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Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers.

Thai QA, Oshiro EM, Tamargo RJ.

Department of Neurosurgery, Division of Vascular Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-7713, USA.

BACKGROUND AND PURPOSE--The chronic phase of vasospasm after an aneurysmal subarachnoid hemorrhage may be mediated in part by early leukocyte-endothelial cell interactions. Ibuprofen is an anti-inflammatory agent that inhibits expression of certain cell adhesion molecules and therefore disrupts leukocyte-endothelial cell interactions. Its systemic administration, however, has dose-limiting side effects. We evaluated the effect of the periadventitial delivery of ibuprofen using controlled-release polymers in the rat femoral artery model of chronic posthemorrhagic vasospasm. METHODS--Before the animal studies, the release pharmacokinetics of the ibuprofen-loaded ethylene-vinyl acetate polymers were determined in vitro. Subsequently, the femoral arteries (n=266) of Fischer 344 rats (n=133) were enclosed in latex pouches bilaterally. In the toxicity study (n=15 rats), the animals were randomized into 5 dose groups in which 0%-, 10%-, 20%-, 30%-, or 50%-loaded ibuprofen polymers were evaluated. In the efficacy study, the animals were randomized into 5 time groups in which 50%-loaded ibuprofen polymers were inserted at 0 (n=58 rats), 6 (n=16), 12 (n=13), 24 (n=11), or 48 hours (n=12) after blood injection into the pouch. The rats were killed 12 days after blood exposure, at the time of maximal vasospasm in this model. Vasospasm was expressed as percent lumen patency. To evaluate the effect of ibuprofen on leukocyte migration, 8 rats were randomized into 2 groups. Macrophages and granulocytes were stained by immunohistochemistry with the use of a mouse OX-41 monoclonal antibody and counted in the periadventitial space 24 hours after blood exposure. RESULTS--In vitro pharmacokinetics showed that the 50%-loaded ibuprofen polymer released its total drug load over a 12-day period. In the toxicity study, a nonsignificant arterial vasodilatation with ibuprofen treatment was seen at higher doses, and no deleterious effects were noted on the vessel wall histologically. In the efficacy study, ibuprofen treatment resulted in significant vasospasm inhibition when treatment was initiated at 0 hour (73.7+/-4.9% versus 94.5+/-3.3% [mean+/-SEM percent lumen patency]; P<0.001) and 6 hours (69.2+/-5.7% versus 98.0+/-3.9%; P=0. 002) after blood exposure, but not at 12, 24, or 48 hours. Leukocyte immunohistochemistry showed that ibuprofen treatment resulted in significantly lower periadventitial macrophage and granulocyte counts of 25.0+/-3.9 cells per high-powered field compared with counts of 140.5+/-18.2 cells per high-powered field in the untreated vessels (P<0.001). CONCLUSIONS--The periadventitial, controlled release of ibuprofen from surgically implanted polymers significantly inhibits chronic posthemorrhagic vasospasm in this model when treatment is initiated within 6 hours of blood exposure. Vasospasm inhibition with ibuprofen correlates with a significant decrease in the number of macrophages and granulocytes in the periadventitial space. This study supports the hypothesis that inflammation mediates in part the chronic phase of posthemorrhagic vasospasm and suggests a potential alternative treatment for this condition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9880402&dopt=Abstract ibuprofen Motrin



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Ibuprofen: new explanation for an old phenomenon.

Stuhlmeier KM, Li H, Kao JJ.

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. kstuhlme bidmc.harvard.edu

Nuclear factor-kappaB (NF-kappaB) translocation from the cytoplasm into the nucleus and the subsequent DNA binding is an essential prerequisite in the up-regulation of many pro-inflammatory genes, e.g. tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). The anti-inflammatory drug ibuprofen, thought to exert its beneficial effects mainly by suppressing the production of eicosanoids, inhibited the up-regulation of the pro-inflammatory cytokines IL-1beta and TNF-alpha. This effect was independent of the described potential of ibuprofen as a cyclooxygenase inhibitor. Ibuprofen inhibited the activation and translocation of the key transcription factor NF-kappaB by blocking the degradation of inhibitor-kappaBalpha, a protein that forms a complex with NF-kappaB, thereby preventing the release and subsequent translocation of NF-kappaB into the nucleus and the expression of inflammatory cytokines. The presented data offer a new explanation for the anti-inflammatory effect of ibuprofen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9890559&dopt=Abstract ibuprofen Motrin



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Combined treatment with ibuprofen and the AT1 receptor antagonist candesartan in young spontaneously hypertensive rats.

