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Effects of ibuprofen on doxorubicin toxicity.

Inchiosa MA Jr, Smith CM.

Department of Pharmacology, New York Medical College, Valhalla 10595.

The cardiotoxicity of doxorubicin (Adriamycin) restricts the usefulness of this potent antineoplastic agent. Since the cardiotoxic mechanism (generation of oxygen radicals) is distinct from the primary chemotherapeutic mechanism (intercalation of DNA) efforts to decrease the cardiotoxic potential are warranted. Three nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen and sulindac were tested for effects upon survival in the chronic mouse model of doxorubicin cardiotoxicity. The original premise in these studies was that nonsteroidal anti-inflammatory drugs, through inhibition of cyclooxygenase activity, would suppress the attending generation of superoxide anions and reduce a synergism with oxygen radicals produced by redox cycling of doxorubicin. Acetaminophen was included in the studies as an example of an analgesic agent which lacks anti-inflammatory efficacy. Doxorubicin (4 mg/kg) was injected intraperitoneally at 3-week intervals in Swiss-Webster mice. The interventions were administered in equianalgesic doses in the drinking water for 2 days before and 3 days after the doxorubicin injections. Ibuprofen (1 mg/ml) increased survival from 16.0%, for doxorubicin alone, to 63.6% (p less than 10(-6); none of the other interventions demonstrated protection. Ibuprofen-treated mice also lost less weight during the treatment period than all other doxorubicin injected animals (p less than 10(-6]. Since the three antiinflammatory drugs tested are all cyclooxygenase inhibitors, but only ibuprofen inhibits neutrophil infiltration, the latter mechanism is proposed as the primary basis for the observed protection.

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Ibuprofen attenuates the inflammatory response to Pseudomonas aeruginosa in a rat model of chronic pulmonary infection. Implications for antiinflammatory therapy in cystic fibrosis.

Konstan MW, Vargo KM, Davis PB.

Department of Pediatrics, Rainbow Babies and Childrens Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Chronic pulmonary infection in cystic fibrosis (CF) results in an inflammatory response with persistent neutrophil influx, which contributes to lung damage. Attenuating the response with antiinflammatory agents might delay progression of lung disease. We investigated the effects of the nonsteroidal antiinflammatory agent, ibuprofen, in a rat model of chronic Pseudomonas endobronchial infection and inflammation. The areal percentage of lung inflammation 14 days after animal inoculation with Pseudomonas-containing agarose beads was significantly less in animals treated with ibuprofen (35 mg/kg orally twice daily) (39 +/- 26% SD) compared to animals given placebo (55 +/- 25% SD) (p less than 0.05). Ibuprofen did not increase the pulmonary burden of Pseudomonas, and the ibuprofen-treated infected animals gained weight better than placebo-treated controls. The administered dose of ibuprofen provides plasma concentrations sufficient to inhibit the release of leukotriene B4 (LTB4) from rat neutrophils in vitro. Since LTB4 is a potent pro-inflammatory product that promotes neutrophil adherence, aggregation, migration, degranulation, and superoxide release, inhibition of its production by ibuprofen could inhibit inflammatory damage to the lung in this model. These data in an animal model, taken together with the success of a preliminary trial of alternate-day steroid therapy in mildly affected patients with CF, suggest that antiinflammatory therapy with ibuprofen should be considered for a new therapeutic strategy in CF.

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The effects of ibuprofen and diclofenac on the chemotaxis and adenosine triphosphate level of polymorphonuclear cells in vitro.

Partsch G, Schwarzer C, Eberl R.

Ludwig Boltzmann-Institute of Rheumatology and Balneology, Vienna-Oberlaa, Austria.

Investigations were carried out to determine the effect of ibuprofen and diclofenac on the chemotaxis of human polymorphonuclear cells. The experiments were done with the drugs alone as well as in the presence of leukotriene B4 (LTB4). A modified quantitative bioluminescence assay was used to measure chemotaxis, which allowed the calculation of differences in the spontaneous migration in contrast to the effects of the drugs, and simultaneously, also, the evaluation of whether the inhibition or augmentation of the chemotaxis was due to influences on the adenosine triphosphate (ATP) level of the cells. It was found that high concentrations (10 mM) of either ibuprofen or diclofenac destroy the intracellular ATP of polymorphonuclear cells (PMN). Therefore, the reported inhibition of the chemotaxis by ibuprofen at a concentration of 10 mM cannot be understood as a part of the chemotactic process. In the range of 1 microM and 0.1 mM ibuprofen and diclofenac did not statistically affect the intracellular ATP level of PMN cells but at the same time a distinct inhibition of the chemotactic response of PMN cells was observed. This effect occurred even in the presence of a potent chemoattractant (leukotriene B4). Ibuprofen (0.1 mM) reduced chemotaxis to 67% and the same concentration of diclofenac reduced it to 56% of the values of LTB4 alone.

