1; Ketoprofen; Leukotriene B4; Macaca mulatta; Male; Molar; Periodontal Attachment Loss; Periodontitis; Placebos; Radiographic Image Enhancement; Random Allocation; Subtraction Technique; Thromboxane B2; Tumor Necrosis Factor-alpha; Vitamin E

Topics: Analysis of Variance; Animals; Antioxidants; Dogs; Edema; In Vitro Techniques; Ischemia; Muscle, Skeletal; Necrosis; Peroxidase; Pregnatrienes; Reperfusion; Reperfusion Injury; Steroids, Heterocyclic; Thromboxane B2; Time Factors

1. The effect of purified crotapotin, a non-toxic non-enzymatic chaperon protein normally complexed to a phospholipase A2 (PLA2) in South America rattlesnake venom, was studied in the acute inflammatory response induced by carrageenin (1 mg/paw), compound 48/80 (3 micrograms/paw) and 5-hydroxytryptamine (5-HT) (3 micrograms/paw) in the rat hind-paw. The effects of crotapotin on platelet aggregation, mast cell degranulation and eicosanoid release from guinea-pig isolated lung were also investigated. 2. Subplantar co-injection of crotapotin (1 and 10 micrograms/paw) with carrageenin or injection of crotapotin (10 micrograms/paw) into the contralateral paw significantly inhibited the carrageenin-induced oedema. This inhibition was also observed when crotapotin (10-30 micrograms/paw) was administered either intraperitoneally or orally. Subplantar injection of heated crotapotin (15 min at 60 degrees C) failed to inhibit carrageenin-induced oedema. Subplantar injection of crotapotin (10 micrograms/paw) also significantly inhibited the rat paw oedema induced by compound 48/80, but it did not affect 5-HT-induced oedema. 3. In adrenalectomized animals, subplantar injection of crotapotin markedly inhibited the oedema induced by carrageenin. The inhibitory effect of crotapotin was also observed in rats depleted of histamine and 5-HT stores. 4. Crotapotin (30 micrograms/paw) had no effect on either the histamine release induced by compound 48/80 in vitro or on the platelet aggregation induced by both arachidonic acid (1 nM) and platelet activating factor (1 microM) in human platelet-rich plasma. The platelet aggregation and thromboxane B2 (TXB2) release induced by thrombin (100 mu ml-1) in washed human platelets were also not affected by crotapotin. In addition, crotapotin (10 microg/paw) did not affect the release of 6-oxo-prostaglandin Fla, and TXB2 induced by ovalbumin in sensitized guinea-pig isolated lungs.5. Our results indicate that the anti-inflammatory activity of crotapotin is not due to endogenous corticosteroid release or inhibition of cyclo-oxygenase activity. It is possible that crotapotin may interact with extracellular PLA2 generated during the inflammatory process thereby reducing its hydrolytic activity.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Arachidonic Acid; Carrageenan; Cell Degranulation; Crotoxin; Disease Models, Animal; Edema; Guinea Pigs; Histamine Release; Humans; Injections, Intraperitoneal; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Phospholipases A; Phospholipases A2; Platelet Activating Factor; Platelet Aggregation; Rats; Rats, Wistar; Serotonin; Thromboxane B2

The marine metabolites pacifenol, stypotriol triacetate and epitaondiol were tested for their effects on a number of inflammatory responses. Epitaondiol exhibited a potent topical anti-inflammatory activity related to inhibition of leukocyte accumulation. The other compounds showed a lower potency, similar to that of indomethacin. None of the compounds affected superoxide generation by human neutrophils but pacifenol effectively inhibited the degranulation response. This compound and epitaondiol decreased the release of eicosanoids with a higher potency on the cyclo-oxygenase pathway. Only epitaondiol inhibited human recombinant synovial phospholipase A2 activity in a concentration-dependent manner.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Calcimycin; Cytochrome c Group; Ear, External; Edema; Humans; Inflammation; Leukotriene B4; Mice; Neutrophils; Oxidation-Reduction; Phospholipases A; Phospholipases A2; Sesquiterpenes; Steroids; Stimulation, Chemical; Superoxides; Terpenes; Tetradecanoylphorbol Acetate; Thromboxane B2

The role of eicosanoid metabolism and its relationship with nitric oxide production in the ischemia-reperfusion associated with pancreas transplantation in the rat is explored in this study. Twenty-six male Sprague-Dawley rats were randomized into 3 groups, as follows: group 1, control animals not surgically manipulated; group 2, pancreas transplantation, after 12 hr of organ preservation in University of Wisconsin solution; group 3, same as group 2 but with administration of NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) (10 mg/kg) before organ revascularization. The results show posttransplantation increases in edema and in 6-keto-prostaglandin F1 alpha (x1.9), thromboxane B2 (x4), and prostaglandin E2 (x5) levels in pancreatic tissue. Nitric oxide synthase inhibition reversed the increases in edema and eicosanoid production, which suggests that eicosanoid generation in the recipient rat would be mediated, in part, through a nitric oxide-dependent mechanism.

