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Cyclooxygenase inhibition reduces placental transfer: reversal by carbacyclin.

Kuhn DC, Stuart MJ.

The effect of the cyclooxygenase inhibitors, indomethacin and ibuprofen, on diffusional transfer in the human placenta was assessed with the dual-perfused isolated placental lobe. Antipyrine, a freely diffusible substance, was used as an indicator of placental transfer efficiency. Each inhibitor (100 mumol/L) was perfused for 30 minutes after a baseline period, resulting in a significant reduction in antipyrine clearance. During a subsequent washout period, ibuprofen-inhibited antipyrine clearance returned to baseline values, whereas indomethacin-inhibited clearance remained reduced. An additional 30 minutes perfusion of 500 mumol/L of ibuprofen resulted in a further reduction in antipyrine clearance compared with 100 mumol/L of ibuprofen, suggesting a dosage-related effect. The perfusion of each inhibitor caused a reduced production of 6-keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin) in the fetal circulation. The simultaneous perfusion of carbacyclin, a prostacyclin analogue, at 100 nmol/L and 1 mumol/L resulted in a dosage-dependent reversal of the effects of ibuprofen (500 mumol/L) on antipyrine clearance. The results indicate that the inhibition of cyclooxygenase activity reduces placental transfer and that the effects of these inhibitors are reversed by carbacyclin. This study suggests that the use of cyclooxygenase inhibitors during pregnancy could compromise the developing fetus by reducing placental transfer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3111263&dopt=Abstract ibuprofen Motrin



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Successful treatment of adult respiratory distress syndrome by histamine and prostaglandin blockade in a porcine Pseudomonas model.

Sielaff TD, Sugerman HJ, Tatum JL, Blocher CR.

Porcine Pseudomonas adult respiratory distress syndrome (ARDS) has been shown to respond to combination therapy of 150 mg of cimetidine, 12.5 mg/kg of ibuprofen, 10 mg/kg of diphenhydramine, 0.2 mg/kg of ketanserin, and 30 mg/kg of methylprednisolone (CIDKM or Poly-5) given at 20 and 120 minutes after the onset of a continuous infusion of liver Pseudomonas aeruginosa, 5 X 10(8) colony-forming units (CFU) ml at 0.3 ml/20 kg/min. The present study was designed to determine the minimal, effective therapy by selective deletion of individual agents from CIDKM. Eight groups were studied: saline control (S, n = 9), Pseudomonas control (P, n = 8), and the following Pseudomonas plus treatment groups (each n = 5): CIDKM (cimetidine, ibuprofen, diphenhydramine, and ketanserin), CID (cimetidine, ibuprofen, and diphenhydramine), IC (ibuprofen and cimetidine), ID (ibuprofen and diphenhydramine), and CD (cimetidine and diphenhydramine). Pseudomonas alone produced severe ARDS with significant (p less than .05) decreases in PAO2 cardiac index, and systemic arterial pressure and significant increases in pulmonary artery pressure, extravascular lung water (EVLW) and scintigraphically determined pulmonary albumin flux measured as slope index (SI). Full therapy, CIDKM or Poly-5, showed significant improvement in all parameters. Deletion of methylprednisolone did not significantly effect any parameter measured. The deletion of ketanserin, leaving CID, did not alter treatment efficacy, except for a significant decline in cardiac index at 3 hours. Deletion of ibuprofen from CID resulted in a failure to reverse pulmonary arterial hypertension, hypoxemia, elevated EVLW, and increased SI. Removal of either cimetidine or diphenhydramine from CID resulted in significant increases in EVLW compared with control levels and SI compared with both control levels and CID. These results indicate that a combination of both histamine H1 and H2 receptor blockers and the cyclooxygenase inhibitor, ibuprofen, is effective and essential in the treatment of hypoxemia, early pulmonary hypertension, and pulmonary microvascular injury in this fulminant model of porcine Pseudomonas ARDS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3112984&dopt=Abstract ibuprofen Motrin



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Bioavailability of two dermal formulations of S(+)ibuprofen in rabbit.

Gonzalez-Penas E, Echeverria HC, Mosquera J, Esteras A, Bruseghini L.

