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Combined ibuprofen and monoclonal antibody to tumor necrosis factor-alpha attenuate hemodynamic dysfunction and sepsis-induced acute lung injury.

Mullen PG, Windsor AC, Walsh CJ, Blocher CR, Fisher BJ, Leeper-Woodford SK, Jesmok GJ, Fowler AA 3rd, Sugerman HJ.

Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

A number of key mediators are implicated in the pathophysiology of sepsis. In previous studies of a septic porcine model, ibuprofen pretreatment prevented the early but not the late rise in pulmonary vascular resistance index (PVRI) and the early but not the late fall in arterial PO2 (PaO2), whereas monoclonal antibody to tumor necrosis factor alpha (anti-TNF alpha) prevented the late but not the early rise in PVRI and the late but not the early fall in PaO2. This study examined the impact of pretreatment with combined ibuprofen and anti-TNF-alpha on the course of sepsis and acute lung injury (ALI) in pigs. Three groups were studied for 5 hours. Groups I (n = 9) and II (n = 5) received a 1-hour infusion of Pseudomonas aeruginosa. Group II received ibuprofen (12.5 mg/kg) and anti-TNF-alpha (5 mg/kg) before P. aeruginosa, and a further bolus of ibuprofen at 120 minutes. Group III (n = 11) received sterile saline. Group I demonstrated a significant (p < 0.05) rise in plasma TNF-alpha that was abolished in group II. The SVRI in group II did not change significantly from baseline through the study and the SVRI rose sharply in group I following onset of the infusion of P. aeruginosa, as did PVRI. There was no significant change in PVRI from baseline in group II, except for the final 60 minutes; PVRI in group II was significantly less than in group I throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

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Stereoselective, competitive, and nonlinear plasma protein binding of ibuprofen enantiomers as determined in vivo in healthy subjects.

Paliwal JK, Smith DE, Cox SR, Berardi RR, Dunn-Kucharski VA, Elta GH.

College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.

The plasma protein binding and competitive inhibition parameters of R(-)- and S(+)-ibuprofen were determined in vivo in 12 healthy subjects. Subjects participated in a 4 x 4 Latin square design in which oral solutions of drug were administered as 300 mg R(-)-ibuprofen, 300 mg S(+)-ibuprofen, 300 mg R(-)- + 300 mg S(+)-ibuprofen, and 300 mg R(-)- + 600 mg S(+)-ibuprofen. Unlabeled ibuprofen enantiomers were quantitated using a stereospecific reversed-phase HPLC assay, and plasma protein binding experiments were performed using radiolabeled 14C-enantiomers and an ultrafiltration method at 37C. At therapeutic drug concentrations, the protein binding of each enantiomer was greater than 99%. Furthermore, the binding of ibuprofen enantiomers was stereoselective and mutually competitive, as well as nonlinear. The bound-free data were fitted to a model in which the non-linearity of plasma protein binding and competition between enantiomers for binding sites could be accommodated. There were substantial differences in the affinity of ibuprofen enantiomers for protein binding sites (RP2 = 0.358 +/- 0.185 vs. SP2 = 0.979 +/- 0.501 micrograms/ml; mean +/- SD) but no differences in their binding capacity (RP1 = 160 +/- 86 vs. SP1 = 161 +/- 63 micrograms/ml). Although statistically significant, the differences in competitive inhibition parameters were more modest (SKI = 0.661 +/- 0.363 vs. RKI = 0.436 +/- 0.210 micrograms/ml). As a result, the intrinsic binding (i.e., P1/P2) of R(-)-ibuprofen was greater than S(+)-ibuprofen, and the unbound fraction was significantly greater for S-enantiomer vs. R-enantiomer after a given dose of R-ibuprofen or racemate.

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Optical purity determination of (S)-ibuprofen in tablets by achiral gas chromatography.

Paik MJ, Kim KR.

College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea.

