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The main aim of the study was to examine analgesic effects of the topical opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in a radiant heat tail-flick nociception model. Also, we have tested whether the addition of lauric acid to propylene glycol improves skin permeation for the opioids and NSAIDs. We found that the addition of lauric acid to propylene glycol dramatically improves the penetration of the drugs, measured by the drug's ED(50). We observed a significant dose response shift to the left for all tested drugs. So, morphine's ED(50) was decreased by 19-fold. The duration of the analgesic activity of morphine dissolved in a combination of propylene glycol and lauric acid was much longer compared with the same dose of the drug dissolved in propylene glycol only. Methadone and hydrocodone also produced analgesic activity in this experimental paradigm. We then assessed potential interactions between opioids, ibuprofen and diclofenac using a fixed, low dose of each. The inclusion of either S-ibuprofen or diclofenac to a fixed, low dose of morphine raised the analgesic response from around 20% to 50% and 80%, respectively. Topical methadone and diclofenac alone produced analgesia in 30% of mice. The combination produced analgesia in 100% of mice (100% versus 60%, P<0.001) and the analgesic effect was observed for 90 min. Alone, topical methadone and S-ibuprofen produced analgesia in 25% and 30% of mice, respectively. The combination elicited analgesia in 100% of mice (100% versus 55%, P<0.001) and this analgesic effect lasted for 120 min. Our current findings support the supra-additive interaction of topical mu opioids, S-ibuprofen and diclofenac in a model of moderate to severe pain, radiant heat tail-flick assay.
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Iontophoresis is an important approach to improve transdermal drug delivery. However, The transdermal enhancement mechanism of iontophoresis was not well known. The relationship between the physicochemical properties of drugs and the transdermal enhancement effect of iontophoresis was revealed in this study. Non-steroidal anti-inflammatory drugs (NSAIDs) were used as the models, including aspirin, ibuprofen and indomethacin. Their oil-water partition coefficients were measured. The carbomer-based hydrogels of them were prepared. Iontophoresis significantly enhanced in vitro transdermal delivery across the rat skins. Strong lipophilicity could lead to high permeation of drugs. However, the dissociation extent (indicated as pKa) of drugs was the key factor to determine the transdermal enhancement effect of iontophoresis. The more dissociation the drugs were, the higher the transdermal enhancement effect of iontophoresis. The drug-loaded hydrogels combined with iontophoresis improved the treatment of rat raw's inflammatory syndrome. Iontophoresis significantly improved the drugs penetrating into the hypodermis, dermis and epidermis, more deeply than the application of drugs alone according to the experimental result of 5-carboxylfluorescein hydrogels. Iontophoresis led to the unordered arrangement of skin intercellular lipids, the significantly increased flowability and loose stratum corneum structure. Iontophoresis is a promising approach to improve transdermal drug delivery with safety and high efficiency.
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Changes in global WOMAC scores at 12 months were equivalent. In the randomised trial the difference (topical minus oral) was two points (95% confidence interval -2 to 6); in the preference study, it was one point (-4 to 6). There were no differences in major adverse effects in the trial or study. The only significant differences in secondary outcomes were in the randomised trial. The oral group had more respiratory adverse effects (17% v 7%,95% confidence interval for difference -17% to -2%), the change in serum creatinine was 3.7 mmol/l less favourable (0.9 micromol/l to 6.5 micromol/l); and more participants changed treatments because of adverse effects (16% v 1%, -16% to -5%). In the topical group more participants had chronic pain grade III or IV at three months, and more participants changed treatment because of ineffectiveness.
