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The pharmacokinetics of ibuprofen after burn injury.

Cone JB, Wallace BH, Olsen KM, Caldwell FT Jr, Gurley BJ, Bond PJ.

University of Arkansas for Medical Sciences, Little Rock 72205.

Ibuprofen is an effective antipyretic in the postburn period and produces associated decrements in the hypermetabolic response. Burn injury is capable of altering the kinetics of many drugs, making the predictable use of agents such as ibuprofen difficult. Ten patients with serious burns were studied after the administration of 10 mg/kg ibuprofen suspension. The half-life varied from 1.4 to 5.1 hours, depending on the site of administration and/or the presence of solid food. The reported half-life for ibuprofen suspension is 1.8 to 2 hours. Burn size did not alter ibuprofen half-life or area under the time-concentration curve. Maximum ibuprofen concentration varied greatly, depending on route of administration. Time to maximal temperature reduction was between 2 and 3 hours after drug administration. Although the precise level of ibuprofen needed for cyclooxygenase inhibition is unknown, enteral administration results in levels below the targeted 10 to 20 mcg/ml for much of the traditional 6-hour dosing interval. Future studies with ibuprofen in the burn population must standardize more than just total dose.

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Effect of the platelet-activating factor antagonist, TCV-309, and the cyclo-oxygenase inhibitor, ibuprofen, on the haemodynamic changes in canine experimental endotoxic shock.

Yamanaka S, Iwao H, Yukimura T, Kim S, Miura K.

Department of Pharmacology, Osaka City University Medical School, Japan.

1. The present study was conducted in order to examine the effects of the platelet-activating factor (PAF) antagonist, TCV-309, and the cyclo-oxygenase inhibitor, ibuprofen, on the acute haemodynamic responses to endotoxin in anaesthetized dogs. 2. Endotoxin (2 mg kg-1, i.v.) induced a severe hypotension by decreasing both total peripheral resistance (TPR) and cardiac output. Endotoxin also decreased central venous pressure and increased effective vascular compliance (EVC), indicating a blood pooling in the capacitance vessels. 3. The endotoxin-induced hypotension but not the fall in cardiac output, was markedly attenuated by ibuprofen. Ibuprofen abolished the decrease in TPR and even caused a systemic vasoconstriction. Ibuprofen abolished the increase in EVC. 4. The hypotension caused by endotoxin was attenuated by TCV-309 to a lesser extent than ibuprofen. However, the reduction in cardiac output produced by endotoxin was markedly attenuated by the PAF antagonist. TCV-309 also abolished the increase in EVC. In contrast to ibuprofen, TCV-309 did not affect the decrease in TPR caused by endotoxin. 5. Combined treatment with ibuprofen and TCV-309 markedly attenuated the endotoxin-induced hypotension, but not the fall in cardiac output. Nevertheless, when compared with animals treated with ibuprofen alone, treatment with ibuprofen and TCV-309 partly attenuated the endotoxin-induced reduction in cardiac output and systemic vasoconstriction. 6. These data indicate that dilatation of both resistance vessels and capacitance vessels contributes to the endotoxin-induced hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

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Effect of ibuprofen on regional eicosanoid production and neuronal injury after forebrain ischemia in rats.

Patel PM, Drummond JC, Sano T, Cole DJ, Kalkman CJ, Yaksh TL.

Department of Anesthesiology, University of California, San Diego.