Topics: Adenosine; Allopurinol; Animals; Arginine; Dinoprostone; Edema; Glutathione; Insulin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Organ Preservation; Organ Preservation Solutions; Pancreas Transplantation; Prostaglandins F; Raffinose; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane B2

Three 2-polyprenyl-1,4-hydroquinone derivatives (2-heptaprenyl-1,4-hydroquinone: IS1, 2-octaprenyl-1,4-hydroquinone: IS2 and 2-[24-hydroxy]-octaprenyl-1,4-hydroquinone: IS3) isolated from the Mediterranean sponge Ircinia spinosula, were evaluated for effects on phospholipase A2 activity of different origin (Naja naja venom, human recombinant synovial fluid and bee venom), as well as on human neutrophil function and mouse ear oedema induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). IS1 interacted minimally with these responses. In contrast, IS2 and IS3 inhibited human recombinant synovial phospholipase A2 in a concentration-dependent manner, with minor effects on the rest of the enzymes. Both compounds slightly affected superoxide generation and degranulation in human neutrophils, whereas they decreased thromboxane B2 and leukotriene B4 synthesis and release in a mixed suspension of human platelets and neutrophils stimulated by ionophore A23187, with IC50 values in the microM range. IS3 was the most effective inhibitor of the synthesis of thromboxane B2 by human platelet microsomes and of leukotriene B4 by high speed supernatants from human neutrophils. IS2 and IS3 showed topical anti-inflammatory activity against the TPA-induced ear inflammation in mice, with similar effects on oedema and a higher inhibition of IS3 on leukocyte migration, estimated as myeloperoxidase activity in supernatants of ear homogenates. Some structure-activity relationships were established since differences in the prenylated chain attached to the hydroquinone moiety result in important modifications of these inflammatory responses.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Cell Survival; Edema; Humans; Hydroquinones; In Vitro Techniques; L-Lactate Dehydrogenase; Leukotriene B4; Mice; Microsomes; Neutrophils; Pancreatic Elastase; Phospholipases A; Phospholipases A2; Porifera; Superoxides; Tetradecanoylphorbol Acetate; Thromboxane B2

Leukotrienes have been implicated in the regulation of immune responses, including inflammation and immediate hypersensitivity reactions. Here, we describe the phenotypic analysis of leukotriene-deficient mice generated by inactivation of the 5-lipoxygenase (5LO) gene. These 5LO(-/-) mice were unable to synthesize detectable levels of leukotrienes and were more resistant to lethal anaphylaxis induced by platelet-activating factor. The intensity of an acute inflammatory response induced by arachidonic acid was similar in 5LO(-/-) mice and controls. However, the response in 5LO(-/-) mice, but not in controls, could be virtually eliminated by a cyclooxygenase inhibitor. These data suggest that inflammatory responses are modulated by arachidonic acid metabolites through a variety of interconnected mechanisms. This has important implications for understanding the early events of an inflammatory response and for designing drugs for use in therapeutic intervention.

Topics: Anaphylaxis; Animals; Arachidonate 5-Lipoxygenase; Chemotaxis, Leukocyte; Dinoprostone; Edema; Inflammation; Leukotriene C4; Leukotrienes; Macrophages; Mice; Mice, Knockout; Neutrophils; Platelet Activating Factor; Thromboxane B2