The objective of this work was to develop a method to estimate the average shape and habit of organic crystalline material using X-ray powder diffraction (XRPD), the single-crystal structure, and computational methods. It is proposed that the relative intensities of the peaks in an XRPD pattern from a sample exhibiting a "standard" preferred orientation correlates with the shape of the crystallites present. Models were developed to yield a quantitative "enhancement" factor for each face. The combined simple-forms morphology (CSM) of the material was then produced by indexing the observed faces and modifying the simulated Bravais-Friedel-Donnay-Harker (BFDH) morphology. The average shape of crystallites can be estimated from the CSM by multiplying each face by its enhancement factor. Acetaminophen crystals in two different habits and ibuprofen crystallized from toluene were used. The predicted shapes closely resembled the average shapes observed with microscopy. Results suggested the average shapes of the organic crystalline materials can be estimated by XRPD and the computational simulation. The current limitations are the need to "index" the faces, the size of the crystallites, and the unknown impact of a polydisperse size distribution on the calculation. The method must be used within the limits described; however, it is the only method found that may be adapted to large, more representative sample sizes. The determination of the average morphology is often a "bottle neck" in elucidating other important behaviors of large quantities of crystalline powders used in pharmaceutical development and processing.
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In children 6 to 36 months of age undergoing tympanocentesis for acute otitis media, the authors measured pain and distress throughout all phases of the procedure and recovery using physiological (heart rate) and behavioral measures (cry duration, Global Mood Scale score, and pain visual analog scales). They compared--in a randomized controlled trial--3 pain reduction interventions: acetaminophen, acetaminophen plus codeine, and ibuprofen plus midazolam.
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4-Methylaminoantipyrine (MAA), the active metabolite of dipyrone, largely attenuated or even completely abolished the inhibition of arachidonic acid-induced platelet aggregation, thromboxane formation and P-selectin expression by aspirin. Similar results were obtained for other pyrazolinones, as well as for the conventional NSAIDs ibuprofen and naproxen. Moreover, MAA attenuated the effect of aspirin on COX activity of platelet microsomes, suggesting a competition with aspirin at the COX-1 enzyme. This was confirmed by docking studies, which revealed that MAA forms a strong hydrogen bond with serine 530 within the COX-1, thereby preventing enzyme acetylation by aspirin.
A total of 176 children undergoing (adeno) tonsillectomy over a 5-month period (Sept 2013-Jan 2014) were included in the study. Data were prospectively collected on analgesia used peri-operatively and patients were discharged on regular paracetamol and ibuprofen for 7 days and three doses of oral morphine sulphate solution to be used on days 3, 4 and 5. Pain scores were recorded on days 1-10 post-operatively using the Wong Baker Faces Pain Rating scale.
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Ninety-nine subjects participated. Twenty-five received oral ibuprofen and topical benzocaine (median pain scores on a 10-point scale for speculum placement, ECC, and biopsy were 0.75, 3.00, and 3.38, respectively), 24 received oral placebo and topical benzocaine (1.00, 3.75, and 2.63), 24 received oral ibuprofen and topical placebo (0.63, 3.75, and 2.25), and 26 received oral and topical placebos (0.75, 3.50, and 3.00). There were no statistically significant differences in patient visual analogue pain scale scores across the four groups (statistical power, ECC = 0.74, cervical biopsy = 0.62). Younger women and women who had pain with speculum placement were more likely to have increased pain during ECC. Increased pain during biopsy was associated with history of severe dysmenorrhea but no other demographic or historical factors. Women overall reported ECC and biopsy to be mildly painful, with median scores of 3.5 for ECC and 2.75 for biopsy on a 10-point scale. The range in pain scores was large, with some women reporting severe pain (for ECC minimum = 0.25, maximum = 10.0; biopsy: minimum = 0.0, maximum = 9.0).
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The introduction of fast-tracking multidisciplinary programs allows good results in postoperative outcome in many surgical specialties. We evaluated a multimodal clinical program (based on mininvasive surgery, epidural anesthesia and early mobilization and feeding) in abdominal aortic surgery.
