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Pharmacokinetics of ibuprofen in febrile children.

Nahata MC, Durrell DE, Powell DA, Gupta N.

College of Pharmacy, Ohio State University, Columbus.

Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3-10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC. The maximum observed serum concentrations of ibuprofen ranged from 17-42 micrograms.ml-1 at 5 mg.kg-1 and 25-53 micrograms.ml-1 at 10 mg.kg-1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean tmax, oral clearance and elimination half life were 1.1 h, 1.2 ml.min-1.kg-1, and 1.6 h, respectively in patients at 5 mg.kg-1 doses; the corresponding values were 1.2 h, 1.4 ml.min-1.kg-1, and 1.6 h in those receiving 10 mg.kg-1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients. These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.

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Ibuprofen inhibits localized bone resorption in the middle ear.

Jungkeit MC, Chole RA.

Department of Otolaryngology, University of California, Davis, School of Medicine 95616.

Localized osteoclastic bone resorption plays a significant role in the pathogenesis of several diseases of the middle ear as well as orthodontic tooth movement and long bone remodeling. The mechanisms of control of localized bone loss and systemic bone resorption may be different but both may be mediated by a final common pathway which includes prostaglandins. Prostaglandins seem to have a predominantly stimulatory effect on bone resorption, although the exact mechanism is poorly understood. Ibuprofen, a nonsteroidal antiinflammatory drug, is known to inhibit the synthesis of prostaglandins. It is likely that ibuprofen, through its inhibition of prostaglandin synthesis, would decrease the localized osteoclastic bone resorption in a previously described animal model system. Mongolian gerbils were divided into three groups: low dose ibuprofen (10 mg/kg per day), high dose ibuprofen (30 mg/kg per day), and a control group. Following surgical implantation of catheters to the right bullae of each gerbil, pressure was applied for 8 days, stimulating osteoclastic bone resorption. After killing the animals and histomorphometric analysis of the bullae from each, comparisons were made between each group using osteoclast surface (percentage of bone area covered by osteoclasts), osteoclast number (number of osteoclasts/mm bone length), and osteoclast profile area (in microns2). Significantly lower osteoclast surface (Oc.S/BS) was found in pressurized bullae from both treatment groups when compared with pressurized bullae from controls (P less than 0.05) and significantly lower osteoclast number (N.Oc/T.L) in pressurized bullae from both treatment groups when compared with pressurized bullae from controls (P less than 0.05). These differences were found to be dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

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Effects of ibuprofen on pulmonary oedema in an animal smoke inhalation model.

Stewart RJ, Yamaguchi KT, Knost PM, Mason SW, Roshdieh BB, Samadani S, Chang BL.

Department of Surgery, Valley Medical Center, Fresno, California.

The ability of ibuprofen to lower extravascular lung water significantly was examined in an animal smoke inhalation model. Adult New Zealand White rabbits weighing 3-5 kg were anaesthetized and intubated. They were then allowed to breathe cooled cotton smoke until the carboxyhaemoglobin (COHb) reached a level of 60 per cent or higher. Each ibuprofen-treated animal received a dose of 50 mg/kg either intraperitoneally or intravenously. Ibuprofen was administered to animals that received smoke inhalation alone and those that received smoke inhalation combined with a 10 per cent BSA partial skin thickness thermal injury. Control groups were established for both of the above-mentioned groups. Peak carboxyhaemoglobin levels as well as CO half-lives were not significantly different between ibuprofen-treated groups and the controls. Ibuprofen treatment resulted in significantly (P less than 0.05) decreased lung water in both smoke, and smoke plus thermal injury groups as compared to controls. These results suggest that ibuprofen promotes the reduction of early-onset lung water resulting from smoke inhalation injury alone or from smoke inhalation injury plus a thermal injury.

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Interindividual variability in the enantiomeric disposition of ibuprofen following the oral administration of the racemic drug to healthy volunteers.

Avgerinos A, Hutt AJ.

Department of Pharmacy, Brighton Polytechnic, Moulsecoomb, United Kingdom.

The plasma disposition of the enantiomers of ibuprofen has been investigated following the oral administration of the racemic drug (400 mg) to 24 healthy male volunteers. The plasma elimination of (R)-ibuprofen was found to be more rapid than that of the S-enantiomer [plasma half-life: (R) 2.03 h; (S) 3.05 h; 2P less than 0.001], resulting in a progressive enrichment in the plasma content of this isomer, some 64% of the total area under the plasma concentration time curves (AUC) being due to the pharmacologically active enantiomer. The influence of dose on the pharmacokinetic characteristics of the enantiomers of ibuprofen, over the range 200-800 mg, was investigated in three subjects. Examination of dose-normalized AUC values and oral clearance indicate the dose dependence of (R)-ibuprofen disposition.

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Stereoselective high-performance liquid chromatographic determination of ketoprofen, ibuprofen and fenoprofen in plasma using a chiral alpha 1-acid glycoprotein column.

Menzel-Soglowek S, Geisslinger G, Brune K.

Department of Pharmacology and Toxicology, University of Erlangen-Nurnberg, F.R.G.