Departamento de Quimica Organica y Farmaceutica, Facultad de Farmacia, Universidad de Navarra, Navarra, Spain. mgpenas unav.es

Ibuprofen (CAS 15687-27-1) is widely used in painful situations and, usually, is administered in the racemic form. Since enantiomers may exert different pharmacodinamic and pharmacokinetic effects, the pharmaceutical industry has placed new emphasis on the preparation of new formulations of enantiomerically pure drugs that must be pharmacokinetically characterised prior to their administration in human beings. In this study, the absorption kinetics of two topical formulations of S(+)ibuprofen in rabbits was investigated. The S(+)ibuprofen levels in rabbit plasma were determined by a non-chiral HPLC method, whereas the absence of the R(-)ibuprofen enantiomer in plasma was confirmed by a chiral HPLC method. The results showed that S(+)ibuprofen was absorbed through the rabbit skin upon administration and the obtained levels varied with the formulation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14677375&dopt=Abstract ibuprofen Motrin



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Effect of nitroglycerin and ibuprofen on left ventricular topography and rupture threshold during healing after myocardial infarction in the dog.

Jugdutt BI.

Department of Medicine, University of Alberta, Edmonton, Canada.

The effect of nitroglycerin and ibuprofen, given between 2 and 7 days after left anterior descending coronary artery ligation, on the mechanical resistance of the infarcted left ventricle to rupture or the rupture threshold (balloon technique), and on topography (computerized planimetry) and function (two-dimensional echocardiography) at 7 days (n = 32) and 42 days (n = 34) postligation was studied in 66 dogs randomly allocated to sham (no infarction, n = 22) and infarction subgroups (15 controls; 15 received nitroglycerin, 30 mg oral isosorbide dinitrate b.i.d.; 14 received ibuprofen, 200 mg t.i.d. orally). Nitroglycerin decreased mean arterial and left atrial pressures, decreased diastolic cross-sectional area, and improved systolic function, while ibuprofen increased diastolic area. Infarction subgroups showed infarct shrinkage and more infarct hydroxyproline at 6 weeks. Compared with shams, all infarct subgroups showed early expansion and thinning, with further marked late thinning in controls. Nitroglycerin produced less expansion and thinning both at 1 and 6 weeks, while ibuprofen produced marked early thinning. Rupture threshold was less at 6 weeks than 1 week with controls and ibuprofen but remained unchanged with nitroglycerin. Passive prerupture stiffness was less at 6 weeks than at 1 week in controls but remained unchanged with nitroglycerin and ibuprofen. Thus, reduced expansion and thinning with nitroglycerin during the first week after infarction improved function, mechanical strength, and resistance to distension at 6 weeks.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3139268&dopt=Abstract ibuprofen Motrin



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Role of polymorphonuclear leukocytes in hyperoxic lung injury. Prevention of neutrophil influx into the lung endothelium during oxygen exposure by ibuprofen.

Das DK, Bandyopadhyay D, Hoory S, Steinberg H.

Cardiovascular Division, University of Connecticut School of Medicine, Farmington 06032.

The present study examines the role of PMN in hyperoxic lung injury using a nonsteroidal anti-inflammatory drug, ibuprofen. New Zealand white rabbits were exposed to 100% oxygen or air for 1 to 4 days. The animals were divided into two groups: the treatment group received ibuprofen with drinking water, and the control group received water alone. After exposure to oxygen or air, the rabbits were injected with indium-III-oxine labeled PMN. Influx or radioactive PMN into the lung was detected using gamma scintigraphic technique only in 72 h and 96 h oxygen-exposed animals which were not treated with ibuprofen. Ibuprofen-treated animals did not exhibit any PMN influx into the lung. Blood gas analysis of all 72 h oxygen-exposed animals did not show any abnormal values, although analysis of dry/wet weight ratios and histopathological examinations indicated noncardiogenic edema formation. After 96 h of oxygen exposure, both ibuprofen-treated and untreated groups suffered from severe acidosis. Gross cytoplasmic edema and partial destruction of lung endothelium were also observed. Mortality was 50% after 96 h of oxygen exposure. Our study, thus, demonstrates that ibuprofen cannot prevent hyperoxic lung injury although it inhibits the influx of PMN into the injured lung, suggesting that PMN are not directly involved in the injury process.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3151052&dopt=Abstract ibuprofen Motrin



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Inefficient central nervous system delivery limits the use of ibuprofen in neurodegenerative diseases.

Mannila A, Rautio J, Lehtonen M, Jarvinen T, Savolainen J.

Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. anne.mannila uku.fi

Chronic use of non-steroidal anti-inflammatory drugs may reduce the risk or delay the onset of Alzheimer's disease. To date, only limited information exists on the brain distribution of these drugs. The objective of this study was to determine the absolute brain delivery of ibuprofen by using constant in vivo infusion in rats. Ibuprofen was infused to steady-state concentrations both in plasma and brain tissue. Ibuprofen levels in plasma and brain tissue were measured by RP-HPLC after the plasma and the brain samples were purified by protein precipitation and solid phase extraction, respectively. Results indicate that both plasma and brain concentrations reached steady-state within 6h, and that the brain to plasma ratio of ibuprofen was only 0.02. Thus, limited brain penetration prevents the possible use of ibuprofen in treating or preventing neurodegenerative disorders such as Alzheimer's disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15626583&dopt=Abstract ibuprofen Motrin



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Effects of ibuprofen on neutrophil function and acute lung injury in canine endotoxin shock.

Balk RA, Jacobs RF, Tryka AF, Townsend JW, Walls RC, Bone RC.

Department of Medicine, University of Arkansas for Medical Sciences, Little Rock.

The role of the polymorphonuclear leukocyte in the development of acute lung injury has been the subject of much controversy. Experimental lung injury is associated with peripheral leukopenia and the intrapulmonary sequestration of leukocytes. We have previously shown that ibuprofen, a nonsteroidal anti-inflammatory drug, can improve the hemodynamic alterations of canine endotoxin shock. Ibuprofen has also been found to decrease leukocyte adherence. We investigated the dose response of ibuprofen on the increased neutrophil adherence and the extent of lung injury associated with canine endotoxin shock. Single doses of ibuprofen (1, 5, 10, and 20 mg/kg iv) were administered 15 min after Escherichia coli endotoxin. Endotoxemia resulted in leukopenia and an increased neutrophil adherence in both aortic and pulmonary artery blood. Endotoxin-treated animals exhibited increased neutrophils in the bronchoalveolar lavage fluid, a marker of lung injury. The 20-mg/kg ibuprofen dose decreased aortic granulocyte adherence at 30 min, while all ibuprofen doses decreased the aortic adherence at 120 min. The increased pulmonary artery neutrophil adherence was not affected by ibuprofen. Histologically, lung injury was manifested by intravascular leukostasis. Ibuprofen treatment did not affect the histologic or morphometric extent of the lung injury. The leukopenia and increased neutrophil adherence occur rapidly after endotoxemia and are associated with subsequent intravascular sequestration of leukocytes. Agents designed to prevent lung injury must either be given before the insult or be able to block the effects of the toxic products released by the activated granulocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3168505&dopt=Abstract ibuprofen Motrin



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Ibuprofen reduces the progression of permeability edema in an animal model of hyperdynamic sepsis.

Gnidec AG, Sibbald WJ, Cheung H, Metz CA.

Richard Ivey Critical Care Trauma Centre, Victoria Hospital, London, Ontario, Canada.

Since severity of acute lung injury (ALI) is reduced by pretreatment with non-steroidal agents, we hypothesized that ibuprofen would ameliorate ALI when administered after the onset of septic lung injury. Twenty-four hours after cecal ligation and perforation (CLP) in 23 sheep during a 4 h study period (period S), pulmonary lymph flow (QL) increased 16.2 +/- 12.1 ml/min (P less than 0.01) from base line, whereas lymph-to-plasma total protein concentration ratios ([L/P]TP) remained unchanged. During the subsequent 24 h of study (period D), 10 sheep received parenteral ibuprofen, 12.5 mg/kg every 6 h, and 13 sheep served as untreated septic controls. Throughout period D, a progressive increase in QL (16.2 +/- 16.3 ml/60 min) from period S was greater in the untreated than in the ibuprofen (2.5 +/- 9.0 ml/60 min, P less than 0.02) group. Between base line and period D, increase in lung wet-to-dry weight ratios was greater in the untreated group than in the ibuprofen group (P less than 0.05). Concurrently mean pulmonary arterial pressure increased 4.7 +/- 7.3 mmHg in the untreated group (P less than 0.05) during period D vs. 0.0 +/- 5.2 mmHg in the ibuprofen group (NS). When administered after septic ALI had been established by CLP, ibuprofen reduced an otherwise progressive increase in both fluid flux and extravascular lung water.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3182470&dopt=Abstract ibuprofen Motrin