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This study was used to find solid state characteristics of ibuprofen loaded spray-congealed solid lipid microparticles (SLMs) by employing simple lipids as matrices, with or without polymeric additives, and the impact of solid drug-matrix miscibility on sustaining drug release. Solid miscibility of ibuprofen with two lipids, cetyl alcohol (CA) and stearic acid (SA), were investigated using differential scanning calorimetry (DSC). SLMs containing 20% w/w ibuprofen with or without polymeric additives, PVP/VA and EC, were produced by spray congealing, and the resultant microparticles were subjected to visual examination by scanning electron microscopy (SEM), thermal analysis using DSC, and hot-stage microscopy. Intermolecular interactions between lipids and drug as well as additives were investigated by Fourier-transformed infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). X-ray diffractometry (XRD) was utilized to study polymorphic changes of drug and matrix over the course of a year. Ibuprofen was found to depress the melting points of CA and SA in a colligative manner, reaching maximum solubility at 10% w/w and 30% w/w for CA and SA, respectively. Drug encapsulation efficiencies and yields of spray-congealed SLMs containing 20% w/w ibuprofen were consistently high for both lipid matrices. CA and SA were found to adopt their stable γ- and β-polymorphs, respectively, immediately after spray congealing. The spray congealing process resulted in ibuprofen adopting an amorphous or poorly crystalline state, with no further changes over the course of a year. SEM, DSC, and hot stage microscope studies on the SLMs confirmed the formation of a solid dispersion between ibuprofen and CA and a solid solution between ibuprofen and SA. SA was found to sustain the release of ibuprofen significantly better than CA. PVP/VA and EC showed some interactions with CA, which led to an expansion of unit cell dimensions of CA upon spray congealing, whereas they showed negligible interactions with SA. PVP/VA and EC both hastened drug release in both CA and SA matrices, despite PVP/VA being hydrophilic and EC being hydrophobic. CA and SA are useful as lipid matrices that do not exhibit polymorphism when spray-congealed. Sustained release of ibuprofen was achieved with the formation of a solid solution with SA. Solid miscibility of drug in lipid matrix has a large impact on the ability of the SLMs to sustain the release of a drug. Polymeric additives generally disrupted structural integrity of SLMs and led to faster drug release.
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We have examined the synthesis of hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins) and the ability of these cyclodextrin ethers to form guest-host complexes with guest molecules. The hydroxybutenyl cyclodextrin ethers were prepared by a base-catalyzed reaction of 3,4-epoxy-1-butene with the parent cyclodextrins in an aqueous medium. Reaction byproducts were removed by nanofiltration before the hydroxybutenyl cyclodextrins were isolated by co-evaporation of water-EtOH. Hydroxybutenyl cyclodextrins containing no unsubstituted parent cyclodextrin typically have a degree of substitution of 2-4 and a molar substitution of 4-7. These hydroxybutenyl cyclodextrins are randomly substituted, amorphous solids. The hydroxybutenyl cyclodextrin ethers were found to be highly water soluble. Complexes of HBen-beta-CD with glibenclamide and ibuprofen were prepared and isolated. In both cases, the guest content of the complexes was large, and a significant increase in the solubility of the free drug was observed. Dissolution of the complexes in pH 1.4 water was very rapid, and significant increases in the solubility of the free drugs were observed. Significantly, after reaching equilibrium concentration, a decrease in the drug concentration over time was not observed.
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Gestational ages of infants were 29 wk (male) and 30 wk (female). Both infants developed intestinal perforations without signs of necrotizing enterocolitis. The perforations cured with Penrose drainage alone.
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The ruthenium compound [Ru(2)Cl(Ibp)(4)] (or RuIbp) has been reported to cause significantly greater inhibition of C6 glioma cell proliferation than the parent HIbp. The present study determined the effects of 0-72h exposure to RuIbp upon C6 cell cycle distribution, mitochondrial membrane potential, reactive species generation and mRNA and protein expression of E2F1, cyclin D1, c-myc, pRb, p21, p27, p53, Ku70, Ku80, Bax, Bcl2, cyclooxygenase 1 and 2 (COX1 and COX2). The most significant changes in mRNA and protein expression were seen for the cyclin-dependent kinase inhibitors p21 and p27 which were both increased (p<0.05). The marked decrease in mitochondrial membrane potential (p<0.01) and modest increase in apoptosis was accompanied by a decrease in anti-apoptotic Bcl2 expression and an increase in pro-apoptotic Bax expression (p<0.05). Interestingly, COX1 expression was increased in response to a significant loss of prostaglandin E(2) production (p<0.001), most likely due to the intracellular action of Ibp. Future studies will investigate the efficacy of this novel ruthenium-ibuprofen complex in human glioma cell lines in vitro and both rat and human glioma cells growing under orthotopic conditions in vivo.
