Motrin
Effects of ibuprofen and hypoxia on neutrophil apoptosis in neonates.

Hanna N, Graboski S, Laskin DL, Weinberger B.

Division of Neonatology, Department of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08903, USA.

BACKGROUND: Ibuprofen is a cyclooxygenase inhibitor that is effective in treating patent ductus arteriosus in preterm infants. However, recent trials have suggested that it may increase the risk of developing necrotizing enterocolitis and chronic lung disease. Apoptosis of neutrophils is impaired in newborns, leading to reduced clearance of activated cells and possibly contributing to the susceptibility of infants to these inflammatory diseases. OBJECTIVES: In the present studies, we investigated the hypothesis that ibuprofen reduces neonatal neutrophil apoptosis in the setting of hypoxia or lipopolysaccharide (LPS). METHODS: Neutrophils and peripheral blood mononuclear cells were isolated from adult and cord blood and cultured in the presence or absence of ibuprofen (1.5 mM), hypoxia (<5% O2), and bacterial LPS (100 ng/ml). Apoptosis was quantified by measuring binding of FITC-Annexin V using flow cytometry. Cytokine concentrations in cell supernatants were measured by ELISA. RESULTS: After 24 h, 20% of adult and 14% of neonatal neutrophils were apoptotic. Apoptosis was reduced by hypoxia in both adult and neonatal cells. Ibuprofen further reduced neutrophil apoptosis, but only when the cells were cultured in the presence of mixed leukocytes. This suggests that the effects of ibuprofen on apoptosis are dependent on soluble products secreted by peripheral blood mononuclear cells. We found that production of tumor necrosis factor (TNF)-alpha by neonatal leukocytes was significantly increased by ibuprofen, and was further increased following exposure to ibuprofen in the presence of LPS and hypoxia. In contrast, production of macrophage inflammatory protein (MIP)-1alpha was not affected by treatment with ibuprofen, and ibuprofen blocked induction of this chemokine by LPS. CONCLUSION: We conclude that the net effect of ibuprofen on neutrophils is antiapoptotic, especially in the presence of hypoxia or LPS. This effect may be mediated, in part, by increased production of TNF-alpha by peripheral blood mononuclear cells. These data suggest that treatment of infants with ibuprofen, in the presence of infection and/or tissue hypoperfusion/hypoxia, may contribute to the development of inflammatory diseases. 2004 S. Karger AG, Basel.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15263833&dopt=Abstract ibuprofen Motrin



Motrin
Renal effects of intermittent versus continuous infusion of ibuprofen in the primate.

Rao PS, Cavanagh D, Dietz JR.

Department of Obstetrics and Gynecology, University of South Florida College of Medicine, Tampa 33612.

The clinical use of nonsteroidal anti-inflammatory drugs is gaining wide acceptance and acute oliguric renal failure in association with the administration of ibuprofen has been reported. This study was designed to evaluate the renal effects of intermittent versus continuous intravenous infusion of ibuprofen (Motrin) over a 24-h period in the anesthetized non-pregnant baboon. A total of 50 mg/kg of ibuprofen was either infused continuously or given as a bolus in four divided doses (intermittent). Control animals received only normal saline. Mean aortic pressure showed a tendency to decrease with time in all groups studied with a significant decrease occurring in the infusion group. There were no significant changes in the renal artery flow, renal resistance, central venous pressure and heart rate within the groups. Serum urea nitrogen decreased and was significantly different from the baseline value at 24 h in the infusion group. Serum creatinine, however, showed no such changes. Although, urinary output and creatinine clearance showed a tendency to decrease in the treated groups, it was not significantly different. Plasma renin activity decreased from 9.95 to 2.3 ng/ml/hr in the control group but showed no significant changes in others. Serum levels of angiotensin converting enzyme were well maintained. The circulating levels of ibuprofen reached a steady state after 2 h in the infusion group. The results of this study demonstrate that continuous infusion of ibuprofen does not possess an advantage over its intermittent administration. Despite the modifications we have observed in renal flow and function, this drug appears to be safe in the dose levels we have used in these experiments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7846093&dopt=Abstract ibuprofen Motrin



Motrin
Experimental determination of a drug targeting index for S(+)ibuprofen using the rat air pouch model of inflammation.

Stevens AJ, Martin SW, Brennan BS, Rowland M, Houston JB.

