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Ibuprofen: effect on inducible nitric oxide synthase.

Stratman NC, Carter DB, Sethy VH.

CNS Diseases Research, Pharmacia and Upjohn Inc., Kalamazoo, MI 49001, USA.

Treatment with ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDS) has been reported to decrease the incidence as well as slow down the progression of Alzheimer's disease. Understanding the mechanism of this therapeutic effect would provide a target for development of drugs which may be devoid of side effects observed with NSAIDs. In addition to inhibiting cyclooxygenase (COX), the NSAIDs have recently been shown to decrease inducible nitric oxide synthase (iNOS) activity. Ibuprofen and other NSAIDs had no direct effect on catalytic activity of iNOS, but decreased levels of iNOS mRNA. The mechanism of action of ibuprofen on reduction of iNOS activity has been further investigated in the present study using rat primary cerebellar glial cell cultures. In addition, the effect of ibuprofen on COX mRNA expression and prostaglandin formation was also studied. Glial cells treated with E. coli lipopolysaccharide (LPS) and interferony (INFgamma) for 16 h expressed iNOS and COX. Ibuprofen did not directly inhibit iNOS activity. However, when ibuprofen was incubated at the same time with LPS and INFgamma for 16 h, enzyme activity was reduced, with an IC50 of 0.76 mM. Ibuprofen concentration-dependently decreased iNOS mRNA levels, with an IC50 > 2 mM. Thus, there was no correlation between decrease in iNOS activity and reduction in iNOS mRNA levels. Ibuprofen decreased iNOS protein levels, as determined by Western blot, with an IC50 of 0.89 mM. The data suggest that the reduction in iNOS activity by ibuprofen is due to inhibition of post-transcriptional processing of this enzyme. Ibuprofen had no effect on constitutive COX (COX-1) or inducible COX (COX-2) mRNA expression. However, ibuprofen inhibited PGE2 formation with an IC50 of 0.86 mM. The anti-inflammatory actions of ibuprofen have been related to inhibition of COX and, subsequently, reducing prostaglandin formation. Since the potency of ibuprofen for inhibition of PGE2 formation and reduction in iNOS activity are similar, it is suggested that, at therapeutically effective doses, a decrease in iNOS activity may also occur in vivo. Therefore, reduction in iNOS protein levels in the brain may have a role in preserving the integrity of neurons in individuals susceptible to Alzheimer's disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9406924&dopt=Abstract ibuprofen Motrin



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Effects of acetyl salicylate and ibuprofen on fluoroquinolone MICs on Salmonella enterica serovar typhimurium in vitro.

Coban AY, Birinci A, Ekinci B, Durupinar B.

Ondokuz Mayis University Medical School, Department of Microbiology and Clinical Microbiology, Samsun, Turkey. yilmazden hotmail.com

In this study, the effects of acetylsalicylate and ibuprofen at 2, 4 and 8 mM concentration were investigated on ofloxacin, ciprofloxacin, levofloxacin and pefloxacin minimum inhibitory concentrations (MICs) for 14 Salmonella enterica serovar typhimurium clinical isolates, one standard strain (SZH KUEN 557), SH7616 (acr mutant), SH5014 (parent strain of acr mutant) and PP120 (soxRS mutant) strains. All isolates were susceptible to the 4 fluoroquinolones. In the presence of 2, 4 and 8 mM acetylsalicylate and ibuprofen, 2- to 8-fold increases were observed in fluoroquinolone MICs. This rise was higher, especially in the presence of acetylsalicylate. In spite of this rise, none of the MICs were in the range of resistance limits in vitro. Except for a 2-fold increase in levofloxacin MICs, we did not observe any difference in MICs of ofloxacin, ciprofloxacin, and pefloxacin in the presence of 2, 4 and 8 mM acetylsalicylate and ibuprofen for SH7616 and PP120 strains. According to the in vitro results of this study, it can be suggested that use of acetylsalicylate or ibuprofen together with clinical treatment of bacteria, especially bacteria which show intermediate resistance, will cause resistance. However, since clinical data are insufficient, further studies are needed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15216945&dopt=Abstract ibuprofen Motrin



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Effect of radiation and ibuprofen on normoxic renal carcinoma cells overexpressing hypoxia-inducible factors by loss of von Hippel-Lindau tumor suppressor gene function.