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These results demonstrate that NSAIDs have activity against HNSCC cells in vitro and may have clinical applications in combination with other therapeutic regimens.
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This work describes the analysis of 15 pharmaceutical compounds, belonging to different therapeutic classes (anti-inflammatory/analgesics, lipid regulators, antiepileptics, β-blockers and antidepressants) and with diverse physical-chemical properties, in Spanish soils with different farmland uses. The studied compounds were extracted from soil by ultrasound-assisted extraction (UAE) and determined, after derivatization, by gas chromatography with mass spectrometric detection (GC-MS). The limits of detection (LODs) ranged from 0.14 ng g(-1) (naproxen) to 0.65 ng g(-1) (amitriptyline). At least two compounds where detected in all samples, being ibuprofen, salicylic acid, and paracetamol, the most frequently detected compounds. The highest levels found in soil were 47 ng g(-1) for allopurinol and 37 ng g(-1) for salicylic acid. The influence of the type of crop and the sampling area on the levels of pharmaceuticals in soil, as well as their relationship with soil physical-chemical properties, was studied. The frequent and widespread detection of some of these compounds in agricultural soils show a diffuse contamination, although the low levels found do not pose a risk to the environment or the human health.
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In this pilot study, not packing simple cutaneous abscesses did not result in any increased morbidity, and patients reported less pain and used fewer pain medications than packed patients.
The administration of PRN medication by mental health nurses is an important, yet poorly explored aspect of psychiatric inpatient care. An examination of nurses' reasons for administering PRN medication is essential in ensuring its appropriate and effective use. Data were gathered from the drug charts of 44 inpatients on two acute psychiatric wards. Most PRN medication was given orally and the most frequently administered drugs were procyclidine, lorazepam, ibuprofen, diazepam and droperidol. The main reason for administering PRN medication was because patients had 'requested' it. Results were broadly consistent with previous research. It is recommended that nurses should give clear and specific reasons for administering PRN medication based on a valid assessment. Implications for clinical practice and further research are also discussed.
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A randomised, blinded, prospective animal study with 296 male C57BL/6N mice was performed to evaluate the biomechanical, biomolecular, biochemical, and histological impact of anti-inflammatory medications on fracture healing. A reproducible closed tibia fracture was created and stabilised with an intramedullary pin. Animals were randomised to placebo, ketorolac, ibuprofen, celecoxib, or rofecoxib treatment groups with biomechanical and biochemical testing at 4, 8, and 12 weeks. A second arm of the study was conducted in which animals were randomised to indomethacin or placebo treatment with biomechanical testing at 12 weeks. Histological and biomolecular studies were performed at 2 weeks on all groups in the first arm of the study. Biomechanical testing consisted of three-point bending evaluating maximum load, energy absorbed to maximum load, and stiffness. Safranin O-Fast Green stain was performed for histology. Biochemical quantifications of chondroitin and dermatan sulphate, hydroxyproline, total protein, and DNA content were performed. Osteocalcin and collagen types II and X were evaluated by in situ hybridisation. Some mechanical differences were seen between ketorolac and placebo at 4 weeks with respect to energy absorbed, but there were no differences in maximum load or stiffness seen between any treatment group and placebo at any time point. Indomethacin, celecoxib, rofecoxib, ibuprofen, and ketorolac did not significantly affect fracture healing in this young murine model.
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The presence of water-rich and water-lean nanodomains in a transparent, pressurized "water-acetone-CO2" mixture was revealed by Raman spectroscopy. This nano-structured liquid can be classified as a surfactant-free microemulsion-like system and has the capacity to dissolve hydrophobic compounds, such as ibuprofen, in the presence of large amounts of water. This finding opens new opportunities in the fields of confined reactions and material templating.