Some pharmacologic activities of a micronized flavonoid complex consisting of 90% diosmin + 10% hesperidin (Daflon 500 mg*) have been investigated by use of various experimental models: (1) interference with mechanisms of edema (synthesis of arachidonic acid derivatives, microvascular hyperpermeability induced by bradykinin, ischemia, or streptozotocin), (2) interference with lymphatic drainage (thoracic duct fistula in the dog).. Daflon 500 mg inhibited prostaglandin E2 (PGE2) and thromboxane A2 (TxA2) synthesis during a one-month oral daily treatment (100 mg.kg-1.day-1) in the rat, after induction of chronic inflammation by subcutaneous implantation of sponge fragments. Microvascular hyperpermeability induced by bradykinin or ischemia in the rat cremaster muscle was reduced after an oral treatment with Daflon 500 mg (100 mg.kg-1 twice daily). Microvascular hyperpermeability of the streptozotocin-induced diabetic rat was antagonized when Daflon 500 mg (300 mg.kg-1 once daily) was given orally as a preventive treatment. In the anesthetized dog, an increase in lymphatic flow, correlated with administered doses, was observed after IV injection of Daflon 500 mg. Lymphatic flow was maximal twenty minutes after injection of the drug (12.5 mg.kg-1) and was three times higher than the basal flow.. The protective effect of Daflon 500 mg against the formation of perivascular edema and its therapeutic value in the treatment of venous stasis could be explained by its inhibitory activity on the inflammatory process or ischemia-induced hyperpermeability and by its stimulatory effect on the pulsatile activity of lymphatic vessels.

Topics: Animals; Capillary Permeability; Diabetes Mellitus, Experimental; Dinoprostone; Diosmin; Dogs; Drug Combinations; Edema; Flavonoids; Hesperidin; Inflammation; Kidney Glomerulus; Lymph; Muscles; Rats; Thoracic Duct; Thromboxane B2

Like indomethacin, BW755C, diphenhydramine and methysergide, 2-phenyl-4-quinolone (YT-1) suppressed the polymyxin B-induced hind-paw edema. This inhibitory effect of YT-1 was also demonstrated in adrenalectomized mice. YT-1 inhibited the antidromic stimulation of saphenous nerve-induced plasma leakage in dorsal paw skin and reduced the volume of plasma exudation in PCA reaction. Bradykinin-, substance P- and compound 48/80-induced mouse ear edema was suppressed by YT-1 in a dose-dependent manner. In isolated rat peritoneal mast cells, YT-1 produced a dose-dependent inhibition of bradykinin-, substance P- and compound 48/80-induced histamine and beta-glucuronidase release. YT-1 also reduced the TXB2 formation from PMN leukocytes with IC50 2.0 +/- 0.5 microM, however with little effect on LTB4 formation. Histamine- and serotonin-induced plasma exudation in ear edema were reduced by YT-1. Moreover, the maximal response of ileum contraction caused by histamine and serotonin were also suppressed by YT-1 in a dose-dependent manner. In compound 48/80-pretreatment mice, YT-1 failed to suppress the bradykinin- and substance P-induced ear edema to a significantly greater extent than diphenhydramine combined with methysergide did. These results indicate that the inhibitory effect of YT-1 on local edema formation is not through the release of steroid hormones from adrenal gland, and is probably by suppressing the release of chemical mediators from mast cells, inhibition of prostaglandins formation, and noncompetitive but selective protection of the vasculature against the histamine- and serotonin-induced plasma extravasation.

Topics: Animals; Ear Diseases; Edema; Guinea Pigs; Hemorrhage; Hindlimb; Histamine; Ileum; In Vitro Techniques; Leukotriene B4; Mast Cells; Mice; Mice, Inbred ICR; Muscle Contraction; p-Methoxy-N-methylphenethylamine; Quinolones; Rats; Rats, Sprague-Dawley; Serotonin; Skin; Thromboxane B2

The anti-inflammatory effects of Ph CL28A, a potentiator of prostacyclin output and inhibitor of leukotriene (LT) synthesis, were assessed in two models of acute inflammation. In paw oedema induced by carrageenan in rats, Ph CL28A (10-100 mg/kg), given i.p. at the same time as the carrageenan, inhibited oedema for up to 4 h. When indomethacin or Ph CL28A was given locally into the paw with carrageenan, indomethacin inhibited oedema formation but Ph CL28A potentiated the oedema for up to 4 h. As Ph CL28A does not inhibit cyclo-oxygenase, its anti-inflammatory effects in this model may reflect its ability to increase prostacyclin output. In pleurisy induced by carrageenan in rats, there were increases in leukocytes, LTB4, thromboxane B2 (TxB2) and 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) in the pleural fluid over 3 h. In this model, Ph CL28A (30 mg/kg) given i.p. decreased leukocyte numbers and LTB4 but did not affect TxB2 or 6-oxo-PGF1 alpha. Indomethacin decreased both prostanoids but did not affect leukocyte accumulation. The beneficial effects of Ph CL28A in two different models of acute inflammation suggests that it may have potential as an anti-inflammatory agent.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Azo Compounds; Blood Pressure; Carrageenan; Edema; Epoprostenol; Hydroxyprostaglandin Dehydrogenases; Indomethacin; Leukotriene B4; Male; Pleurisy; Radioimmunoassay; Rats; Rats, Wistar; Thromboxane B2

