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Effect of ibuprofen on monocyte activation by liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (CGP 19835A): can ibuprofen reduce fever and chills without compromising immune stimulation?

Fujimaki W, Griffin JR, Kleinerman ES.

Department of Cell Biology (HMB 173), University of Texas M. D. Anderson Cancer Center, Houston 77030.

The purpose of this study was to determine the effects of ibuprofen on the ability of liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) to activate human blood monocytes in vitro. We undertook these experiments because the major toxic side-effects following L-MTP-PE infusion, fever and chills, could be prevented when ibuprofen was given orally immediately before L-MTP-PE infusion. It was therefore important to determine whether ibuprofen interfered with the macrophage-activation properties of L-MTP-PE. Peripheral blood monocytes were isolated from normal donors, then incubated with L-MTP-PE in the presence or absence of ibuprofen. The cytotoxic properties of the monocytes were assessed by a radioisotope-release assay against A375 cells. Ibuprofen at dose levels of 40 micrograms/ml suppressed the generation of the cytotoxic phenotype but did not interfere with the killing process once the cells were activated. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) production, as well as the mRNA expression of these cytokines, was suppressed by 40 micrograms/ml ibuprofen. Since IL-1 and TNF play a crucial role in the cytotoxic function of monocytes, these findings may explain the mechanism by which ibuprofen inhibited the generation of the cytotoxic phenotype by L-MTP-PE. By contrast, ibuprofen dose levels up to 10 micrograms/ml had no effect on the generation of monocyte-mediated cytotoxicity by L-MTP-PE and no effect on the production, secretion, or mRNA expression of TNF and IL-1. Therefore, we concluded that if ibuprofen is to be used to control the side-effects of L-MTP-PE, blood levels of up to 10 micrograms/ml are desirable. In two of three patients, we determined that an oral dose of 200 mg given immediately before L-MTP-PE infusion could achieve these desired blood levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8422667&dopt=Abstract ibuprofen Motrin



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Induction of peroxisomal beta-oxidation by nonsteroidal anti-inflammatory drugs.

Foxworthy PS, Perry DN, Eacho PI.

Lilly Research Laboratory, Eli Lilly and Company, Greenfield, Indiana 46140.

Several chemical and pharmacologic agents have been identified as peroxisome proliferators in rodents. Most of these compounds contain a lipophilic backbone linked to an acid moiety, generally a carboxylate. Since ibuprofen and other nonsteroidal anti-inflammatory drugs share these structural characteristics, their effects on peroxisomal beta-oxidation were examined. Ibuprofen, flurbiprofen, and indomethacin caused dose-related increases in peroxisomal beta-oxidation in cultured rat hepatocytes. The dose-response for ibuprofen and flurbiprofen was roughly equivalent to that of clofibric acid, whereas indomethacin was less active. Ibuprofen and flurbiprofen are arylpropionic acids, which are structurally similar to the aryloxyisobutyric acid clofibric acid. Indomethacin differs structurally in that the acid substitution is on an indole ring. This structural difference may be responsible for the difference in activity. Ibuprofen and clofibric acid were also compared in vivo following 2-week dietary administration to rats. Ibuprofen increased relative liver weight and peroxisomal beta-oxidation and reduced serum lipids. Clofibric acid was more active than ibuprofen in vivo, particularly with respect to induction of peroxisomal beta-oxidation (16.8-fold vs 3-fold, respectively). The difference in activity of the two compounds in vivo was not consistent with the results in vitro. The disparity in peroxisomal activity of ibuprofen in the two test systems may be related to pharmacokinetic factors which are not present in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8442005&dopt=Abstract ibuprofen Motrin



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Lack of presystemic inversion of (R)- to (S)-ibuprofen in humans.

Hall SD, Rudy AC, Knight PM, Brater DC.

Department of Medicine, Indiana University School of Medicine, Wishard Memorial Hospital, Indianapolis 46202.