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Alpha-1 adrenergic blocker use is related with a greater incidence of expulsion of ureteral calculi, smaller or greater than 5mm, and fewer episodes of pain when compared to ibuprofen. However it is necessary larger samples to enhance the power analysis of the expulsion of ureteral calculi larger than 5mm and the episodes of pain.
The purposes of this study were to determine the most effective nursing intervention to decrease pain for patients with minor musculoskeletal trauma and moderate pain at triage and to examine patient satisfaction.
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The long-term stability of pharmaceutical formulations of poorly-soluble drugs in polymers determines their bioavailability and therapeutic applicability. However, these formulations do not only often tend to crystallize during storage, but also tend to undergo unwanted amorphous-amorphous phase separations (APS). Whereas the crystallization behavior of APIs in polymers has been measured and modeled during the last years, the APS phenomenon is still poorly understood. In this study, the crystallization behavior, APS, and glass-transition temperatures formulations of ibuprofen and felodipine in polymeric PLGA excipients exhibiting different ratios of lactic acid and glycolic acid monomers in the PLGA chain were investigated by means of hot-stage microscopy and DSC. APS and recrystallization was observed in ibuprofen/PLGA formulations, while only recrystallization occurred in felodipine/PLGA formulations. Based on a successful modeling of the crystallization behavior using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the occurrence of APS was predicted in agreement with experimental findings.
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This study was undertaken as part of the NIH "Facilities of Research Excellence-Spinal Cord Injury" project to support independent replication of published studies. Here, we repeat key parts of a study reporting that rats treated with ibuprofen via subcutaneous minipump exhibited greater recovery of motor function and enhanced axonal growth after spinal cord injury. We carried out 3 separate experiments in which young adult female Sprague-Dawley rats received dorsal over-hemisections at T6-T7, and then were implanted with osmotic minipumps for subcutaneous delivery of ibuprofen or saline. Motor function was assessed with the BBB Locomotor Rating Scale, footprint analysis, and with a grid walk task. Combined group sizes for functional analyses were n=34 rats treated with ibuprofen and n=39 controls. Bladder function was assessed by measuring the amount of urine retained in the bladder twice per day. Four weeks post-injury, CST axons were traced by injecting BDA into the sensorimotor cortex; 5HT axons were assessed by immunostaining. Analysis of data from all rats revealed no significant differences between groups. Analysis of data excluding rats with lesions that were larger than intended indicated improved locomotor function in ibuprofen-treated rats at early post-lesion intervals in one of the individual experiments. Rats that received Ibuprofen did not demonstrate statistically significant improvements in bladder function. Quantitative analyses of CST and 5HT axon distribution also did not reveal differences between ibuprofen-treated and control rats. Taken together, our results only partially replicate the findings that treatment with ibuprofen improves motor function after SCI but fail to replicate findings regarding enhanced axon growth.