The effect of mobile phase composition, pH and temperature on the chiral resolution and retention of some 2-arylpropionic acids using the chiral alpha 1-acid glycoprotein column EnantioPac is described. Furthermore, a direct stereoselective high-performance liquid chromatographic assay to determine the enantiomers of ketoprofen, ibuprofen and fenoprofen in plasma is presented. Detection was at 260, 220 and 220 nm for ketoprofen, ibuprofen and fenoprofen, respectively. The limit of detection was 0.1 micrograms/ml for the enantiomers of ketoprofen and ibuprofen, and 0.25 micrograms/ml for the enantiomers of fenoprofen. The method was demonstrated to be applicable for stereoselective pharmacokinetic studies of ketoprofen, ibuprofen and fenoprofen after administration under clinical conditions.

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Role of a nonsteroidal anti-inflammatory agent, ibuprofen, in coronary revascularization after acute myocardial infarction.

Clement R, Das DK, Engelman RM, Otani H, Bandhyopadhyay D, Hoory S, Antar M, Rousou JA, Breyer RH, Prasad MR.

Department of Surgery, University of Connecticut School of Medicine, Farmington.

The efficacy of using a nonsteroidal anti-inflammatory agent such as ibuprofen for the salvage of ischemic and reperfused myocardium was investigated by examining its ability to improve global and regional functions as well as to preserve high-energy phosphate compounds and inhibit creatine kinase release from an isolated in-situ pig heart subjected to 1 h of normothermic regional ischemia followed by 1 h of global hypothermic arrest and 1 h of normothermic reperfusion. Preperfusion of the heart for 15 min prior to ischemic insult with 50 microM ibuprofen failed to mitigate the myocardial reperfusion injury. Ibuprofen, however, functioned as an anti-inflammatory agent, as judged by its ability to inhibit the influx of indium-111-labeled polymorphonuclear leukocytes and chromium-51 (51Cr)-labeled platelets into the ischemic and reperfused heart. It also blocked the cyclooxygenase pathway, as evidenced by the significant reduction of 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations in the perfusate. Inhibition of cyclooxygenase resulted in increased accumulation of nonesterified fatty acids, particularly arachidonic acid, in the heart. These results suggest that although ibuprofen can inhibit polymorphonuclear leukocyte and platelet influx into the ischemic and reperfused heart, it causes further damage to the already ischemic heart by reducing prostacyclin concentration and increasing free fatty acids in the heart.

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Reperfusion-induced arrhythmias are not prevented by ibuprofen in isolated rat heart.

Bernier M, Alyea EP, Hearse DJ.

Rayne Institute, St. Thomas' Hospital, London, U.K.

Free radicals have been implicated in the genesis of reperfusion-induced arrhythmias and the cyclooxygenase pathway has been suggested as a potential source. We have therefore assessed whether a cyclooxygenase inhibitor, ibuprofen, is able to reduce reperfusion-induced injury in the isolated perfused rat heart. A duration of 10 min of regional ischemia, which resulted in a high (83%) incidence of ventricular fibrillation, was selected and hearts (n = 12/group) were perfused with ibuprofen (2, 20, or 30 mg/L) throughout the experiment. Ibuprofen did not affect heart rate, although it did produce a dose-dependent increase in coronary flow. However, at all doses studied, ibuprofen had no effect upon the time to onset, incidence, or duration of arrhythmias. In subsequent studies with 30 min of regional ischemia, ibuprofen (30 mg/L) again caused vasodilatation but without effect upon heart rate or severity of arrhythmias. In conclusion, we were unable to obtain evidence in support of the concept that cyclooxygenase activity or cyclooxygenase-derived free radicals are involved in the genesis of ischemia- and reperfusion-induced arrhythmias.

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Ibuprofen-induced Walker 256 tumor cell death: cytochrome c release from functional mitochondria and enhancement by calcineurin inhibition.

Campos CB, Degasperi GR, Pacifico DS, Alberici LC, Carreira RS, Guimaraes F, Castilho RF, Vercesi AE.

Departamento de Patologia Clinica, Faculdade de Ciencias Medicas, Universidade Estadual de Campinas, Campinas, SP 13083-970, Brazil. cbcampos fcm.unicamp.br

The participation of mitochondria in the mechanism of tumor cell death induced by non-steroid anti-inflammatory drugs is uncertain. Here we show that ibuprofen induces death of Walker 256 tumor cells independently on mitochondrial depolarization as estimated by flow cytometry using DioC(6)(3). Oligomycin increased mitochondrial transmembrane potential in both ibuprofen-treated and non-treated cells, indicating that ATP synthesis was sustained during cell death. Cyclosporin A, but not bongkrekic acid, both mitochondrial permeability transition inhibitors, increased the percentage of cell death in the presence of ibuprofen. FK506, a calcineurin inhibitor like cyclosporin A, also increased ibuprofen-induced cell death. Moreover, we showed that cytochrome c was released during ibuprofen-induced cell death. In conclusion, death of Walker 256 tumor cells induced by ibuprofen does not impair mitochondrial function, involves cytochrome c release and is accompanied by a rescue pathway via calcineurin activation.

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