An optical purity test was indirectly performed on (S)-ibuprofen as its diastereomeric (R)-(+)-1-phenylethylamide derivative using achiral gas chromatography (GC). The method for the determination of trace (R)-ibuprofen (optical impurity), within the range 1.0 to 50 ng, from a racemic ibuprofen standard was linear (r = 0.9997) with acceptable precision (% RSD < or = 5.3) and accuracy (% RE = 0.7 - -3.9). Similar results were obtained with the method validation for the quantification of (S)-ibuprofen within the range 0.1 to 2.0 microg using a (S)-ibuprofen standard. When applied to seven different commercial (S)-ibuprofen products, their optical purities (98.7 - 99.1%) were determined with good precision (% RSD < or = 4.0).

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Effects of nonsteroidal anti-inflammatory drugs on microvascular dynamics.

Slater C, House SD.

Department of Biology, College of Arts and Sciences, Seton Hall University, South Orange, New Jersey 07079.

Techniques of intravital microscopy were used to assess the effect of the nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and ibuprofen, on the microcirculation. Hemodynamics in venules of the rat mesentery were studied in terms of vessel diameter, red blood cell velocity, and leukocyte-endothelium interactions: leukocyte-endothelium adhesion (LEA), white blood cell (WBC) marginating flux, and WBC velocity. Measurements were made during (1) control conditions (topical suffusion with ringer-gelatin drip), (2) topically suffused indomethacin or ibuprofen, (3) an induced inflammatory response (suffusion with the chemoattractant N-Formyl-Methionyl-Leucyl-Phenylalanine (FMLP)), and (4) concomitant suffusion with FMLP and NSAID. Short term topical suffusion (90 sec) with indomethacin and ibuprofen had little or no effect on control hemodynamics. Five-minute suffusions with indomethacin (5 x 10(-5) to 5 x 10(-4) M) significantly increased LEA while ibuprofen (5 x 10(-3) M) significantly decreased LEA. Topical suffusion with the chemotactic agent FMLP induced inflammation and significantly increased LEA in venules. Treatment with indomethacin during induced inflammation had no effect on the inflammatory reaction in terms of the microvascular hemodynamics measured in this study. Treatment with ibuprofen during induced inflammation significantly reduced LEA and increased red blood cell velocity. In conclusion, although both of the NSAIDs studied here are known to block the cyclooxygenase pathway of arachidonic acid metabolism, the actions of indomethacin and ibuprofen on the inflammatory process are very different with an important effect of ibuprofen being to decrease LEA.

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The effect of ibuprofen on microvascular thrombosis in an experimental rabbit model.

Nguyen T, Guinn OA, Wortham K, Rothkopf DM.

Department of Surgery, University of Massachusetts Medical Center, Worcester 01655.

The efficacy of ibuprofen in reducing microvascular thrombosis in a well-established experimental model was studied. Bilateral 2-mm arterial inversion grafts were constructed in the femoral arteries of New Zealand White rabbits. The experimental group (n = 40 grafts) received subcutaneous injections of ibuprofen 15 mg/kg t.i.d. beginning 1 day preoperatively and continued for 7 days postoperatively. The control group (n = 42 grafts) received injections of an equivalent volume of saline three times per day. Patency was evaluated at 7 days by the distal milking test. Seventy-three percent of the ibuprofen grafts were patent at 7 days, whereas 57% of the control grafts remained open. This difference in microvascular patency was not statistically significant. Representative scanning electron micrographs revealed a moderate reduction in aggregated platelets and overall clot density in the patent ibuprofen arterial inversion grafts compared with the patent control specimens. Although the use of ibuprofen as a sole antithrombotic agent cannot be recommended as the result of this study, it may be efficacious when used in conjunction with other agents such as dextran 40.

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Hepatocellular proliferation in ibuprofen-treated mice.

Bendele AM, Hulman JF, White S, Brodhecker C, Bendele RA.

Toxicology Division, Eli Lilly and Co., Greenfield, Indiana 46140.