Acid aspiration leads to lung injury characterized by polymorphonuclear neutrophil leukocytes (PMN) sequestration and edema. This study investigates whether localized acid aspiration leads to activation of circulating PMN and triggers both local and remote PMN sequestration and whether these cells are responsible for increase in pulmonary permeability and systemic organ edema.. Rats pretreated with intravenous saline solution or rendered neutropenic (nitrogen mustard or antineutrophil serum) underwent tracheostomy and insertion of a cannula into a lung segment. This was followed by instillation of either 0.1 N HCl or saline solution.. After 30 minutes leukopenia was noted (2650 white blood cells/mm3) in saline-treated, acid-lavaged rats, and circulating PMN produced H2O2 (20 femtomole dichlorofluorescein/PMN compared with 3 femtomole in control animals (both, p < 0.05). PMN were progressively sequestered in the nonaspirated lung, the heart, and kidney. Permeability and edema developed in the lungs and systemic organs. In neutropenic rats there was a reduction of aspiration-induced thromboxane B2 and leukotriene B4 synthesis (p < 0.05), decrease in lung wet to dry weight and protein level in bronchoalveolar lavage of the aspirated and nonaspirated lungs, and reduction in myeloperoxidase activity in the heart and kidney and in wet to dry weight of these organs (all, p < 0.05).. These data indicate that localized acid aspiration activates circulating neutrophils and promotes their sequestration in the lungs and systemic organs. These cells are largely responsible for the multisystem organ edema.

Topics: Animals; Edema; Hydrochloric Acid; Hydrogen Peroxide; Kidney; Leukopenia; Lung; Male; Mechlorethamine; Myocardium; Neutrophils; Peroxidase; Pneumonia, Aspiration; Rats; Rats, Sprague-Dawley; Thromboxane B2

A series of pyrazolo[1,5-a]pyrimidin-7-ones (1c-17c) were synthesized to evaluate in vivo and in vitro effects induced by structural modifications at the 2 position of 4,7-dihydro-4-ethyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-one (FPP028). This substance, which has been previously studied, is a weak inhibitor of prostaglandin biosynthesis and a nonacid analgesic and anti-inflammatory agent devoid of ulcerogenic properties. To gain more insight into the mechanism of action of this class of compounds, several in vivo tests were carried out, such as carrageenan-induced rat paw edema and pleurisy. In vitro tests include some studies of leukocyte functions, such as superoxide production and myeloperoxidase release. In vitro effects on arachidonic acid-, adenosine 5'-diphosphate-, and platelet-activating factor-induced platelet aggregation were also studied. Different anti-inflammatory activities were observed, depending on the nature of substituents at the 2 position; these differences are probably linked to the capacity of these compounds to inhibit leukotrienes and/or prostaglandin biosynthesis with different selectivity. 4,7-Dihydro-4-ethyl-2(2-thienyl)pyrazolo[1,5-a]pyrimidin-7-one (7c) proved to be the most interesting compound of the novel synthesized series, showing powerful pharmacological activity in vivo as well as in vitro, together with very weak acute toxicity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Chemotaxis, Leukocyte; Edema; Humans; In Vitro Techniques; Leukotriene B4; Neutrophils; Peroxidase; Platelet Aggregation Inhibitors; Pleurisy; Pyrazoles; Pyrimidines; Rats; Rats, Wistar; Superoxides; Thromboxane B2

The effectiveness of 5-lipoxygenase (LO) and dual LO/cyclooxygenase (CO) inhibitors when administered by the topical or oral routes was significantly decreased in corticosterone depleted (adrenalectomized, Adx) mice as compared to sham mice in the mouse arachidonic acid (AA) induced ear edema model. In contrast, rat carrageenan paw edema was inhibited similarly in sham and Adx animals by 5-LO and dual 5-LO/CO inhibitors. Supplementation of cortisol levels (100 micrograms/dl) in human whole blood for 2 hr increased the observed inhibition of LTB4 biosynthesis by A-64077, WY-50,295 tromethamine and naproxen while having no effect on thromboxane B2 (TXB2) biosynthesis. Thus, corticosteroids may have a permissive effect by modulating 5-LO inhibitor effects on mouse AA induced ear edema and human blood leukocytes.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Corticosterone; Cyclooxygenase Inhibitors; Edema; Eicosanoids; Humans; In Vitro Techniques; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Rats; Thromboxane B2

