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Effect of ibuprofen and dexamethasone on Kupffer cell complement receptor function after endotoxemia and the phagocytosis of erythrocytes.

Commins LM, Loegering DJ, Minnear FL.

Department of Physiology, Albany Medical College, New York 12208.

Depression of Kupffer cell complement receptor (CR) function is associated with several states of depressed host defense. This study was carried out to determine if ibuprofen and dexamethasone, which decrease the mortality rate following endotoxemia, could prevent the depression of CR function caused by endotoxemia and the phagocytosis of antibody-coated erythrocytes (EIgG). The depression of CR function caused by endotoxin was completely prevented by the administration of ibuprofen or dexamethasone. Thus, the ability of these drugs to prevent the depression of macrophage function may contribute to their salutory effects during endotoxin shock. In contrast to the effect with endotoxemia, the depression of CR function caused by the phagocytosis of EIgG was not modified by pretreatment with ibuprofen or dexamethasone. Additional studies demonstrated that the depression of CR function caused by EIgG was probably not due to EIgG in the blood or bound to Kupffer cells, interfering with the receptor probe for access to the CR. This study has shown that ibuprofen and dexamethasone can prevent the depression of CR function caused by endotoxin but not the depression caused by the phagocytosis of EIgG. These results suggest that different mechanisms mediate the depression of CR function caused by endotoxin and the phagocytosis of EIgG.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2495867&dopt=Abstract ibuprofen Motrin



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[Aortic expression of monocyte chemotactic protein-1 (MCP-1) gene in rabbits with experimental atherosclerosis]

[Article in Polish]

Sekalska B.

Z Samodzielnej Pracowni Patobiochemii i Biologii Molekularnej Katedry Biochemii Klinicznej i Diagnostyki Laboratoryjnej Pomorskiej Akademii Medycznej w Szczecinie, al. Powstancow Wlkp. 72, 70-111 Szczecin.

The theory of Ross describes atherosclerosis as a process induced by inflammatory reactions involving cytokines, cell adhesion molecules, and chemokines. The latter have been identified as the principal mediator of cell recruitment into the vascular wall when accumulating monocytes become a source of foam cells. The most potent monocyte attractant among known chemokines is the monocyte chemotactic protein-1 (MCP-1). This protein is synthesized in vivo by cells of the vascular wall and its expression is largely controlled by NF-kB nuclear transcription factor. The importance of inflammation for the induction and progression of atherosclerosis suggests that anti-inflammatory drugs could be a useful modality in this condition. The present work was undertaken to: 1) adapt the RT-PCR technique to measurements of MCP-1 gene expression in rabbit aorta, 2) assess MCP-1 gene expression in rabbit aorta during atherosclerosis induced with a cholesterol-rich diet, 3) evaluate the effect of ibuprofen on MCP-1 gene expression in rabbit aorta during atherosclerosis induced with a cholesterol-rich diet. The study was done in 72 rabbits assigned to eight even groups on the basis of body weight and starting cholesterol and triglyceride concentrations in serum. All rabbits were fed a standard chow. In some groups, the diet was supplemented with cholesterol and/or ibuprofen. Two months later rabbits in four groups, i.e. control (K2), control with ibuprofen (IK2), cholesterol-rich (M2) and cholesterol-rich with ibuprofen (IM2) were weighed and blood was sampled for measurements of cholesterol and triglyceride concentrations in serum. The liver, heart, kidneys and adrenals were collected at autopsy and weighed. Additionally, a fragment of the ascending aorta was obtained for RT-PCR. The extent of atherosclerosis in aorta was determined using planimetry. Another month later this procedure was repeated for the remaining groups K3, IK3, M3 and IM3. RT-PCR was applied to measure MCP-1 gene expression in relation to constitutive expression of the GAPDH gene. Significantly lower expression was found in rabbits given ibuprofen (groups IK2, IK3, IM3) as compared with groups K2, K3 and M2 (Tab. 1, Fig. 1). Significantly higher concentrations of cholesterol and triglycerides, as well as liver and adrenal mass indices were revealed in rabbits fed a cholesterol-rich diet with or without ibuprofen, in comparison to groups K2, K3, IK2 and IK3. No atherosclerotic lesions were disclosed in control groups. Atheromatous lesions were demonstrated in rabbits fed a cholesterol-rich diet with or without ibuprofen, occupying more than 60% of the intimal surface. The following conclusions were made: 1) RT-PCR corrected for contamination of RNA samples with genomic DNA is a reliable technique for studying MCP-1 gene expression in rabbit aorta, 2) Three months of cholesterol-rich diet is without effect on MCP-1 gene expression in rabbit aorta, 3) Ibuprofen suppresses MCP-1 gene expression in the aorta without affecting the progression of atherosclerosis induced with the cholesterol-rich diet.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15552841&dopt=Abstract ibuprofen Motrin