Female B6C3F1 mice were treated with ibuprofen for 2 wk or 90 days to monitor effects on hepatocellular proliferation during acute and subchronic exposure. Proliferation was assessed by bromodeoxyuridine labeling. Mice treated with 100, 200, or 400 mg/kg ibuprofen for 2 wk had significantly increased liver weights. A dose-related increase in the number of labeled hepatocytes per 1,000 hepatocytes suggested that the weight increases were in part a result of hepatocellular proliferation. Hepatocellular hypertrophy also contributed to the increased liver size as indicated by decreases in the number of hepatocytes per high power field. Ultrastructural evaluation indicated that hepatocyte peroxisome size increased significantly in treated mice. Mice treated with 100 or 200 mg/kg ibuprofen for 90 days and given bromodeoxyuridine during the last 2 wk of ibuprofen exposure had statistically significant increases in relative liver weights. However, the number of labeled hepatocytes per 1,000 hepatocytes was not increased, and there was no evidence of hepatocellular hypertrophy. Mice given 200 mg/kg ibuprofen for 90 days had significantly decreased serum triglycerides. These findings indicate that ibuprofen treatment of mice results in hepatomegaly characterized by hepatocellular hypertrophy and hyperplasia. Peroxisomal changes may be contributory to the pathogenesis of this lesion.

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Equipotent inhibition by R(-)-, S(+)- and racemic ibuprofen of human polymorphonuclear cell function in vitro.

Villanueva M, Heckenberger R, Strobach H, Palmer M, Schror K.

Institut fur Pharmakologie, Heinrich-Heine-Universitat Dusseldorf, Federal Republic of Germany.

1. The effects of racemic (rac) ibuprofen and its S(+)- and R(-)-enantiomers on functions of human polymorphonuclear cells (PMN) and platelets were studied in vitro. 2. Rac-ibuprofen inhibited PMN functions (O2- generation, beta-glucuronidase release, LTB4 formation). Similar IC50 values (40-100 microM) were obtained for the S(+)- and R(-)-enantiomers. 3. All forms of ibuprofen inhibited cyclooxygenase-related platelet functions (aggregation, thromboxane formation). The S(+)-enantiomer was about twice as active as the racemate while the R(-)-enantiomer was at least 10-fold less active. This demonstrates that the S(+) is the only cyclooxygenase inhibitory component of the racemate. 4. The concentrations of rac-ibuprofen in PMN and platelets were similar to those in the incubation medium and represented equal concentrations of the enantiomers. This indicates that neither interconversion nor tissue accumulation of the compounds occurred. 5. These data indicate that antineutrophil effects of ibuprofen on human PMN are independent of cyclooxygenase inhibition. Therefore, R(-)-ibuprofen may be superior to the S(+)-isomer for the treatment of PMN-dependent inflammatory diseases. However, effective free drug concentrations may not be obtained in vivo.

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[Effect of indomethacin and ibuprofen on blood pressure of patients treated with nifedipine or captopril]

[Article in Polish]

Halawa B.

Katedry i Kliniki Kardiologii AM, Wroclawiu.

Non-steroidal anti-inflammatory agents may moderately increase blood pressure thus affecting hypotensive agents effectiveness. This study aimed at evaluating arterial blood pressure, serum 6-keto-PGF1 and aldosterone as well as plasma renin activity in hypertensive patients treated with indomethacin or ibuprofen with captopril or indomethacin or ibuprofen with nifedipine. Captopril given at the same time as indomethacin or ibuprofen did not decrease both systolic and diastolic blood pressures. However, no interaction between nifedipine administered simultaneously with indomethacin or ibuprofen was noted. Serum 6-keto-PGF1 and aldosterone as well as plasma renin activity were decreased in both groups of treated patients. Mechanism of indomethacin and ibuprofen hypertensive action seems to se related with their ability to inhibit prostacyclin biosynthesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8415243&dopt=Abstract ibuprofen Motrin