Department of Pharmacy, University of Manchester, U.K.

We have used the rat air pouch model of inflammation and S(+)ibuprofen as an experimental model system to enable the quantitative assessment of the pharmacokinetic determinants of site specific drug delivery. S(+)ibuprofen (50 & 1mg/kg) was administered directly into six day old air pouches immediately following the injection of the irritant carrageenan. Serial exudate and plasma samples were collected and analysed for ibuprofen by HPLC. The procedure was repeated following administration of S(+)ibuprofen (20 & 5mg/kg) intravenously. The parameters describing events in the air pouch and plasma indicated linear kinetics over the doses employed. The dose normalised AUCs were then used to formulate a quantitative measure of benefit for S(+)ibuprofen delivered directly to the air pouch. A Drug Targeting Index (DTI) was calculated from the ratio of AUC in the air pouch and plasma following direct intrapouch administration divided by the same ratio following intravenous administration and gave a value of 130. This pharmacokinetic measure of benefit represents the maximum advantage afforded by the site specific delivery of S(+)ibuprofen as the whole of the administered dose is delivered directly to the site of action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7858958&dopt=Abstract ibuprofen Motrin



Motrin
Selective inhibition of fatty acid oxidation in colonocytes by ibuprofen: a cause of colitis?

Roediger WE, Millard S.

Department of Surgery, Queen Elizabeth Hospital, Adelaide, Australia.

Ibuprofen is associated with initiation or exacerbation of ulcerative colitis. As ibuprofen selectively inhibited fatty acid oxidation in the liver or caused mitochondrial damage in intestinal cells, its effect on substrate oxidation by isolated colonocytes of man and rat was examined. Ibuprofen dose dependently (2.0-7.5 mmol/l) and selectively inhibited 14CO2 production from labelled n-butyrate in colonocytes from the proximal and distal human colon (n = 12, p = < 0.001). Glucose oxidation was either unaltered or increased. Because short chain fatty acid oxidation is the main source of acetyl-CoA for long chain fatty acid synthesis, the inhibition of prostaglandin synthesis by ibuprofen in the colonic mucosa could also occur at this level. Because the concentrations of ibuprofen that can be attained in the human colon are not known, conclusions drawn from current dosages are tentative. The inhibition of fatty acid oxidation by ibuprofen may be biochemically implicated in the initiation and exacerbation of ulcerative colitis, manifestation of which would depend on the ibuprofen concentrations reached in the colon.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7890237&dopt=Abstract ibuprofen Motrin



Motrin
Influence of ibuprofen on the infection with Listeria monocytogenes.

Hockertz S, Heckenberger R, Emmendorffer A, Muller M.

Fraunhofer Institute for Toxicology, Department of Immunology, Hannover, Fed. Rep. of Germany.

Listeria monocytogenes is a bacterial infection, which is facultatively localized in monocytes and macrophages. The influence of ibuprofen (CAS 15687-27-1), a nonsteroidal anti-inflammatory drug (NSAID), on this bacterial infection in balb/c mice was investigated. One day prior to sublethal infection, balb/c mice were treated intravenously with various therapeutic concentrations of ibuprofen alone or ibuprofen in combination with a suboptimal dosage of murine recombinant interferon gamma, a lymphokine produced by T-helper cells. Three days post-infection, parasite burdens of the mainly infected organs, spleen and liver, were determined by the colony-forming unit assay. It was shown that the prophylactic treatment with ibuprofen in a concentration of 4 mg/kg body weight resulted in a more than 10-fold reduction of viable Listeria monocytogenes in the spleen, whereas in liver 12 mg/kg Ibuprofen was necessary for a comparable kill of viable bacteria. A higher concentration of ibuprofen did not resulted in a higher antibacterial efficacy. In order to clarify the mechanism of ibuprofen action, molecular-biological experiments were performed to measure the messenger RNA (mRNA) induced by ibuprofen. It is presented here that therapeutic concentrations of ibuprofen induced significant higher amounts of mRNA for interleukin-1 in human monocytes compared to untreated cells. These findings support the hypothesis that ibuprofen influences the complex immune system to overcome a bacterial infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7893261&dopt=Abstract ibuprofen Motrin



Motrin
Effect of hydrophilic and lipophilic vehicles on skin permeation of tegafur, alclofenac and ibuprofen with or without permeation enhancers.