Interleukin-2 (IL-2), an agent known to activate neutrophils (PMN) with thromboxane (Tx)B2 release, produces pulmonary edema within 6 hours of intravenous infusion. This study tests the role of PMN in mediating the edema. Anesthetized rats received 10(6)U recombinant human IL-2 (n = 15) or vehicle (n = 14) as a constant intravenous infusion during a period of 1 hour. At this time there was leukopenia 3.63 +/- 0.43 (x10(3)/mm3) relative to vehicle-infused control rats 6.12 +/- 0.86 and a decline in PMN, 2.19 +/- 0.14 relative to control value of 3.33 +/- 0.05 (both p less than 0.05). After 6 hours edema, as measured by increase in the wet to dry weight (W/d) ratio, was present in the lungs (4.93 +/- 0.20 relative to control 4.06 +/- 0.10), heart (4.09 +/- 0.11 versus 3.76 +/- 0.08), liver (3.50 +/- 0.10 versus 3.18 +/- 0.10), and kidney (4.25 +/- 0.07 versus 4.00 +/- 0.07) (all p less than 0.05). There was increased lung permeability demonstrated by bronchoalveolar lavage fluid protein concentration of 1970 +/- 210 micrograms/mL relative to control 460 +/- 90 micrograms/mL (p less than 0.05). Interleukin-2 resulted in lung PMN sequestration of 53 +/- 7 PMN/10 high-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05) and increased plasma TxB2 levels to 1290 +/- 245 pg/mL relative to control 481 +/- 93 pg/mL (p less than 0.05). Pretreatment of other rats (n = 8) with selective anti-rat neutrophil antiserum 18 hours before the experiment led to a peripheral PMN count 10% of baseline and prevented edema in the lungs (W/d ratio 4.20 +/- 0.16) and heart (3.67 +/- 0.07) (both p less than 0.05) but not liver or kidney. Protein in lung lavage was reduced to 760 +/- 220 micrograms/mL (p less than 0.05). The protection afforded by leukopenia was associated with lack of PMN sequestration and prevention of the increase in plasma Tx levels (484 +/- 120 pg/mL, p less than 0.05). These data indicate that the rapid induction of lung and heart edema with a 1-hour infusion of IL-2 in the rat is mediated, in large part, by activated PMNs.

Topics: Animals; Bronchoalveolar Lavage Fluid; Bronchopulmonary Sequestration; Chemical and Drug Induced Liver Injury; Edema; Interleukin-2; Kidney Diseases; Leukocyte Count; Leukopenia; Liver Diseases; Male; Neutrophils; Platelet Count; Pulmonary Edema; Rats; Rats, Inbred Strains; Recombinant Proteins; Thromboxane B2

Interleukin 2 (IL-2) is a potent cytokine with diverse effects, including the ability to stimulate lymphocyte differentiation into cells capable of lysing tumor. Its therapeutic efficacy is limited because of side effects such as breakdown of the microvascular barrier and edema. Control of the microvascular barrier is in part regulated by endothelial cell cytoskeletal contractile proteins. This study tests whether the cyclopeptides that maintain actin filament organization and distribution and reduce macromolecular flux across the endothelial cell junction in vitro would similarly maintain barrier tightness and prevent early edema produced by IL-2 in vivo. Anesthetized rats were treated at 30-min periods with intravenous saline (0.5 ml, n = 41), phalloidin (20 micrograms in 0.5 ml, n = 21), or antamanide, (20 micrograms in 0.5 ml, n = 21), starting 30 min before the 1-h infusion of 10(6) U of recombinant human IL-2 or saline. Six hours after the start of IL-2, there was edema in the saline/IL-2 group, as measured by increased wet-to-dry ratios (W/D) in the lungs, heart, and kidney. With saline/IL-2, bronchoalveolar lavage (BAL) fluid contained an elevated protein concentration and higher plasma thromboxane levels compared with controls. The number of neutrophils sequestered in the lungs was more than twice that of saline controls. Phalloidin significantly attenuated edema in lung and reduced BAL protein leak. Antamanide treatment was as effective in limiting lung and heart edema, but, in contrast to phalloidin, antamanide prevented kidney edema and did not lead to an alteration in the liver W/D. Antamanide also prevented BAL fluid protein leak.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Capillary Permeability; Chemical and Drug Induced Liver Injury; Edema; Edema, Cardiac; Interleukin-2; Kidney Diseases; Liver Diseases; Male; Peptides, Cyclic; Phalloidine; Pulmonary Edema; Rats; Rats, Inbred Strains; Thromboxane B2