Pollock DM, Morsing P.

Vascular Biology Center, Medical College of Georgia, Augusta 30912-2500, USA. DPollock mail.mcg.edu

The current study was conducted to determine the potential influence of ibuprofen on the renal and systemic response to AT1 receptor blockade in conscious rats developing spontaneous hypertension. Experiments used spontaneously hypertensive rats (SHR) during the early developmental phase of hypertension (6 to 7 wk old). Six groups of rats were given the following during a 2-wk treatment protocol: (1) candesartan cilexetil (AT1 receptor antagonist) at 1 mg/kg body wt per d; (2) candesartan cilexetil at 10 mg/kg per d; (3) ibuprofen at 30 mg/kg per d; (4) a combination of candesartan cilexetil at 1 mg/kg per d + ibuprofen; (5) candesartan cilexetil at 10 mg/kg per d + ibuprofen; and (6) untreated (controls). All compounds were added to the drinking water at concentrations adjusted to maintain the desired dosage. In the young untreated SHR, systolic arterial pressure significantly increased from 134+/-4 to 170+/-11 mmHg. Candesartan at 1 mg/kg per d prevented any increase in arterial pressure (131+/-5 mmHg at week 0 versus 131+/-4 mmHg at week 2). At a dose of 10 mg/kg per d, candesartan lowered arterial pressure from 131+/-2 to 91+/-4 mmHg. Ibuprofen treatment alone had no effect on the increase in arterial pressure observed in young SHR over the study period, and had no effect on the changes produced by candesartan at either dose. In the two groups of rats receiving candesartan at 10 mg/kg per d (with and without ibuprofen), a significant increase in urine volume and water intake was observed; urine volume rose from 9.5+/-1.0 to 22.9+/-1.1 ml/d in rats given only candesartan and from 11.5+/-0.7 to 22.0+/-0.6 ml/d in rats given candesartan + ibuprofen. Urine volume and water intake were unchanged in all other groups. These effects on water handling are consistent with previous findings that chronic angiotensin II inhibition inhibits water reabsorption in the kidney. These results demonstrate that nonsteroidal anti-inflammatory drug treatment has no effect on the antihypertensive efficacy and diuretic effects of AT1 receptor blockade in rats developing hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9892151&dopt=Abstract ibuprofen Motrin



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Spinal action of ketorolac, S(+)- and R(-)-ibuprofen on non-noxious activation of the catechol oxidation in the rat locus coeruleus: evidence for a central role of prostaglandins in the strychnine model of allodynia.

Hall SR, Milne B, Loomis C.

Department of Anaesthesia, Queen's University, Kingston, Ontario, Canada.

BACKGROUND: Blockade of spinal glycine receptors with intrathecal strychnine produces an allodynia-like state in the anesthetized rat. Innocuous hair deflection in the presence of intrathecal strychnine induces a nociceptive-like activation of catechol oxidation in the locus coeruleus and enhances cardiovascular responses. Because prostaglandins play a central role in augmenting pain, this study evaluated the effect of intrathecal nonsteroidal antiinflammatory drugs in strychnine-induced allodynia. METHODS: In urethane-anesthetized rats, changes in catechol oxidation in the locus coeruleus, measured using in vivo voltammetry, and cardiovascular parameters evoked by hair deflection of caudal dermatomes were determined after strychnine (40 microg) or saline were administered intrathecally. Subsequently, the effects of 30 microg ketorolac, 10 microg S(+)-ibuprofen, and 10 microg R(-)-ibuprofen administered intrathecally were evaluated. RESULTS: After strychnine was administered intrathecally, hair deflection evoked an increase in the locus coeruleus catechol oxidation (peak, 149.7+/-7.2% of baseline) and mean arterial blood pressure (peak, 127.5+/-3.8% of baseline). These responses were not observed after saline was administered intrathecally. All hair deflection-evoked, strychnine-dependent peak responses were attenuated significantly with intrathecally administered ketorolac and S(+)-ibuprofen but not with R(-)-ibuprofen. CONCLUSIONS: Locus coeruleus catechol oxidation is a sensitive biochemical index of strychnine-induced allodynia and is correlated temporally with the cardiovascular responses evoked by hair deflection during spinal glycinergic inhibition. The ability of intrathecally administered ketorolac and S(+)-ibuprofen, but not R(-)-ibuprofen, to suppress the locus coeruleus catechol oxidation and cardiovascular peak responses evoked during strychnine-induced allodynia provide evidence that central prostaglandins play an important role in the abnormal sensory processing of strychnine-induced allodynia.

