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Ibuprofen improves survival but does not ameliorate increased gut mucosal permeability in endotoxic pigs.

Fink MP, Kaups KL, Wang H, Rothschild HR.

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

Intravenous lipopolysaccharide (LPS) decreases superior mesenteric arterial blood flow and increases ileal mucosal permeability in pigs. We tested the hypothesis that these phenomena can be ameliorated by pretreatment and posttreatment with ibuprofen. Pentobarbital-anesthetized immature swine were mechanically ventilated (fraction of inspired oxygen, 0.5) and infused with Ringer's lactate (RL) solution (0.8 mL/kg per minute). Animals in group RL (n = 10) received no other interventions. Animals in group RL + LPS (n = 15) were infused with LPS (50 micrograms/kg) from a time range equal to 0 through 60 minutes. Animals in group RL + LPS + ibuprofen (n = 10) were similarly infused with LPS, but in addition, they received ibuprofen (10 mg/kg at -30 minutes and 10 mg/kg per hour from -30 through 210 minutes). Intestinal permeability was assessed by measuring plasma-to-lumen clearances of two hydrophilic probes (chromium 51-labeled edetic acid monohydrate [EDTA] and urea) and by expressing the results as a clearance ratio (CEDTA/CUREA). Survival was 100%, 67%, and 100% in groups RL, RL + LPS, and RL + LPS + ibuprofen, respectively. Among survivors only, CEDTA/CUREA increased significantly over time in both endotoxic groups, but not in nonendotoxic controls. Treatment with ibuprofen transiently blocked LPS-induced mesenteric hypoperfusion. These data indicate that mediators other than cyclooxygenase-derived metabolites of arachidonic acid are responsible for the adverse effect of LPS on mesenteric permeability to hydrophilic solutes in this porcine model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1734850&dopt=Abstract ibuprofen Motrin



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Ibuprofen lowers body temperature and metabolic rate of humans with burn injury.

Wallace BH, Caldwell FT Jr, Cone JB.

University of Arkansas for Medical Sciences, Little Rock.

A group of 15 burned children and young adults with large burns (mean, 41% +/- 15% BSA) were administered ibuprofen (40 mg/kg for 3 days). Each patient served as his or her own control in this crossover study (with and without ibuprofen). Paired calorimetric and temperature studies and urinary nitrogen measurements were performed. No nitrogen-sparing effect was identified for this dose of ibuprofen. However, patients demonstrated a statistically significant reduction in average rectal temperature (0.67 degrees C decreases) (p less than 0.01) and in metabolic rate (11.4% decreases) (p less than 0.01) while taking ibuprofen. Linear regression analysis of the reduction in temperature versus the reduction in metabolic rate yielded a statistically significant correlation (p less than 0.01) with a slope of 13.6% reduction in metabolic rate per degree centigrade reduction in the 72-hour average rectal temperature. These results support the hypothesis that ibuprofen attenuates the hypermetabolic response to thermal injury by blunting the temperature elevation that is usually seen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1740794&dopt=Abstract ibuprofen Motrin



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Ibuprofen attenuates plasma tumor necrosis factor activity during sepsis-induced acute lung injury.

Leeper-Woodford SK, Carey PD, Byrne K, Fisher BJ, Blocher C, Sugerman HJ, Fowler AA 3rd.

Department of Medicine, Medical College of Virginia, Richmond 23298.

Plasma tumor necrosis factor (TNF) activity, cardiac index, extravascular lung water, systemic and pulmonary arterial pressures, pulmonary vascular resistance index, and arterial PO2 were monitored for 300 min in four groups of anesthetized pigs: saline-infused animals (n = 5), saline-infused animals given ibuprofen (12.5 mg/kg iv) at 0 and 120 min (n = 4), animals infused for 60 min with live Pseudomonas aeruginosa (Ps, 5 x 10(8) organisms/ml at 0.3 ml.20 kg-1.min-1, n = 6), and animals infused for 60 min with Ps plus ibuprofen administered at 0 and 120 min (n = 4). Infusion of Ps induced significant elevations (greater than 4-fold increase in units/ml of TNF by 60 min, P less than 0.05) in plasma TNF activity (L929 cytolysis assay) and alterations (P less than 0.05) in all hemodynamic and pulmonary parameters within 30-60 min. Ibuprofen administration in sepsis significantly decreased peak TNF activity by 2 units/ml and attenuated many of the physiological alterations due to sepsis. These results show that ibuprofen attenuates sepsis-induced injury and that alterations of acute septic insult are correlated with reduced plasma TNF activity in septic animals given ibuprofen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1757329&dopt=Abstract ibuprofen Motrin



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Stereoselective systemic disposition of ibuprofen enantiomers in the dog.