Interleukin-2 (IL-2) produces toxicity characterized by generalized edema within 24 hours. This study tests whether the rate of IL-2 administration modulates the onset of edema and examines thromboxane (Tx) and neutrophils as possible mediators of this event. Recombinant human IL-2, 10(5) U (n = 7), 10(6) U (n = 9), or vehicle (n = 8) were given to anesthetized rats intravenously during a period of 1 hour. At 6 hours edema, as measured by increase in wet to dry weight (w/d) ratio, was present in the heart, liver, and kidney, with 10(5) U IL-2 and in the lung, heart, liver and kidney, with 10(6) U IL-2, relative to values with vehicle-infused controls (all p less than 0.05). With a 1-hour infusion of 10(6) U IL-2, there was an increase in plasma thromboxane (Tx)B2 level to 1290 +/- 245 pg/mL, higher than 481 +/- 93 pg/mL in control rats (p less than 0.05); lung polymorphonuclear leukocyte (PMN) sequestration of 53 +/- 7 PMN/10 higher-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05); and increased bronchoalveolar lavage (BAL) fluid protein concentration of 1970 +/- 210 micrograms/mL relative to 460 micrograms/mL in controls (p less than 0.05). When 10(6) U IL-2 was given as a 1-minute intravenous bolus (n = 9), edema was not demonstrated, plasma TxB2 levels were similar to controls, there was no leukosequestration, and BAL protein levels were normal. These data indicate that a constant infusion but not the rapid bolus administration of IL-2 produces in rats multiple-system organ edema, increased plasma TxB2, sequestration of PMNs, and microvascular permeability. These findings may explain the early toxicity seen in patients given high-dose IL-2 in cancer treatment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchoalveolar Lavage Fluid; Edema; Heart Diseases; Infusions, Intravenous; Injections, Intravenous; Interleukin-2; Kidney Diseases; Liver Diseases; Male; Neutrophils; Pulmonary Edema; Rats; Rats, Inbred Strains; Recombinant Proteins; Thromboxane A2; Thromboxane B2

Topics: Animals; Cerebrovascular Disorders; Disease Models, Animal; Edema; Ischemia; Male; Motor Activity; Prostaglandins; Rabbits; Reperfusion; Spinal Cord; Thromboxane B2

Edema formation and prostanoid production (prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were studied in a model of neoplastic epidural cord compression (NSCC) in rats harboring a thoracolumbar tumor. Tumor-free and tumor-bearing animals were randomized for three treatments at 12-hour intervals with saline, dexamethasone (10 mg/kg i.p.), or indomethacin (10 mg/kg i.p.). Increase in water content was observed only in the compressed lumbar cord segments of paralyzed rats; the cervical and thoracic segments did not differ from controls. The rate of release of prostaglandins was evenly distributed along the spinal segments in tumor-free rats. In tumor-bearing rats, a consistent significant increase in PGE2 production was found in the compressed lumbar segment in the presence of neurological dysfunction: early (limp tail), P less than 0.05; paraplegia, P less than 0.001. A significantly elevated PGE2 synthesis preceded the increase in water content by 2 to 3 days. A 2-fold increase in TXB2 was detected in only one of three experiments, and synthesis of 6-keto-PGF1 alpha was elevated to 4 times the normal value (P less than 0.005) in two of three experiments. Dexamethasone failed to inhibit prostaglandin synthesis in the spinal cord of normal controls or paralyzed rats, whereas in nonneural tissues (liver, uterus) it reduced synthesis of the three metabolites by at least 50%, thus demonstrating a differential effect on central nervous system (CNS) vs. non-CNS tissues. Dexamethasone also failed to reduce the increased water content of the compressed segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Water; Dexamethasone; Dinoprostone; Edema; Indomethacin; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred F344; Spinal Cord; Spinal Cord Compression; Spinal Cord Neoplasms; Thromboxane B2

Injection of brewer's yeast into the rat paw results in edema and a subsequent hyperalgesia. The edema was accompanied by an increase in 5-lipoxygenase products, and the hyperalgesia coincided with the formation of both cyclooxygenase and 5-lipoxygenase products. When administered perorally, indomethacin inhibited cyclooxygenase product formation, phenidone inhibited 5-lipoxygenase product formation, and 3-amino-1-(m-[trifluoromethyl]-phenyl)-2-pyrazoline (BW 755C) inhibited formation of products of both pathways. These compounds were also effective analgesic agents. The correlation of these effects with the suppression of hyperalgesia suggests the participation of products from both cyclooxygenase and 5-lipoxygenase pathways in the mediation of hyperalgesia.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Arachidonate 5-Lipoxygenase; Dinoprostone; Edema; Eicosanoic Acids; Hyperalgesia; Hyperesthesia; Mycoses; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Pyrazoles; Rats; Saccharomyces cerevisiae; Thromboxane B2