Palayoor ST, Burgos MA, Shoaibi A, Tofilon PJ, Coleman CN.

Radiation Oncology Branch, Center for Cancer Research and the Molecular Radiation Therapeutics Branch, Division of Cancer and Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland, USA. Palayoor mail.nih.gov

PURPOSE: Tumor hypoxia is a major limiting factor for radiation therapy. Hypoxia-inducible factors (HIFs) are overexpressed in several human cancers and are considered prognostic markers and potential targets for cancer therapy. The purpose of the present study was to investigate the impact of HIFs on radiosensitivity. EXPERIMENTAL DESIGN: Renal clear cell carcinoma (RCC) cell lines overexpressing HIFs under normoxic conditions because of inactivation of von Hippel-Lindau tumor suppressor gene function (VHL-ve) and their matched pairs in which overexpression of HIFs was abolished by expression of functional VHL (VHL+ve) were irradiated. Radiosensitivity was determined by clonogenic assay. HIF and VHL protein levels were evaluated by Western blot analysis. RCC cells were also treated with ibuprofen, a radiosensitizer and HIF inhibitor in prostate cancer cells. The effect of ibuprofen on radiosensitization and HIF and VHL proteins was compared in RCC matched-pair cell lines. RESULTS: The data showed only small differences in the radiosensitivity between the cells overexpressing HIFs and cells with basal HIF levels. The dose-modifying factors for C2, 786-0, and A498 RCC cells were 1.14, 1.14 and 1.15, respectively. Radiation did not alter HIF or VHL protein levels. Ibuprofen inhibited HIFs in VHL+ve cells expressing basal levels of HIFs. In VHL-ve cells overexpressing HIFs, the inhibition was very modest. Ibuprofen radiosensitized C2 RCC cells to the same extent irrespective of their HIF status. CONCLUSIONS: Overexpression of HIFs in RCC cells harboring VHL mutations has only a modest effect on the radiosensitivity. Radiosensitization by ibuprofen appears to be independent of HIF status.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15217953&dopt=Abstract ibuprofen Motrin



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Stereoselective disposition of suspensions of conventional and wax-matrix sustained release ibuprofen microspheres in rats.

Adeyeye CM, Chen FF.

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA. adeyeyechri duq3.cc.duq.edu

PURPOSE: The aim of the study is to evaluate stereoselective in vivo disposition of suspensions of conventional and wax-matrix sustained release ibuprofen microspheres in rats. METHODS: Male wistar rats were dosed i.v. with 20 mg/kg, or orally with conventional suspension, and three suspension formulations of sustained release microspheres (having three different particle sizes) of racemic ibuprofen. Blood samples were analyzed stereoselectively by reverse phase HPLC. RESULTS: The mean Cmax for (S)- and (R)-ibuprofen decreased with increased particle size of the drug or microspheres in the suspension dosage forms, while the Tmax increased with increased particle size. The mean S/R ratio (AUC0-48) of the suspensions decreased with increase in particle size of the drug or microspheres and these ratios (for both conventional and sustained formulations) were higher than that of the i.v., an indication of presystemic inversion. Decrease in the ratios with increased particle size is suggestive of formulation dependent inversion. The plasma concentration-time data of the sustained release formulations showed bimodal profiles, irrespective of the particle size of the microspheres. The second peak observed after 8 hours is indicative of colonic absorption. CONCLUSIONS: Stereoselective disposition of ibuprofen microspheres showed higher bioavailability compared to the conventional suspension. Bimodal disposition is influenced by dosage form while presystemic inversion is both site-specific, and dosage form dependent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9453073&dopt=Abstract ibuprofen Motrin



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Stimulation of adipose differentiation related protein (ADRP) expression by ibuprofen and indomethacin in adipocyte precursors and in adipocytes.