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Ibuprofen attenuates hypochlorous acid production from neutrophils in porcine acute lung injury.

Carey PD, Byrne K, Jenkins JK, Sielaff TD, Walsh CJ, Fowler AA 3rd, Sugerman HJ.

Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.

Hypochlorous acid (HOCl), a neutrophil-generated oxidant, has been implicated in tissue destruction in sepsis-induced acute lung injury (ALI). Ibuprofen, a cyclooxygenase inhibitor, successfully attenuates many of the physiological derangements in ALI. The aim of this study was to examine the role of PMN hypochlorous acid in sepsis-induced ALI and evaluate the effect of ibuprofen therapy. Neutrophils from three groups of young (15-25 kg), anesthetized swine were studied: controls (C, n = 7) received 0.9% NaCl, septic animals (Ps, n = 8) received live Pseudomonas aeruginosa (5 x 10(8) CFU/ml at 0.3 ml/20 kg/min) for 60 min, and ibuprofen-treated animals (Ps + I, n = 6) received Ps plus ibuprofen 12.5 mg/kg administered at 0 and 120 min. Neutrophils were isolated from peripheral blood at 0, 60, and 300 min and the rate and total production of HOCl were assessed on the basis of the ability of the amino acid taurine to trap HOCl. Results: Septic (Ps) PMNs produce 32% more HOCl, P less than 0.01, at 300 min than at baseline which was associated with a marked increase in both extravascular lung water (6.44 +/- 0.8 ml/kg, t = 0 vs 16.03 +/- 2.6 ml/kg, t = 300, P less than 0.01) and bronchoalveolar protein content (115 +/- 13 micrograms/ml, t = 0 vs 633 +/- 104 micrograms/ml, t = 300, P less than 0.01). Ibuprofen significantly attenuated (P less than 0.05) HOCl production when compared to Ps, in conjunction with significantly (P less than 0.05) reduced levels of extravascular lung water and bronchoalveolar lavage protein.

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Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron.

Kennedy TP, Rao NV, Noah W, Michael JR, Jafri MH Jr, Gurtner GH, Hoidal JR.

Division of Allergy, Critical Care and Respiratory Medicine, Duke University Medical Center, Durham, North Carolina 27710.

Because ibuprofen protects from septic lung injury, we studied the effect of ibuprofen in oxidant lung injury from phosgene. Lungs from rabbits exposed to 2,000 ppm-min phosgene were perfused with Krebs-Henseleit buffer at 50 ml/min for 60 min. Phosgene caused no increase in lung generation of cyclooxygenase metabolites and no elevation in pulmonary arterial pressure, but markedly increased transvascular fluid flux (delta W = 31 +/- 5 phosgene vs. 8 +/- 1 g unexposed, P less than 0.001), permeability to albumin (125I-HSA) lung leak index 0.274 +/- 0.035 phosgene vs. 0.019 +/- 0.001 unexposed, P less than 0.01; 125I-HSA lavage leak index 0.352 +/- 0.073 phosgene vs. 0.008 +/- 0.001 unexposed, P less than 0.01), and lung malondialdehyde (50 +/- 7 phosgene vs. 24 +/- 0.7 mumol/g dry lung unexposed, P less than 0.01). Ibuprofen protected lungs from phosgene (delta W = 10 +/- 2 g; lung leak index 0.095 +/- 0.013; lavage leak index 0.052 +/- 0.013; and malondialdehyde 16 +/- 3 mumol/g dry lung, P less than 0.01). Because iron-treated ibuprofen failed to protect, we studied the effect of ibuprofen in several iron-mediated reactions in vitro. Ibuprofen attenuated generation of .OH by a Fenton reaction and peroxidation of arachidonic acid by FeCl3 and ascorbate. Ibuprofen also formed iron chelates that lack the free coordination site required for iron to be reactive. Thus, ibuprofen may prevent iron-mediated generation of oxidants or iron-mediated lipid peroxidation after phosgene exposure. This suggests a new mechanism for ibuprofen's action.