Eicosanoids are known mediators of inflammation, vascular permeability, and are involved in microcirculatory blood flow regulation. To study their potential involvement in the pathophysiology of CNS trauma we used a rabbit spinal cord trauma model. Rabbits were subjected to lumbar spinal cord trauma produced by a modification of the Allen weight-drop method. TXB2, 6-keto-PGF1 alpha, PGE2, and 5-hydroxyeicosatetraenoic acid (5-HETE) release from spinal cord slices incubated ex vivo were measured by radioimmunoassay at 5, 30 min, 24 hrs, and 2 wks after trauma. Five and 30 min after trauma the TXB2/6-keto-PGF1 alpha ratio was elevated and the release of 5-HETE at 5 min after trauma increased in the injured spinal cord whereas release of 6-keto-PGF1 alpha and PGE2 remained at base-line levels. In the thoracic spinal cord, TXB2 and 6-keto-PGF1 alpha release were increased at 30 min after trauma. Release of 5-HETE from the injured spinal cord was also elevated 24 hrs after trauma. Two wks after trauma, TXB2 and 6-keto-PGF1 alpha release were also elevated in the injured spinal cord. Measurements of tissue water content by microgravimetry indicated progressive edema in the injury site while histopathological evaluation indicated progressive damage and tissue destruction. The results of this study suggest that eicosanoids may be involved in the pathophysiology of spinal cord trauma through two potential mechanisms: 1) site specific increase in the TXB2/6-keto-PGF1 alpha ratio immediately following trauma which is due primarily to an increase in TXA2 synthesis; 2) the increase synthesis of 5-HETE which signals the activation of the 5-lipoxygenase pathway of arachidonate metabolism and production of mediators that are involved in inflammatory mechanisms and may affect local blood flow regulation and blood-spinal cord barrier integrity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Culture Techniques; Dinoprostone; Edema; Hydroxyeicosatetraenoic Acids; Male; Prostaglandins E; Rabbits; Spinal Cord; Spinal Cord Injuries; Thromboxane B2

We determined the effect of topically applied ibuprofen on formation of second-degree burn edema and prostanoid production, a possible causative factor. Six adult sheep were given second-degree burns on both flanks with water at 80 degrees C while they were under general anesthesia. Lymph (QL), draining the flank areas, was used to monitor edema formation and prostanoid production. A 5% ibuprofen cream was applied at 2 and 5 hours after the burn and full-thickness biopsy specimens of burned hide were obtained at 8 hours for determination of water content. The QL increased sixfold in nontreated and 2.5 times in treated burn tissue. The lymph/plasma (L/P) protein ratio increased from 0.4 to 0.58 in both sides. Lymph TxB2 was increased from baseline of 200 pg/ml to 500 +/- 100 and 310 +/- 90 pg/ml in untreated and treated sides, respectively. Lymph 6-keto-PGF1 alpha increased from a baseline of 50 +/- 10 to 150 +/- 40 and 90 +/- 80 pg/ml in untreated and treated sides. The difference between PG content of lymph in treated and untreated sides was significant. Plasma prostanoids, except for a transient early rise, remained at preburn baseline. Lymph ibuprofen content on the treated side rose to 1.9 +/- 0.8 mcg/ml with no detectable plasma level. Water content of hide increased from a control value of 74 +/- 2% to 84 +/- 2% in untreated burn, while the value in the treated side was 76 +/- 4%, a significant difference between the two sides. We conclude that topically applied ibuprofen decreases both local edema and prostanoid production in burn tissue without altering systemic production.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Topical; Animals; Burns; Edema; Ibuprofen; Lymph; Prostaglandin Antagonists; Prostaglandins; Sheep; Thromboxane B2

An increased accumulation of tissue thromboxane A2 occurred shortly after spinal cord injury. Prostacyclin formation was not affected. The magnitude of the increase in thromboxane and the extent of post-traumatic vascular damage as determined by extravasation of 125I-labeled human serum albumin were both dependent on the degree of injury. These findings raise the possibility that activation of arachidonic acid metabolism with a preponderance in thromboxane formation may contribute to microvascular injury in experimental spinal cord contusion.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Vessels; Edema; Epoprostenol; Rats; Rats, Inbred Strains; Spinal Cord; Spinal Cord Injuries; Thromboxane A2; Thromboxane B2