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[Concentrations of ibuprofen and the protein and pH value of synovial fluid and plasma following oral administration of ibuprofen in patients with arthritis]

[Article in German]

Rau R, Berner G, Wagener HH, Vogtle-Junkert U.

Evangelisches Fachkrankenhaus, St. Augustin/Bonn.

Concentrations of Ibuprofen and Protein Concentration and pH-Value in Synovial Fluid and Plasma Following Oral Administration of Ibuprofen in Patients Suffering from Arthritis. In 16 patients suffering from arthritis of the knee the concentration of ibuprofen in the synovial fluid was examined in correlation with the synovial fluid volume, cell count, pH value and protein concentration. The mean ibuprofen concentration in plasma 4 h after oral administration of 400 mg ibuprofen amounted to 15.45 micrograms/ml, the concentration in the synovial fluid was 9.4 micrograms/ml. Due to the inflammatory nature of the effusions the protein concentration in the synovial fluid was evidently increased to an average of 4.46 g/dl and thus was about 65% of the mean plasma protein concentration of 6.88 g/dl. The ibuprofen in the synovial fluid showed a correlation to the protein concentration. On the other hand, there were no significant differences between the pH value in the plasma and in the synovial fluid. There was no tendency to an acid pH. Furthermore, there was no correlation between ibuprofen concentration and cell count. The tests showed that the "accumulation" of the nonsteroidal antiinflammatory drug in the synovial fluid is positively correlated with the high protein concentration but not with the pH value.

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Clindamycin and ibuprofen effects on chlamydial salpingitis in mice.

Blanco JD, Patterson RM, Ramzy I, Turner T.

Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, Lubbock 79430.

To evaluate the effects of clindamycin and ibuprofen on a model of upper genital tract chlamydial infection in mice, 64 Swiss Webster white mice were inoculated in the left ovarian bursa with a mouse pneumonitis strain of Chlamydia trachomatis. Chlamydia-inoculated mice received clindamycin, ibuprofen, clindamycin and ibuprofen, or no treatment. Mice were killed at intervals, and their genital tracts were examined grossly and microscopically for evidence of infection and cultured for Chlamydia. Sixty-seven per cent of inoculated, untreated mice manifested gross evidence of inflammation compared with 22.4% of mice in any treatment group (P less than .025). C. trachomatis was isolated in 10.2% of mice treated with any drug regimen, whereas 46.7% of untreated mice were culture-positive (P less than .025). In this model, therapy with clindamycin, ibuprofen, or both drugs in combination decreased gross and histologic evidence of inflammation as well as the rate of recovery of C. trachomatis from the genital tract.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2595517&dopt=Abstract ibuprofen Motrin



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Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs--1. In vitro studies of ibuprofen and flurbiprofen.

Knihinicki RD, Williams KM, Day RO.

Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Darlinghurst, N.S.W., Australia.

The mechanism of inversion of the enantiomers of 2-arylpropionic acids was investigated in vitro using tissue homogenates. Crude rat liver homogenate was shown to mediate the inversion of R to S-ibuprofen, but not inversion of the S to the R-enantiomer. Inversion required CoA and ATP as cofactors. In contrast, R-ibuprofen was not inverted by homogenates of kidney or small intestine and there was no inversion of the enantiomers of flurbiprofen by any of these tissue homogenates. Long-chain acyl-CoA synthetase was partially purified from rat liver microsomes and bound to Matrex Gel Red A. R-Ibuprofen was shown to be a substrate for this enzyme while S-ibuprofen and R and S-flurbiprofen were not substrates. These data are consistent with the hypothesis that the stereospecificity of inversion is controlled by the acyl-CoA synthetase. R-Ibuprofen-CoA did not racemize in either buffer solution (pH 7.4) or human plasma consistent with the hypothesis that racemization of the CoA thioesters is mediated enzymatically.

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[Pharmacological study of kako-bushi-matsu: analgesic action and acute toxicity]

[Article in Japanese]

Murayama M, Namiki Y.

