R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice.

PubMed

Schmitz, Katja; de Bruin, Natasja; Bishay, Philipp; Männich, Julia; Häussler, Annett; Altmann, Christine; Ferreirós, Nerea; Lötsch, Jörn; Ultsch, Alfred; Parnham, Michael J; Geisslinger, Gerd; Tegeder, Irmgard

2014-11-01

R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4(+)CD25(+)FoxP3(+) regulatory T cells, CTLA4(+) inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

PubMed Central

Kumpulainen, Elina; Välitalo, Pyry; Kokki, Merja; Lehtonen, Marko; Hooker, Andrew; Ranta, Veli-Pekka; Kokki, Hannu

2010-01-01

AIMS This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h−1 70 kg−1. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (Vss) was 8.1 l 70 kg−1. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants. PMID:20840447

Determination of Flurbiprofen in Human Plasma by High-Performance Liquid Chromatography.

PubMed

Yilmaz, Bilal; Erdem, Ali Fuat

2015-10-01

A simple high-performance liquid chromatography method has been developed for determination of flurbiprofen in human plasma. The method was validated on an Ace C18 column using UV detection. The mobile phase was acetonitrile-0.05 M potassium dihydrogen phosphate solution (60:40, v/v) adjusted to pH 3.5 with phosphoric acid. The calibration curve was linear between the concentration range of 0.10-5.0 μg/mL. Intra- and inter-day precision values for flurbiprofen in plasma were <4.47, and accuracy (relative error) was better than 3.67%. The extraction recoveries of flurbiprofen from human plasma were between 93.0 and 98.9%. The limits of detection and quantification of flurbiprofen were 0.03 and 0.10 μg/mL, respectively. In addition, this assay was applied to determine the pharmacokinetic parameters of flurbiprofen in six healthy Turkish volunteers who had been given 100 mg flurbiprofen. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A short-term increase of the postoperative naturally circulating dendritic cells subsets in flurbiprofen-treated patients with esophageal carcinoma undergoing thoracic surgery

PubMed Central

Chai, Xiao-qing; Shu, Shu-hua; Zhang, Xiao-lin; Xie, Yan-hu; Wei, Xin; Wu, Yu-jing; Wei, Wei

2016-01-01

The present study evaluated whether flurbiprofen increased the naturally circulating dendritic cells (DCs) subsets in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophageal resection. Compared to healthy donors (n=20), the significantly depressed percentages of plasmacytoid DCs (pDCs), CD1c+ myeloid DCs (mDCs), and CD141+ mDCs among ESCC patients (n=60) were confirmed. Flurbiprofen was administered before skin incision and at the end of operation in group F (n=30), as well as placebo in group C (n=30). The postoperative suppressed percentages of pDCs, CD1c+ mDCs, and CD141+ mDCs increased significantly following the perioperative treatment with flurbiprofen. Flurbiprofen also significantly stimulated the postoperative IFN-f and IL-17 production, but inhibited the immunosuppressive IL-10 and TGF-β levels. Furthermore, flurbiprofen exerted a similar analgesic effect and brought a significantly less sufentanil consumption compared to group C. Taken together, flurbiprofen provided a short-term increase of postoperative naturally circulating DCs in ESCC patients. PMID:26959879

A short-term increase of the postoperative naturally circulating dendritic cells subsets in flurbiprofen-treated patients with esophageal carcinoma undergoing thoracic surgery.

PubMed

Wang, Di; Yang, Xin-lu; Chai, Xiao-qing; Shu, Shu-hua; Zhang, Xiao-lin; Xie, Yan-hu; Wei, Xin; Wu, Yu-jing; Wei, Wei

2016-04-05

The present study evaluated whether flurbiprofen increased the naturally circulating dendritic cells (DCs) subsets in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophageal resection. Compared to healthy donors (n=20), the significantly depressed percentages of plasmacytoid DCs (pDCs), CD1c+ myeloid DCs (mDCs), and CD141+ mDCs among ESCC patients (n=60) were confirmed. Flurbiprofen was administered before skin incision and at the end of operation in group F (n=30), as well as placebo in group C (n=30). The postoperative suppressed percentages of pDCs, CD1c+ mDCs, and CD141+ mDCs increased significantly following the perioperative treatment with flurbiprofen. Flurbiprofen also significantly stimulated the postoperative IFN-f and IL-17 production, but inhibited the immunosuppressive IL-10 and TGF-β levels. Furthermore, flurbiprofen exerted a similar analgesic effect and brought a significantly less sufentanil consumption compared to group C. Taken together, flurbiprofen provided a short-term increase of postoperative naturally circulating DCs in ESCC patients.

Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats.

PubMed

Uwai, Yuichi; Matsumoto, Masashi; Kawasaki, Tatsuya; Nabekura, Tomohiro

2017-01-01

Lithium is administered for treating bipolar disorders and is mainly excreted into urine. Nonsteroidal anti-inflammatory drugs inhibit this process. In this study, we examined the enantioselective effect of flurbiprofen on the disposition of lithium in rats. Pharmacokinetic experiments with lithium were performed. Until 60 min after the intravenous administration of lithium chloride at 30 mg/kg as a bolus, 17.8% of lithium injected was recovered into the urine. Its renal clearance was calculated to be 1.62 mL/min/kg. Neither creatinine clearance (Ccr) nor pharmacokinetics of lithium was affected by the simultaneous injection of (R)-flurbiprofen at 20 mg/kg. (S)-flurbiprofen impaired the renal function and interfered with the urinary excretion of lithium. The ratio of renal clearance of lithium to Ccr was decreased by the (S)-enantiomer. This study clarified that the (S)-flurbiprofen but not (R)-flurbiprofen inhibited the renal excretion of lithium in rats. © 2017 S. Karger AG, Basel.