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Effects of ibuprofen on arylamine N-acetyltransferase activity in human colon tumor cells.

Chung JG, Chang HL, Lin WC, Yeh FT, Hung CF.

Department of Microbiology, China Medical College, Taichung, Taiwan, Republic of China.

The inhibition of arylamine N-acetyltransferase (NAT) activity by ibuprofen was determined in a human colon tumour (adenocarcinoma) cell line. Two assay systems were employed, one with cellular cytosols (9000 g supernatant) and the other with intact colon tumour cell suspensions. The NAT activity in a human colon tumour cell line was inhibited by ibuprofen in a dose-dependent manner in both systems, i.e. the greater the concentration of ibuprofen in the reaction, the greater the inhibition of NAT activities in both systems. The data also indicated that ibuprofen decreases the apparent Km and Vmax of NAT enzyme from human colon tumour cells in both systems examined. This report is the first demonstration to show that ibuprofen affects human colon tumour cell NAT activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9989470&dopt=Abstract ibuprofen Motrin



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Choice of NSAID and management strategy in rheumatoid arthritis and osteoarthritis. The impact on costs and outcomes in the UK.

McCabe CJ, Akehurst RL, Kirsch J, Whitfield M, Backhouse M, Woolf AD, Scott DL, Emery P, Haslock I.

School of Health and Related Research, University of Sheffield, England. c.mccabe sheffield.ac.uk

OBJECTIVE: Although nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective therapy for rheumatoid arthritis, they are associated with significant adverse effects, the management of which imposes additional costs on the healthcare system. Prescribing NSAIDs which have a lower risk of major adverse effects as the first-line NSAID for patients with rheumatoid arthritis and osteoarthritis may be expected to lead to an improvement in clinical outcomes and reduce overall treatment costs. This analysis examines data from a published randomised controlled trial of 5 NSAIDs to explore these hypotheses. DESIGN AND SETTING: Data from a clinical trial comparing 5 NSAIDs were combined with published cost data to construct 2 clinical decision models, reflecting alternative approaches to the management of major and minor adverse effects in the UK. INTERVENTIONS: The 5 NSAIDs evaluated in the analysis were nabumetone, diclofenac, ibuprofen, piroxicam and naproxen, although only the results for ibuprofen and nabumetone are reported. MAIN OUTCOME MEASURES AND RESULTS: The total cost of care per patient receiving nabumetone was estimated to be between 25 pounds sterling (Pound) and 41 Pounds more expensive than ibuprofen. In a hypothetical cohort of 100,000 patients, there were between 690 and 821 more major adverse effects using ibuprofen than nabumetone. The cost per life-year gained (LYG) from using nabumetone rather than ibuprofen ranged between 1880 Pounds and 2517 Pounds (1995 values), depending upon the management of adverse effects. CONCLUSIONS: These results indicate that: (i) prescribing the newer, currently more expensive, NSAIDs will not necessarily lead to cost savings; (ii) the management of adverse effects can have a significant impact on costs; and (iii) the additional cost may be justifiable in terms of the mortality and morbidity gains associated with the new lower-risk NSAIDs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10186459&dopt=Abstract ibuprofen Motrin



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Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and of tumour necrosis factor-alpha ex vivo.

Endres S, Whitaker RE, Ghorbani R, Meydani SN, Dinarello CA.

New England Medical Center Hospitals and Tufts University School of Medicine, Boston, MA, USA.