Post-ischemic metabolism of arachidonic acid by cyclooxygenase results in the elaboration of numerous eicosanoids and in the generation of free radicals. Accordingly, the effect of cyclooxygenase inhibition by ibuprofen on post-ischemic eicosanoid production and delayed neuronal death was evaluated in Wistar-Kyoto rats subjected to incomplete forebrain ischemia. In control (C) and ibuprofen-treated groups (n = 5 each), pre- and post-ischemic eicosanoid production in the caudate nucleus (CN) and dorsal hippocampus (HPC) were evaluated by microdialysis. The ibuprofen-treated animals were given ibuprofen, 15 mg/kg i.v., prior to insertion of microdialysis probes. Forebrain ischemia was induced by bilateral carotid artery occlusion (BCAO) for 10 min with simultaneous hypotension to 35 Torr. The concentrations of thromboxane B2 (TxB2), 6-keto-PGF1 alpha and PGF2 alpha in the microdialysate were measured by radioimmunoassay. In two additional concurrent groups of rats (n = 10 each), neuronal injury in the HPC, CN and cortex (parietal, temporal and entorhinal regions) was evaluated histologically three days after 10 min of forebrain ischemia with and without pre-ischemic ibuprofen administration. In the control microdialysis group, levels of TxB2, 6-keto-PGF1 alpha and PGF2 alpha increased in both CN and HPC after probe insertion. These probe related increases were substantially reduced in the ibuprofen group. After ischemia and reperfusion in the control group, the levels of TxB2 and PGF2 alpha increased in both CN and HPC. Levels of 6-keto-PGF1 alpha increased in the CN but not in the HPC. The administration of ibuprofen substantially reduced post-ischemic TxB2 and PGF2 alpha levels in both CN and HPC and decreased 6-keto-PGF1 alpha levels in the CN. The results of these initial microdialysis studies left the possibility that, in the ibuprofen group, the reduction in eicosanoid levels after probe penetration might have influenced the subsequent post-ischemic eicosanoid production. Therefore, in an additional group of animals (n = 5), ibuprofen was administered after probe insertion. Only PGF2 alpha levels were measured in this group. Increased levels of PGF2 alpha comparable to the original control group were detected after probe penetration. Nonetheless, after ibuprofen administration, the pre- and post-ischemic levels of PGF2 alpha were again significantly reduced. In the histologic evaluation groups, overall neuronal injury was significantly less in the ibuprofen treated animals. This protective effect of ibuprofen was most clearly evident in the CA3 sector of the HPC.(ABSTRACT TRUNCATED AT 400 WORDS)

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Modulation of enantioselective metabolism and inversion of ibuprofen by xenobiotics in isolated rat hepatocytes.

Xiaotao Q, Hall SD.

Department of Medicine, Indiana University School of Medicine, Indianapolis.

R-ibuprofen undergoes chiral inversion by the formation of a coenzyme A (CoA) thioester and subsequent epimerization and hydrolysis. Using isolated rat hepatocytes, the interaction of xenobiotics with the inversion and oxidation pathways of ibuprofen enantiomers was determined from the time course of R- and S-ibuprofen and ibuprofenyl-CoA during 4-hr incubations with R- or S-ibuprofen (25 microM). By fitting a first-order model, the rate constants of the formation of ibuprofenyl-CoA (K12), oxidation of R-ibuprofen (K10), hydrolysis of ibuprofenyl-CoA (K21) and oxidation of S-ibuprofen (K30) were 1.306, 0.284, 6.858 and 0.496 hr-1, respectively. The fractional inversion of R-ibuprofen was 0.75 and the area under the curve for ibuprofenyl-CoA was 203.8 microM min. Coincubation with 50 microM of the cytochrome P450 inhibitors metyrapone and proadifen resulted in significant reductions of K10 and K30; the fractional inversion of R-ibuprofen increased to 116% and 127% and the area under the curve of ibuprofenyl-CoA to 145% and 144% of controls, respectively. Valproic acid and pivalic acid at 50 microM significantly reduced the K12 and increased the K21; the fractional inversion was unchanged but the area under the curve of ibuprofenyl-CoA was significantly reduced to 57% and 28% of controls, respectively. Valproic acid also significantly reduced K10 and K30. p-nitrobenzoic acid at 50 microM significantly increased K21 and reduced the area under the curve of ibuprofenyl-CoA to 44% of control but did not influence the fractional inversion. Selective inhibitors of ibuprofen oxidation were found to enhance significantly hepatocellular exposure to the potentially reactive ibuprofenyl-CoA intermediate.

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A 13C NMR study on ibuprofen metabolism in isolated rat liver mitochondria.

Shieh WR, Gou DM, Liu YC, Chen CS, Chen CY.

Department of Pharmacognosy and Environmental Health Sciences, College of Pharmacy, University of Rhode Island, Kingston 02881.

A 13C NMR approach was taken to study the biotransformation of (R)- and (S)-[2-13C,2-2H]ibuprofen-CoA in isolated rat liver mitochondria. The 13C chemical shift induced by 2H substitution for the C-2 of [2-13C,2-2H]-ibuprofen-CoA is about 0.5 ppm relative to the corresponding 1H-bearing thioester. The C-2 resonances for [2-13C]- and [2-13C,2-2H]ibuprofen-CoA are 5 ppm downfield with respect to their acid counterparts. Consequently, this technique permits real time analyses of the metabolic fate of the doubly labeled substrate in a quantitative manner. The initial rate of the epimerization of (S)-[2-13C,2-2H]ibuprofen-CoA relative to the (R)-counterpart by intact mitochondria was estimated to be 1.5, which is in line with the equilibrium constant determined with the purified epimerase. Contrary to the reports by other groups, this 13C NMR study did not find spontaneous hydrolysis of the CoA-thioester upon being exposed to intact mitochondria. Current focus of this investigation is to extend this NMR methodology to the levels of whole cells and live animals to gain a better understanding of the enantioselective metabolism of ibuprofen.