Presystemic inversion of (R)- to (S)-ibuprofen has been proposed but not directly examined in humans. We investigated the bioavailability of the enantiomers of ibuprofen in 10 healthy volunteers. Low-dose racemic ibuprofen (400 mg) was administered orally and intravenously (60-minute infusion), in random order. There were no significant differences between oral and intravenous doses for the area under the curve values, terminal rate constants, clearances, metabolite formation clearances, and serum protein binding for (R)- and (S)-ibuprofen. The bioavailabilities of (R)-ibuprofen and total ibuprofen were 0.92 +/- 0.11 and 0.95 +/- 0.08, respectively. The fractional inversion of (R)-ibuprofen was determined by two methods (stable isotope method and from the stereochemical composition of the urinary metabolites) that gave similar estimates of inversion for oral dosing (0.56 +/- 0.12 and 0.60 +/- 0.07, respectively) and intravenous dosing (0.56 +/- 0.09 and 0.60 +/- 0.06, respectively). We conclude that the bioavailability of both enantiomers of ibuprofen is complete and find no evidence of significant presystemic inversion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8477555&dopt=Abstract ibuprofen Motrin



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Effectiveness of dual cyclooxygense and leukotriene blockade with ibuprofen and LY203647 during canine endotoxic shock.

Passmore JC, Jimenez AE.

Department of Physiology and Biophysics, School of Medicine, University of Louisville, Kentucky 40292.

Ibuprofen and the leukotriene antagonist, LY203647, were used to evaluate the effectiveness of LY203647 in the dual blockade of cyclooxygenase and leukotriene to maintain hemodynamic parameters in endotoxemia. Ibuprofen pretreatment alone or dual blockade (ibuprofen plus LY203647) protected blood pressure and renal blood flow at 1 and 3 hr after endotoxin infusion. Cardiac output at 1 hr after endotoxin in dogs treated with ibuprofen was slightly but significantly decreased. Dual pretreatment prevented this decrease at 1 hr; however, cardiac output was similar in both groups by 3 hr. Dual blockade administered after endotoxin induced increases in blood pressure and cardiac output at 3 hr. LY203647 pretreatment alone did not prevent the postendotoxemic declines in any measured parameters. The increased plasma SGOT and lactate of endotoxemia were exacerbated by LY203647 and blunted by ibuprofen treatment. We conclude that the addition of LY203647 to ibuprofen treatment offers no additional significant protection of hemodynamic parameters.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8481974&dopt=Abstract ibuprofen Motrin



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Hemodynamic responses to changes in carotid sinus pressure after endotoxin and ibuprofen.

Abel FL, Bond RF, Augustine SD.

Department of Physiology, University of South Carolina School of Medicine, Columbia 29208.

The hemodynamic responses to changes in carotid sinus pressure (CSP) were evaluated in nine pentobarbital-anesthetized dogs during control, endotoxin-treatment, and ibuprofen (after endotoxin) treatment periods. Both carotid sinuses were isolated and perfused at varying pressures with oxygenated blood in the vagotomized animal. Alterations in carotid sinus pressure and the resultant responses were measured at 15-min intervals during a 30-min control period, for 60 min after 1 mg/kg endotoxin, and for 60 min after 10 mg/kg ibuprofen given after endotoxin. The results showed a reduction in calculated gain for mean arterial pressure (MAP) (change in arterial pressure/change in CSP), heart rate, and peripheral resistance (TPR) after endotoxin, without a corresponding reduction in cardiac output (CO) gain. These gain changes were accompanied by a decrease in absolute MAP, CO, and TPR. An indicator for cardiac performance gain also increased. Relatively, arterial pressure was partially maintained by an increase in CO despite a loss in ability to vasoconstrict. Ibuprofen failed to correct the MAP gain, and only partially restored MAP, but shifted a greater relative response to peripheral resistance. To test if TPR would also decrease if the decrease in CO was prevented, three additional animals were studied with a pump in series with the heart to maintain CO; TPR again dropped after endotoxin. The results indicate a loss of peripheral arterial tone after endotoxin, partially restored by ibuprofen. The CO response indicates a peripheral vascular failure rather than a central or carotid sinus failure mechanism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8481978&dopt=Abstract ibuprofen Motrin



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[Efforts toward the formulation of the therapeutic stereoisomer of ibuprofen]

[Article in French]

Romero AJ, Rhodes CT.