Ahn HY, Amidon GL, Smith DE.

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

The pharmacokinetics of ibuprofen are complicated by the unidirectional metabolic inversion of the (-)-R- to (+)-S-enantiomer. Chiral inversion is of therapeutic significance since the drug's pharmacologic activity has been shown to depend upon the (+)-S-isomer. As a result, the present study was undertaken to determine if chiral inversion occurs systemically and to elucidate further the kinetics of the inversion process. Experiments were performed in the beagle dog after intravenous bolus injections of ibuprofen enantiomers separately [100 mg (-)-R, n = 4; 100 mg (+)-S, n = 4] and as admixtures of varying proportions [100 mg (-)-R + 100 mg (+)-S, n = 4; 100 mg (-)-R + 200 mg (+)-S, n = 2]. Plasma samples of (-)-R- and (+)-S-enantiomers were measured by a stereospecific HPLC assay after all drug administrations. Based on the area under the plasma concentration-time curves for (+)-S after administration of each enantiomer alone, chiral inversion was 70 to 75%. A progressive reduction in total plasma clearance of (-)-R-ibuprofen is also observed as increasing amounts of (+)-S-enantiomer are added to the system. The results demonstrate that chiral inversion occurs to a significant extent in the systemic circulation in dog and that R-to-S inversion of ibuprofen may be inhibited by its (+)-S-enantiomer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1788165&dopt=Abstract ibuprofen Motrin



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Physical characterization and dissolution properties of ibuprofen: Eudragit coprecipitates.

Kislalioglu MS, Khan MA, Blount C, Goettsch RW, Bolton S.

College of Pharmacy, University of Rhode Island, Kingston 02881.

Ibuprofen:Eudragit coprecipitates were prepared in 10:3 ratios and their physical properties and related dissolution characteristics were determined. The Eudragit polymers used for the studies were three anionics (Eudragit L100, Eudragit L100-55, and Eudragit S-100), one anionic:cationic mixture used in a 1:1 ratio (Eudragit S100 + E100), and four zwitterionics (Eudragits RL 100, RS 100, RSPM, and RLPM). Physical characterizations were made using qualitative and quantitative X-ray diffractometry, IR spectrophotometry, and differential scanning calorimetry (DSC). Except for Eudragit S100 + E100 coprecipitates, no sizeable interaction at a molecular level was detected between the drug and the polymer. The crystalline structure of the drug was slightly modified in the coprecipitates. Regardless of the lack of interaction, dissolution of ibuprofen was retarded from all the coprecipitates studied (except Eudragit L100), especially in the pH 6.8 to 7.5 media in which the drug is freely soluble. The dissolution rate constants of the coprecipitates, calculated using Higuchi equation, demonstrated that dissolution decreased in the order of anionics greater than zwitterionic greater than anionic + cationic mixtures. The data obtained suggest that the release mechanisms involved are the swelling and slower dissolution of the polymer matrix relative to precipitated ibuprofen. The coprecipitates possess improved flow properties compared with ibuprofen with the exception of Eudragit RLPM and Eudragit RSPM. Eudragit coprecipitates can be useful tools in preparing ibuprofen sustained-release tablets. The coprecipitation technique used is simple and minimizes the use of organic solvents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1791544&dopt=Abstract ibuprofen Motrin



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Cost-effectiveness of low-level heat wrap therapy for low back pain.

Lloyd A, Scott DA, Akehurst RL, Lurie-Luke E, Jessen G.