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Developmental toxicity evaluation of ibuprofen and tolmetin administered in triple daily doses to Wistar CRL:(WI)WUBR rats.

Burdan F.

Experimental Teratology Unit of the Human Anatomy Department, Medical University of Lublin, Lublin, Poland. fb3 wp.pl

BACKGROUND: Ibuprofen and tolmetin are popular non-steroidal anti-inflammatory drugs. Previous animal studies taken with single daily doses showed their good prenatal tolerability. However, since both cyclooxygenase (COX) inhibitors have a short half-life, the current report presents drug developmental effects after triple daily doses administration, as they are used in human. METHODS: Drugs were separately, orally dosed to pregnant rats triple daily 8 hr apart from day 8 to 21 (GD=1-plug day). The total daily doses were set at 25.5, 255.0, and 600.0 mg/kg for ibuprofen and 25.5, 255.0, and 2550.0 mg/kg for tolmetin. Fetuses were delivered on GD 21 and routinely examined. Comprehensive clinical and developmental measurements were done. RESULTS: Maternal toxicity and intrauterine growth retardation were found in groups exposed to the highest doses of both drugs. An increase of external variations was reported in groups exposed to the middle and highest dose of ibuprofen and to the highest dose of tolmetin. Skeletal variations were significantly different only in litters treated with the highest doses of the drugs. Pooled statistical analysis showed a higher incidence of midline and ventricular septal (VSD) defect in rat fetuses exposed to COX inhibitors when compared with historical control data. For ibuprofen, the influence on VSD was similar to aspirin. CONCLUSION: Both COX inhibitors were toxic to dams in the highest doses evaluated, which caused a significantly greater incidence of intrauterine growth retardation and developmental variations. 2004 Wiley-Liss, Inc.

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A prospective, population-based study of acute ibuprofen overdose: complications are rare and routine serum levels not warranted.

McElwee NE, Veltri JC, Bradford DC, Rollins DE.

Intermountain Regional Poison Control Center, Salt Lake City, Utah 84132.

The availability of ibuprofen without a prescription requires assessment of its acute toxicity in the general population. We report results from a prospective study of 329 cases of ibuprofen overdose from a statewide cohort that were reported to our poison center between April 1985 and November 1986; 85 patients had ibuprofen serum concentrations measured. Gastrointestinal disturbances and central nervous system depression were the most common clinical findings (42% and 30% of patients, respectively), but the severity was mild; only one patient had severe symptoms that could be attributed to ibuprofen. Ibuprofen serum concentrations correlated poorly with gastrointestinal symptoms (r = -.177), central nervous system findings (r = .176), presence of coingestants (r = .078), and presence of potentially life-threatening symptoms (r = .087). We evaluated the usefulness of a previously published nomogram to predict ibuprofen toxicity; the positive predictive value for severe symptoms was 6% for all patients and 0% for patients ingesting ibuprofen alone. We conclude that the frequency of life-threatening complications from ibuprofen overdose is low, the nomogram is not predictive of toxicity, and routine serum concentration determinations are not useful as an adjunct in the management of overdose cases.

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Interaction of captopril and ibuprofen on glomerular and tubular function in humans.

Allon M, Pasque CB, Rodriguez M.

Nephrology Section, University of Oklahoma School of Medicine, Oklahoma City.

Renal hemodynamics and tubular solute and water handling were evaluated in normal subjects during water diuresis, before and after the acute administration of captopril, ibuprofen, or the combination of both drugs. The glomerular filtration increased after captopril administration but did not change after ibuprofen alone or in combination with captopril. Renal plasma flow increased with captopril alone and captopril plus ibuprofen but did not change after ibuprofen alone. Urine volume and Na excretion increased with captopril and decreased after ibuprofen; coadministration of ibuprofen attenuated the tubular effects produced by captopril alone. FELi, fractional delivery of solute to the distal nephron, and FELi-FENa, fractional distal reabsorption of solute, both significantly increased after captopril and decreased after ibuprofen but did not change with the combined regimen. (FELi-FENa)/FELi, fractional reabsorption of distally delivered Na, significantly decreased after captopril and increased after ibuprofen but remained unchanged after captopril plus ibuprofen. Thus captopril and ibuprofen have opposing effects on tubular Na and water handling, which are attenuated by the addition of the other drug. This interaction may have clinical relevance in patients with heart failure or hypertension, in whom captopril is used to enhance Na and water diuresis.

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