Lee CK, Uchida T, Kitagawa K, Yagi A, Kim NS, Goto S.

Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

The effects of an ethanol/panasate 800 (tricaprylin) (40/60) system as a lipophilic vehicle, and an ethanol/water (60/40) system as a hydrophilic vehicle, with or without permeation enhancers for in vitro skin permeation and in vivo skin absorption of tegafur, alclofenac and ibuprofen with different lipophilicity, were evaluated. The in vitro and in vivo skin permeability of tegafur, alclofenac and ibuprofen was enhanced by the use of ethanol/panasate 800 (40/60) or ethanol/water (60/40) binary vehicles as a donor composition. However, the two vehicles showed contrastive properties in relation to the extent of permeation enhancement of the three drugs: tegafur > alclofenac > ibuprofen for the ethanol/panasate 800 (40/60) system, and ibuprofen > or = alclofenac > tegafur for the ethanol/water (60/40) system. When lauric acid, as a permeation enhancer, was added to both of the binary vehicles, the in vitro and in vivo skin permeability of three drugs further increased, and the in vivo absorption rate of the drugs from the ethanol/water (60/40) system was larger than that from the ethanol/panasate 800 (40/60) system. In conclusion, it was suggested that the ethanol/panasate 800 (40/60) lipophilic binary vehicle is useful for hydrophilic drugs, and conversely, the skin absorption of lipophilic drugs can be improved by the use of the ethanol/water (60/40) hydrophilic binary vehicle with or without lauric acid as a permeation enhancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7907514&dopt=Abstract ibuprofen Motrin



Motrin
Development and validation of a liquid chromatographic method for the quantitation of ibuprofen enantiomers in human plasma.

Naidong W, Lee JW.

Harris Laboratories Inc., Lincoln, NE 68501.

A method for the quantitation of ibuprofen enantiomers in human plasma has been developed and validated. Separation of R- and S-ibuprofen was achieved on a silica-bonded beta-cyclodextrin column with a mobile phase of acetonitrile-0.02% (v/v) triethylamine in water adjusted to pH 4.0 with glacial acetic acid in water (60:40, v/v). The UV detection was performed at 220 nm. The established linearity range was 1-25 micrograms ml-1 (r > 0.99). The limit of quantitation was designed as 1 microgram ml-1 for each enantiomer. Interday precision and accuracy for the standards were 2.2-5.9% relative standard deviation (RSD) and -2.9(-)+3.5% relative error for R-ibuprofen, and 1.9-6.3% RSD and -7.1(-)+4.4% relative error for S-ibuprofen. Interday precision and accuracy for quality controls at 2.5, 7.5 and 17.5 micrograms ml-1 were 6.1-6.4% RSD and -1.4(-)+0.8% relative error for R-ibuprofen, and 5.7-5.9% RSD and -1.2(-)+2.8% relative error for S-ibuprofen. p-Isopropylbenzoic acid was used as an internal standard. The run time was 26 min. Interference from various lots of human plasma were not observed. Stability results of on-system, re-injection, bench-top, freeze-thaw cycles and sample storage were established.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7918771&dopt=Abstract ibuprofen Motrin



Motrin
Assessment of ibuprofen-associated nephrotoxicity in renal dysfunction.

Chen CY, Pang VF, Chen CS.

Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Republic of China.

Ibuprofen-incurred nephrotoxicity in renal insufficiency was assessed by examining renal functional and pathological changes in rabbits with pre-existing renal failure after receiving consecutive doses of ibuprofen. The pharmacokinetic behavior of ibuprofen enantiomers in rabbits with renal dysfunction appeared to qualitatively parallel that of their human counterparts. Modifications of the pharmacokinetic profile occurred in a stereoselective fashion: (R)-ibuprofen disposition was independent of renal conditions, whereas (S)-ibuprofen clearance was significantly hampered. Pathological damage associated with ibuprofen use in renal dysfunction was evident from the renal necropsy specimens, which was characterized by tubular necrosis and interstitial nephritis. This animal model study indicates clearly that renal insufficiency is a causative factor for ibuprofen-induced interstitial nephritis. Moreover, based on the evidence of interstitial lymphocytic infiltration, this nephrotoxic syndrome is assumed to be a manifestation of a disordered cellular immunity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7932183&dopt=Abstract ibuprofen Motrin