We investigated the effect of oral aspirin and ibuprofen on the ex vivo synthesis of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumour necrosis factor-alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by stimulated peripheral blood mononuclear cells (PBMC) from healthy volunteers. Seven volunteers took 325 mg of aspirin daily for 14 days. Three weeks after ending aspirin medication, ex vivo IL-1 beta and TNF synthesis induced by exogenous IL-1 alpha was elevated threefold compared to the pre-aspirin value (P = 0.01 and P = 0.005, respectively). Using lipopolysaccharide (LPS) as a stimulus, no influence of oral aspirin was observed. The increase in cytokine synthesis did not parallel decreased synthesis of prostaglandin E2 (PGE2). Seven weeks after discontinuation of aspirin, cytokine and PGE-2 production returned to pre-aspirin levels. Another seven volunteers took 200 mg of ibuprofen daily for 12 days. Again, there was no effect on LPS- or Staphylococcus epidermidis-induced cytokine synthesis. However, IL-1 alpha-induced synthesis of IL-1 beta was elevated to a mean individual increase of 538% (P < 0.001) and synthesis of TNF was elevated to 270% (P < 0.001) at the end of ibuprofen medication and 2 weeks after discontinuation of ibuprofen. There were parallel increases in PGE2 and both returned to their pre-ibuprofen levels 5 weeks after stopping. Although inhibitors of cyclo-oxygenase blunt PGE2-mediated symptoms such as fever and pain, we conclude that short term use of either aspirin or ibuprofen results in a 'rebound' increase in cytokine-induced cytokine synthesis that is not observed in LPS-induced cytokines.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8698389&dopt=Abstract ibuprofen Motrin



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Decreased left ventricular contractility during porcine endotoxemia is not prevented by ibuprofen.

Herbertson MJ, Werner HA, Studer W, Russell JA, Walley KR.

Pulmonary Research Laboratory, St. Paul's Hospital, University of British Columbia, Vancouver, Canada.

OBJECTIVE: We investigated whether ibuprofen could prevent early decrease in left ventricular contractility that occurs during porcine endotoxemia. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Adolescent crossbred pigs (n = 28). INTERVENTIONS: Anesthetized pigs were instrumented to measure hemodynamics and left ventricular pressures (using a Millar catheter) and volumes (using a conductance catheter). Pigs were then treated in four groups, according to pretreatment using ibuprofen (15 mg/kg) or saline and subsequent treatment using endotoxin (0111:B4, 50 microg/kg) or saline. MEASUREMENTS AND MAIN RESULTS: Measurements of hemodynamics and left ventricular pressures and volumes were repeated after pretreatment with ibuprofen (or saline in controls), and at hourly intervals for 4 hrs after the start of endotoxin or control saline infusions. Left ventricular contractility was primarily assessed using the slope of the end-systolic pressure-volume relationship. Data were analyzed, using a repeated-measures analysis of variance. The slope of the end-systolic pressure-volume relationship was decreased at 4 hrs by 41 +/- 9% in the saline/endotoxin group (p < .05) and by 36 +/- 14% in the ibuprofen/endotoxin group (p < .05), so that ibuprofen pretreatment had no significant effect on the decrease in left ventricular contractility. Mean arterial pressure decreased in the saline/endotoxin group by 23 +/- 12% at 1 hr (p < .05) and by 35 +/- 12% (p < .05) at 4 hrs. Ibuprofen significantly reduced the decrease in mean arterial pressure (2 +/- 6% increased at 1 hr, and 17 +/- 12% decreased at 4 hrs, both p<.05 compared with saline/endotoxin). Cardiac output increased by 25% (p < .05) in the first hour, but then decreased to be slightly (NS) below baseline at 4 hrs in both endotoxin groups. Mean pulmonary arterial pressure was increased in the saline/endotoxin group by 154 +/- 52% (p < .05) at 30 mins and by 118 +/- 40% (p < .05) at 4 hrs. Ibuprofen prevented the very acute increase in pulmonary arterial pressure (increased by 11 +/- 33% at 30 mins, p < .05 compared with saline/endotoxin) and significantly reduced the pulmonary hypertension at 4 hrs (increased by 70 +/- 25%, p < .05 compared with both baseline and saline/endotoxin). CONCLUSIONS: We conclude that products of the cyclooxygenase pathway do not play a major role in the early decrease in left ventricular contractility after endotoxin. However, ibuprofen may have a role in reducing the other cardiovascular effects of sepsis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8706459&dopt=Abstract ibuprofen Motrin