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Ibuprofen treatment of endotoxin-induced mastitis in cows.

DeGraves FJ, Anderson KL.

Department of Large Animal Surgery and Medicine, College of Veterinary Medicine, Auburn University, AL 36849.

Ibuprofen treatment was compared with saline solution treatment in an endotoxin-induced experimental model of bovine mastitis. Acute mastitis was induced in healthy lactating Holstein cows (n = 12) by intramammary inoculation of 1 mg of Escherichia coli 026:B6 lipopolysaccharide in a single quarter per cow. Cows were assigned at random to ibuprofen (25 mg/kg of body weight, IV, n = 6) or 0.9% sodium chloride solution control (1.25 ml/kg, IV, n = 6) treatment groups. Ibuprofen or saline solution was administered once, 2 hours after endotoxin administration. The clinical course of endotoxin-induced mastitis and hematologic, clinical biochemical, and plasma mineral changes were monitored and compared between ibuprofen-treated and control cows. Clinical monitoring and blood sample collection were performed at 0, 2, 4, 6, 8, 12, 24, 48, 96, and 192 hours after endotoxin challenge. Rectal temperature and heart and respiratory rates were significantly (P < or = 0.05) increased in saline treated cows, compared with cows treated with ibuprofen. Blood eosinophil count and serum phosphorus, sodium, and total carbon dioxide concentrations were significantly (P < or = 0.05) decreased in saline-treated cows, compared with cows treated with ibuprofen. Ibuprofen treatment did not significantly change ruminations per minute, electrical conductivity of milk, quarter size, or quarter inflammation. The remaining hematologic, serum biochemical, plasma mineral, and coagulation values also were not changed significantly in response to ibuprofen treatment. Untoward effects attributed to ibuprofen administration were not observed. These results indicate that ibuprofen may provide empiric relief of clinical signs of coliform-induced mastitis.

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Pharmacokinetics of ibuprofen in lactating dairy cows.

DeGraves FJ, Anderson KL, Aucoin DP.

Department of Large Animal Surgery and Medicine, College of Veterinary Medicine, Auburn University, AL 36849.

The pharmacokinetics of ibuprofen were studied in 6 adult lactating dairy cows after a single IV or oral administration of ibuprofen (25 mg/kg of body weight). Ibuprofen concentrations in milk and serum were analyzed by use of high-performance liquid chromatography. The lower limit of detection of the ibuprofen assay was 50 ng/ml. Serum ibuprofen concentration-time curves after IV administration best fit an open two-compartment model. Harmonic mean volume of distribution at steady state was 0.14 (range, 0.12 to 0.17) L/kg, elimination half-life was 1.55 (range, 1.33 to 1.73) hours, and total clearance was 86.2 (range, 68.8 to 106.2) ml/kg/h. Harmonic mean oral bioavailability was 99% (range, 79 to 112). Adverse effects were not observed in cows given ibuprofen.

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Effect of ibuprofen on the inflammatory response to surgical wounds.

Dong YL, Fleming RY, Yan TZ, Herndon DN, Waymack JP.

Shriners Burns Institute, Galveston Unit, TX 77555-1220.

Patients suffering severe trauma frequently become immunosuppressed following injury. This can predispose patients to infectious sequelae. Biochemically, these patients synthesize excessive quantities of cyclooxygenase products (prostaglandins). It has been hypothesized that the prostaglandins cause the immunosuppression and that inhibition of the cyclooxygenase enzyme could thus prevent the immunosuppression. We investigated the effect of the cyclooxygenase inhibitor ibuprofen on the inflammatory response. Rats were subjected to a 30% total body surface area burn and were administered either ibuprofen for a period of 7 days or 14 days, or were administered the carrier for 14 days. The rats were then killed and multiple immunologic variables were measured. Ibuprofen was found to decrease neutrophil chemiluminescence, lymphocyte blastogenesis, and helper/inducer T-lymphocyte infiltration of a sponge matrix model. The same ibuprofen protocol decreased survival in a cecal ligation and puncture model. In conclusion, the cyclooxygenase enzyme system appears to produce metabolites essential for optimal survival following traumatic injury.

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