Acid aspiration leads to an inflammatory response characterized by the activation and pulmonary entrapment of platelets and while blood cells (WBCs. We speculate that thromboxane (Tx) produced by these activated cells alters lung permeability and diminishes cardiac performance. The lungs of dogs were aspirated with 0.1N HCl (3 ml/Kg). Within 30 minutes in six untreated controls, cardiac index (CI) decreased from 121 to 104 ml/min . kg (P less than ).05), mean arterial pressure decreased from 142 to 120 mm Hg (P less than 0.05), Pao2 decreased from 91 to 73 mm Hg (P less than 0.05), and TxB2 levels increased from 70 to 130 pg/ml (P less than 0.05). Pulmonary WBC sequestration occurred after 2 hours, while at 21/2 hours edema fluid was noted in the endotracheal tube. Six dogs were treated with infusion of the imidazole derivative ketoconazole 1 hour after aspiration (2.5 mg/kg bolus followed by 10 mg/kg . hr for 2 hours). After 30 to 60 minutes of treatment, CI rose from 106 to 143 ml/min . kg (P less than 0.05), TxB2 decreased from 130 to 70 pg/ml (P less than 0.05). At 21/2 hours, plasma from treated animals used to incubate a papillary muscle led to developed tension 8% higher than that in controls (P less than 0.05). Sequestration of WBC was not observed. After 4 hours, 24 ml endotracheal edema fluid was collected in contrast to 127 ml in controls (P less than 0.05). A hamster cheek pouch used for bioassay of microvascular permeability yielded 78 leakage sites/cm2 with control edema fluid and 26/cm2 with fluid from treated animals (P less than 0.05). The importance of WBC Tx synthesis in the induction of permeability was tested by stimulation of isolated WBCs with ionophore in the presence or absence of ketoconazole (0.4 Microgram/ml). Ketoconazole reduced the number of leakage sites in the hamster cheek pouch from 196/cm2 noted in controls to 28/cm2 (P less than 0.05). These data support our hypothesis that Tx directly or indirectly lead to cardiac depression and WBC-mediated permeability.

Topics: Animals; Capillary Permeability; Cardiac Output; Cardiovascular System; Cricetinae; Dogs; Edema; Hemodynamics; Hydrochloric Acid; Imidazoles; Inhalation; Ketoconazole; Leukocytes; Lung; Papillary Muscles; Piperazines; Respiration; Thromboxane B2; Thromboxanes; Time Factors

Systemic treatment of rats with captopril (50 mg/kg body wt per os), a specific competitive inhibitor of angiotensin l-converting enzyme, significantly inhibits vascular permeability changes induced by the intradermal injection of the vasoactive mediators histamine, bradykinin, serotonin, and compound 48/80. This effect of captopril is both dose- and time-dependent with approximately 60% inhibition of edema formation observed 7 h after captopril treatment (100 mg/kg body wt per os). The inhibitory effect of captopril on edema formation is temporally unrelated to the inhibition of serum angiotensin l-converting enzyme activity or serum prostaglandin E2 levels and is not inhibited by systemic treatment of rats with indomethacin. The data suggest that captopril may have potent antiinflammatory activity through as yet undefined mechanisms.

Topics: Animals; Bradykinin; Capillary Permeability; Captopril; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Edema; Male; Peptidyl-Dipeptidase A; Proline; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Skin; Thromboxane B2

To examine the possibility that prostaglandin metabolism is pathophysiologically important in Raynaud's phenomenon, peripheral venous 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TXB2) concentrations were measured in 45 patients with severe Raynaud's phenomenon. Patients with Raynaud's phenomenon had a significantly higher plasma concentration of 6-keto PGF1 alpha compared to controls (p less than .001), although their plasma TXB2 concentration was not statistically different from control patients. Subgroup analysis revealed that only patients with progressive systemic sclerosis (PSS) had an elevated plasma 6-keto PGF1 alpha concentration. To gauge the functional significance of the 6-keto PGF1 alpha elevations, seven patients with Raynaud's phenomenon were chronically administered indomethacin (50 mg P.O. b.i.d.); six of the seven patients noted no improvement in their Raynaud's phenomenon. Three of the patients developed pedal edema shortly after starting indomethacin. This study suggests that the increased plasma 6-keto PGF1 alpha concentration in Raynaud's phenomenon may be due to a compensatory release of prostacyclin and that the pathophysiologic defect does not involve the thromboxane mechanism.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Edema; Female; Humans; Indomethacin; Male; Middle Aged; Raynaud Disease; Thromboxane B2