Ye H, Serrero G.

Neurosciences Department, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Adipose differentiation related protein (ADRP) is a 50 kDa protein expressed at high level in differentiated adipocytes. ADRP expression is very low in undifferentiated adipocytes and increases rapidly and dramatically as the cells undergo adipose differentiation. In the present study, we demonstrate that ADRP expression at the mRNA and protein level is stimulated in adipocyte precursor cells in a time- and dose-dependent fashion by treatment with cyclooxygenase inhibitors, particularly indomethacin and ibuprofen. Lipoxygenase inhibitors such as AA861 and nordihydroguaiaretic acid were ineffective. Stimulation of ADRP expression was observed with 10(-5) M ibuprofen but maximal stimulation required a concentration of 3 x 10(-4) M. Nuclear run-on experiments indicated that indomethacin or ibuprofen stimulated the transcription of the ADRP gene in undifferentiated adipocytes. In addition to stimulating the induction of ADRP in undifferentiated cells, ibuprofen and indomethacin also stimulated the level of ADRP mRNA and protein in differentiated adipocytes. These experiments provide new information on the regulation of ADRP, an early inducible gene in the adipocyte differentiation programme in adipocyte precursors and in adipocytes and identify a new target for cyclooxygenase inhibitor action during adipocyte differentiation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9480894&dopt=Abstract ibuprofen Motrin



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Effect of clofibrate on the chiral disposition of ibuprofen in rats.

Scheuerer S, Williams KM, Brugger R, McLachlan AJ, Brune K, Day RO, Geisslinger G.

Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Germany.

A potentially clinically important interaction has been described between clofibrate and ibuprofen in vitro. To determine whether this in vitro interaction is paralleled by a change in pharmacokinetics of ibuprofen in vivo two groups of rats were treated orally with clofibrate (n = 8, 280 mg/kg/day) or vehicle (n = 7) for 3 days. On day 3, 2 hr after the last dose of clofibrate, the rats were given an i.v. dose of pseudoracemic ibuprofen (20 mg/kg, 10 mg R-ibuprofen, 10 mg 13C-S-ibuprofen). Plasma concentrations of the enantiomers were monitored by a stereospecific gas chromatography mass spectrometry assay. The clearance of R-ibuprofen more than doubled in the clofibrate-treated group (mean +/- S.E.M.; 29.4 +/- 4.0 ml/min) as compared to control rats (13.0 +/- 1.4 ml/min; P = .003). This increase was similarly reflected in the clearance by inversion (treated, 23.2 +/- 3.2 ml/min, untreated, 10.0 +/- 1.2 ml/min; P = .003) and there was also an increase in the rate of inversion (treated, t1/2 inversion, 8.3 +/- 1.6 min; untreated, 13.9 +/- 1.4 min; P = .029). By contrast, the estimates of fractional chiral inversion were not affected by clofibrate and were in close agreement whether estimated by the area under the plasma concentration-time curve approach (treated, 0.79 +/- 0.02; untreated, 0.72 +/- 0.02) or by deconvolution (treated, 0.78 +/- 0.02; untreated, 0.73 +/- 0.02). There was a significant increase in volume of distribution at steady-state (treated, 4.42 +/- 1.12 liter/kg; untreated, 1.03 +/- 0.30 liter/kg; P = .017) observed for the R-enantiomer but not the S-enantiomer (treated, 1.04 +/- 0.13 liter/kg; untreated, 1.10 +/- 0.21 liter/kg). Pretreatment of rats with clofibrate significantly increased the concentrations of ibuprofen in fat, lung, brain and liver tissue. With respect to the protein levels of two key enzymes involved in chiral inversion, clofibrate pretreatment significantly induced expression of long chain acyl-coenzyme A synthetase, although the expression of the epimerase was unaltered. It is concluded, that clofibrate may increase the proportion of R-ibuprofen incorporated into long-lived lipid ("hybrid" lipid) stores.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9495875&dopt=Abstract ibuprofen Motrin