Research Section, Sanwa Shoyaku Co., Ltd., Utsunomiya, Japan.

The analgesic effect and the acute toxicity of a medical drug "kako-bushi-matsu" (S-01), which was produced through several processing of raw aconite roots, were examined in comparison with those of ibuprofen, indomethacin and aspirin. S-01 (p.o.) inhibited the acetic acid- and phenylquinone-induced writhing dose-dependently. From the ED50 values, indomethacin showed more potent inhibitory action on the phenylquinone-induced writhing than on the acetic acid-induced writhing. Ibuprofen and aspirin showed the same tendency as indomethacin. The potency of the writhing inhibition by S-01 was almost to the same degree in both writhing methods. In the tail pressure method, S-01 raised the pain threshold ratio to almost the same degree as ibuprofen did. In Randall-Selitto's method, the analgesic effect of S-01 on inflamed foot was less than that of ibuprofen. In the normal foot, S-01 raised the pain threshold ratio dose-dependently, but ibuprofen did not influence the pain threshold ratio. On adjuvant-induced arthritic pain, S-01 and ibuprofen had an analgesic action, and this action of S-01 was less than that of ibuprofen. The oral LD50 value of S-01 was more than 10,000 mg/kg in mice and rats of both sexes. The above evidence indicates that S-01 has analgesic action and suggests that the mode of the analgesic action of S-01 may differ from those of ibuprofen, indomethacin and aspirin, which inhibit prostaglandin biosynthesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2613110&dopt=Abstract ibuprofen Motrin



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Optimization of the in vitro glucuronidation of ibuprofen using factorial design.

Niemeijer NR, de Boer JH, Gerding TK, de Zeeuw RA.

Department of Analytical Chemistry and Toxicology, University of Groningen, The Netherlands.

Ibuprofen was chosen as a test compound to perform a multivariate design in order to determine the highest yield of the in vitro glucuronidation reaction in relation to the concentration of reacting and activating substances. Preliminary studies with a univariate design indicated that the concentration of Mg2+ had no significant effect on the glucuronidation and that Triton X-100 could be omitted as it appeared to inhibit the glucuronidation. In a 3(3) factorial design the influence of concentrations of ibuprofen, UDP glucuronic acid and enzyme, respectively, on the yield of ibuprofen glucuronide was established. It was concluded that the highest amount of ibuprofen glucuronide formed (within the limits of this design) was achieved with an ibuprofen concentration of 486 microM, a UDP-glucuronic acid concentration of 3 mM and an enzyme concentration of 3.57 mg/ml. Using this methodology it is possible to optimize the glucuronidation yield in a more rational way, which can be useful in the upscaling of enzymatic reactions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2616256&dopt=Abstract ibuprofen Motrin



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Effect of ibuprofen on the pulmonary and systemic response to repeated doses of endotoxin.

Demling RH, LaLonde C, Goad ME.

Longwood Area Trauma Center, Harvard Medical School, Boston, MA 02115.

We infused 10 doses of Escherichia coli endotoxin, 1 microgram/kg, during a 5-day period, into eight unanesthetized sheep with lung and systemic lymph fistulas. The animals were then monitored for an additional 5 days. We noted an attenuation of the lung microvascular permeability changes with the later endotoxin doses. However, a 50% increase in cardiac index and oxygen consumption and a leukocytosis were seen beginning with the ninth endotoxin injection; these persisted throughout the 15-day postendotoxin period, as did an increase in pulmonary artery pressure. The hyperdynamic state was present when plasma prostanoids were only modestly increased, and there was no evidence of increased lung or systemic vascular permeability. Postmortem lung findings, 5 days after endotoxin administration, showed a marked interstitial inflammatory response, with infiltration of macrophages, neutrophils, and some lymphocytes and an increase in interstitial fibrous tissue. Six sheep were then given ibuprofen, 12.5 mg/kg, intravenously before the ninth and tenth doses and on the subsequent day. Ibuprofen significantly attenuated the hyperdynamic state and the pulmonary hypertension. In addition, the lung inflammation and fibrous tissue deposition was markedly attenuated. We conclude that a systemic hyperdynamic state develops that corresponds in time with lung inflammation but not with increased permeability. The lung and systemic changes may be blocked by ibuprofen. The ibuprofen effect may be due to a response other than prostanoid production.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2646746&dopt=Abstract ibuprofen Motrin