Universite de Rhode Island, Faculte de Pharmacie, Departement de Pharmacie Galenique et Biopharmacie, Kingston 02881.

In an on going effort to optimize ibuprofen antiinflammatory therapy, development studies on the active stereoisomer of ibuprofen have been conducted. The effects of pharmaceutical processing on the racemate (RAC-ibuprofen) and the enantiomer (S(+)-ibuprofen) were investigated. The formulation of the new stereospecific system, was impossible using wet granulation. The pharmaceutical development of S(+)-ibuprofen using direct compression appeared as a practical solution to this problem. The biopharmaceutical properties of the resulting tablets were well within pharmacopeia requirements. Nevertheless, mixing S(+)-ibuprofen with the excipients induced a drop in the enthalpy of fusion and after compaction, a low temperature eutectic appeared on the differential scanning calorimetry endotherms. Aging studies indicated that the raw material and pharmaceutical mixtures of S(+)-ibuprofen should be stored under strictly controlled conditions or processed immediately.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8483097&dopt=Abstract ibuprofen Motrin



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Direct determination of ibuprofen and ibuprofen acyl glucuronide in plasma by high-performance liquid chromatography using solid-phase extraction.

Castillo M, Smith PC.

College of Pharmacy, University of Texas, Austin 78712.

A method for the simultaneous determination of ibuprofen and its labile, reactive metabolite, ibuprofen acyl glucuronide, in plasma is described. Reversed-phase high-performance liquid chromatography (HPLC) employed a C18 column using methanol-10 mM trifluoroacetic acid as the mobile phase with ultraviolet detection at 225 or 214 nm. It is essential that blood is handled rapidly and plasma is acidified upon collection prior to freezing. Plasma samples first are deproteinated with acetonitrile, the supernatant is diluted with phosphate buffer, and ibuprofen, ibuprofen glucuronide, and ibufenac (internal standard) are initially isolated by solid-phase extraction on C18 cartridges. Upon elution, the residue is evaporated, dissolved and injected onto the HPLC system. Recovery is 94 +/- 8 and 70 +/- 9% for ibuprofen glucuronide and ibuprofen, respectively. The measurable concentration range is linear from 0.1 to 10 micrograms/ml for ibuprofen glucuronide and from 0.5 to 100 micrograms/ml for ibuprofen. The method is satisfactory for the analysis of ibuprofen and ibuprofen glucuronide from pharmacokinetic studies in humans. The direct determination of ibuprofen glucuronide allows accurate measurement of this conjugate at low levels relative to the parent compound, ibuprofen, a distinct advantage compared to previously employed indirect methods.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8496270&dopt=Abstract ibuprofen Motrin



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Pharmacokinetics of ibuprofen in lactating dairy goats.

DeGraves FJ, Anderson KL, Aucoin DP.

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

Pharmacokinetic variables of ibuprofen were studied in 6 adult lactating dairy goats after single administration of the drug (14 and 25 mg/kg of body weight, IV, and 50 and 100 mg/kg, PO). Each of the goats was given all doses, with a minimum of 1 week between doses. Ibuprofen concentration in serum was analyzed by use of high-performance liquid chromatography. The lower limit of detection for the ibuprofen assay was 50 ng/ml. Ibuprofen pharmacokinetic variables after IV administration best fit an open two-compartment model. Geometric mean (range) volume of distribution at steady state was 0.16 (0.11 to 0.19) and 0.17 (0.15 to 0.19) L/kg, and terminal half-life was 1.08 (0.79 to 1.70) and 1.27 (1.03 to 1.88) hours, for ibuprofen dosages of 14 and 25 mg/kg, respectively. After 50 and 100 mg/kg administered orally, bioavailability was 90.8 and 106%, respectively. Area under the curve increased linearly with dose administered. Adverse effects were not observed in goats given ibuprofen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8498749&dopt=Abstract ibuprofen Motrin