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The concomitant use of herbal medicines and pharmacotherapy is wide spread. We have reviewed the literature to determine the possible interactions between seven popular herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and conventional drugs. Literature searches were performed using MEDLINE, Cochrane Library and EMBASE and we identified 128 case reports or case series, and 80 clinical trials. Clinical trials indicate that St John's wort (Hypericum perforatum), via cytochrome P450 (CYP) and/or P-glycoprotein induction, reduces the plasma concentrations (and/or increases the clearance) of alprazolam, amitriptyline, atorvastatin, chlorzoxazone, ciclosporin, debrisoquine, digoxin, erythromycin, fexofenadine, gliclazide, imatinib, indinavir, irinotecan, ivabradine, mephenytoin, methadone, midazolam, nifedipine, omeprazole, oral contraceptives, quazepam, simvastatin, tacrolimus, talinolol, verapamil, voriconazole and warfarin. Case reports or case series suggest interactions of St John's wort with adrenergic vasopressors, anaesthetics, bupropion, buspirone, ciclosporin, eletriptan, loperamide, nefazodone, nevirapine, oral contraceptives, paroxetine, phenprocoumon, prednisone, sertraline, tacrolimus, theophylline, tibolone, tryptophan, venlafaxine and warfarin. Ginkgo (Ginkgo biloba) decreases the plasma concentrations of omeprazole, ritonavir and tolbutamide. Clinical cases indicate interactions of ginkgo with antiepileptics, aspirin (acetylsalicylic acid), diuretics, ibuprofen, risperidone, rofecoxib, trazodone and warfarin. Ginseng (Panax ginseng) may interact with phenelzine and warfarin. Kava (Piper methysticum) increases the clearance of chlorzoxazone (a CYP2E1 substrate) and may interact with alprazolam, levodopa and paroxetine. Garlic (Allium sativum) interacts with chlorpropamide, fluindione, ritonavir and warfarin; it also reduces plasma concentrations of chlorzoxazone (a CYP2E1 probe). Echinacea might affect the clearance of caffeine (a CYP1A2 probe) and midazolam (a CYP3A4 probe). No interactions have been reported for saw palmetto (Serenoa repens). Numerous interactions between herbal medicines and conventional drugs have been documented. While the significance of many interactions is uncertain, several interactions, particularly those with St John's wort, may have serious clinical consequences.
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This meta-analysis of 34,668 patients receiving > or =1 week and up to 1 year of treatment found no evidence that lumiracoxib was associated with a significant increase in CV risk compared with naproxen, placebo, or all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen).
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This was a multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group, single-dose study in patients experiencing moderate to severe pain after surgical removal of > or = 2 ipsilateral impacted third molars. Patients were randomly assigned to receive oxycodone 5 mg/ibuprofen 400 mg, oxycodone 5 mg/acetaminophen 325 mg, hydrocodone 7.5 mg/acetaminophen 500 mg, or placebo. The primary outcome measures were total pain relief through 6 hours after dosing (TOTPAR6), sum of pain intensity differences through 6 hours (SPID6), and adverse events. Secondary efficacy measures included SPID3 and TOTPAR3, peak pain relief, peak pain intensity difference, time to onset of pain relief, time to use of rescue medication, proportion of patients reporting pain half gone, and the patient's global evaluation.
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We previously reported that the cytosolic phospholipase A(2) (cPLA2) pathway is involved in ventilator-induced lung injury (VILI) produced by high peak inflation pressures (PIP) (J Appl Physiol 98: 1264-1271, 2005), but the relative contributions of the various downstream products of cPLA2 on the acute permeability response were not determined. Therefore, we investigated the role of cPLA2 and the downstream products of arachidonic acid metabolism in the high-PIP ventilation-induced increase in vascular permeability. We perfused isolated mouse lungs and measured the capillary filtration coefficient (K(fc)) after 30 min of ventilation with 9, 25, and 35 cmH2O PIP. In high-PIP-ventilated lungs, K(fc) increased significantly, 2.7-fold, after ventilation with 35 cmH2O PIP compared with paired baseline values and low-PIP-ventilated lungs. Also, increased phosphorylation of lung cPLA2 suggested enzyme activation after high-PIP ventilation. However, treatment with 40 mg/kg arachidonyl trifluoromethyl ketone (an inhibitor of cPLA2) or a combination of 30 microM ibuprofen [a cyclooxygenase (COX) inhibitor], 100 microM nordihydroguaiaretic acid [a lipoxygenase (LOX) inhibitor], and 10 microM 17-octadecynoic acid (a cytochrome P-450 epoxygenase inhibitor) prevented the high-PIP-induced increase in K(fc). Combinations of the inhibitors of COX, LOX, or cytochrome P-450 epoxygenase did not prevent significant increases in K(fc), even though bronchoalveolar lavage levels of the COX or LOX products were significantly reduced. These results suggest that multiple mediators from each pathway contribute to the acute ventilator-induced permeability increase in isolated mouse lungs by mutual potentiation.
Performance on complex cognitive and motor tasks was evaluated in healthy subjects with exercise-induced muscle damage who were treated with a hydrocodone-ibuprofen combination, ibuprofen alone, or placebo.