Fourth Hurdle Consulting Ltd, London, UK. AdamLloyd FourthHurdle.com

OBJECTIVES: To evaluate the cost-effectiveness and budget impact of a new heat wrap therapy for low back pain compared to paracetamol and ibuprofen from the perspective of the UK National Health Service (NHS). METHODS: We evaluated cost-effectiveness using data from a phase III trial comparing the three therapies in 371 patients aged 18 to 55 years presenting with acute uncomplicated low back pain. The primary effectiveness measure used was successful treatment, defined as both clinically meaningful pain relief and clinically meaningful reduction in disability. We conducted a simple evaluation using NHS prescription costs and a modeled extrapolation including the costs of further treatment and consultations for patients treated unsuccessfully or with adverse events. Uncertainty was addressed using nonparametric bootstrapping and sensitivity analyses. RESULTS: Successful treatment was reported by 57% of patients treated with heat wrap therapy, 26% treated with paracetamol and 18% treated with ibuprofen (P < 0.05 for heat wrap vs. both other groups). NHS prescription cost per patient was estimated to be 1.35 pounds Sterling for heat wrap therapy, 0.26 pounds Sterling for paracetamol, and 0.28 pounds Sterling for ibuprofen and cost per successful treatment was 3.52 pounds Sterling for heat wrap therapy compared to paracetamol, and 2.72 pounds Sterling compared to ibuprofen. In the modeled extrapolation, NHS cost per patient was 27.77 pounds Sterling for heat wrap therapy, 34.20 pounds Sterling for paracetamol, and 36.04 pounds Sterling for ibuprofen. Sensitivity analyses indicated that the findings were robust to plausible changes in data and assumptions. CONCLUSIONS: Economic evaluation of this study suggests that the NHS cost of introducing heat wrap therapy in place of oral analgesics would be modest and heat wrap therapy might potentially reduce the total cost of managing episodes of lower back pain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15449633&dopt=Abstract ibuprofen Motrin



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Stereoselective disposition of ibuprofen enantiomers in the isolated perfused rat kidney.

Ahn HY, Jamali F, Cox SR, Kittayanond D, Smith DE.

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

The renal clearance of ibuprofen enantiomer was studied separately in the isolated perfused rat kidney at initial perfusate concentrations of 10 micrograms/ml (n = 4) and 100 micrograms/ml (n = 4). Perfusate and urine samples were measured for R(-) and S(+)-ibuprofen using a stereospecific HPLC assay; urine samples were also analyzed after alkaline hydrolysis. Functional viability of the kidney was assured by determining the fractional excretion of glucose and glomerular filtration rate (GFR) at similar perfusion pressures. The clearance of ibuprofen was equivalent to the apparent formation clearance of conjugated enantiomer since unchanged ibuprofen could not be detected in the urine. At 10 and 100 micrograms/ml, the clearance (+/- SD) of R(-)-ibuprofen was 2.50 +/- 1.28 and 2.19 +/- 1.42 microliters/min, respectively. At 100 micrograms/ml, the clearance of S(+)-ibuprofen was 0.805 +/- 0.290 microliters/min. The protein binding of ibuprofen was found to be concentration dependent and favored the R(-)-enantiomer. The excretion ratio (clearance corrected for free fraction and GFR) of R(-)-ibuprofen was 0.398 +/- 0.209 and 0.295 +/- 0.209 for perfusate concentrations of 10 and 100 micrograms/ml, respectively. The excretion ratio of S(+)-ibuprofen was 0.0886 +/- 0.0335 for perfusate concentrations of 100 micrograms/ml. These results demonstrate that the sum of renal mechanisms involved for the clearance of R(-)- and S(+)-ibuprofen was net reabsorption. Ibuprofen was recovered in the urine solely as conjugated material and no evidence of R(-) to S(+) conversion was observed. In addition, the data suggest that R(-)-ibuprofen is cleared through the kidney faster than its S(+)-enantiomer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1808617&dopt=Abstract ibuprofen Motrin



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Pharmacokinetics of the enantiomers of ibuprofen in the rabbit.

Williams KM, Knihinicki RD, Day RO.

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

The stereoselective disposition of ibuprofen was studied in male New Zealand White (NZW) rabbits (n = 4) following an infusion (0.16 mg/kg/min) to steady-state of each of the enantiomers of ibuprofen with one week between treatments. The mean (+/- SEM) steady-state clearances of (R)-ibuprofen (15.5 +/- 1.1 ml/min/kg) and (S)-ibuprofen (13.6 +/- 1.9 ml/min/kg) were not significantly different from each other (p greater than 0.05) and exceeded the plasma clearance of indocyanine green (4.3 +/- 0.4 ml/min/kg) in a separate group of rabbits (n = 6). When the infusion rate of the enantiomers was doubled there was a significant decrease in the mean clearance of both (R)-ibuprofen (28%; p less than 0.018) and (S)-ibuprofen (24%; p less than 0.003). There was enantiospecific chiral inversion of (R)-ibuprofen to (S)-ibuprofen (fi = 0.30 +/- 0.07) as has been observed in all species so far studied for this 2-arylpropionic acid. The metabolic capacity for elimination of ibuprofen enantiomers was much greater than reported for either fenoprofen or ketoprofen and suggests that the clearance of ibuprofen enantiomers may be flow dependent in this species.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1810148&dopt=Abstract ibuprofen Motrin