Intravenous flurbiprofen for post-thymectomy pain relief in patients with myasthenia gravis

PubMed Central

2012-01-01

Background Post-thymectomy pain in myasthenia gravis (MG) patients can inhibit breathing and coughing. Inappropriate usage of analgesics may exacerbate respiratory inhibition and even cause myasthenic crisis. Flurbiprofen is a non-steroidal anti-inflammatory drug (NSAID) that is commonly used to control moderate postoperative pain and is not associated with respiratory inhibition. We hypothesized that flurbiprofen may provide post-thymectomy pain relief without increasing the risk of complications in MG patients. Methods Two hundred MG patients underwent extended thymectomy from March 2006 to December 2010 and were randomly allocated to a flurbiprofen group (110 patients, 50 mg intravenous flurbiprofen axetil) or a control group (90 patients, 100 mg intramuscular tramadol) as postoperative analgesia. Visual analog scale (VAS) pain score, heart rate, blood pressure, respiratory rate, pulse oximetry (SpO2), and adverse effects were recorded before and up to 24 h after drug administration. Results There were no significant differences in the preoperative clinical characteristics of the flurbiprofen and control (tramadol) groups. Both flurbiprofen and tramadol significantly alleviated post-thymectomy pain (p < 0.05 for both), but patients in flurbiprofen group had significantly lower VAS pain scores at 0.5 h, 2 h, 4 h, and 8 h after surgery (p < 0.05 for all times). There were no significant post-thymectomy changes of heart rate, respiratory rate, mean arterial blood pressure, or SpO2 in either group at all time points. Conclusions Post-thymectomy intravenous administration of flurbiprofen axetil provides safe and effective analgesia for MG patients. PMID:23020939

Flurbiprofen, a Cyclooxygenase Inhibitor, Protects Mice from Hepatic Ischemia/Reperfusion Injury by Inhibiting GSK-3β Signaling and Mitochondrial Permeability Transition

PubMed Central

Fu, Hailong; Chen, Huan; Wang, Chengcai; Xu, Haitao; Liu, Fang; Guo, Meng; Wang, Quanxing; Shi, Xueyin

2012-01-01

Flurbiprofen acts as a nonselective inhibitor for cyclooxygenases (COX-1 and COX-2), but its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear. Mice were randomized into sham, I/R and flurbiprofen (Flurb) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 90 min and unclamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with flurbiprofen prior to I/R insult significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and prevented hepatocytes from I/R-induced apoptosis/necrosis. Moreover, flurbiprofen dramatically inhibited mitochondrial permeability transition (MPT) pore opening, and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that flurbiprofen markedly inhibited glycogen synthase kinase (GSK)-3β activity and increased phosphorylation of GSK-3β at Ser9, which, consequently, could modulate the adenine nucleotide translocase (ANT)–cyclophilin D (CyP-D) complex and the susceptibility to MPT induction. Therefore, administration of flurbiprofen prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through inhibition of MPT and inactivation of GSK-3β, and provides experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings in addition to its conventional use for pain relief. PMID:22714712

Preoperative flurbiprofen axetil administration for acute postoperative pain: a meta-analysis of randomized controlled trials.

PubMed

Wang, Ke; Luo, Jun; Zheng, Limin; Luo, Tao

2017-12-01

Non-steroidal anti-inflammatory drugs have been shown to effectively decrease postoperative pain and reduce opioid requirements. Flurbiprofen axetil is an injectable non-selective cyclooxygenase inhibitor that has a high affinity for inflammatory tissues to achieve targeted drug therapy and prolonged duration of action. This meta-analysis examined the use of preoperative flurbiprofen axetil and its impact on postoperative analgesia. An electronic literature search of the Library of PubMed, Cochrane CENTRAL, and EMBASE databases was conducted in Feb 2016. Searches were limited to randomized controlled trials. The primary outcome was pain scores. The secondary outcomes included cumulative postoperative opioid consumption and opioid-related adverse effects. A total of nine RCT studies involving 457 patients were included in this study. Compared to patients without perioperative flurbiprofen axetil, patients treated with preoperative flurbiprofen axetil had lower pain scores at 2 h (SMD -1.00; 95% CI -1.57 to -0.43, P = 0.0006), 6 h (SMD -1.22; 95% CI -2.01 to -0.43; P = 0.002), 12 h (SMD -1.19; 95% CI -2.10 to -0.28; P = 0.01), and 24 h (SMD -0.79; 95% CI -1.31 to -0.27; P = 0.003) following surgery. Preoperative flurbiprofen axetil had no significant effect on postoperative opioid consumption (SMD -13.11; 95% CI -34.56 to 8.33; P = 0.23). There was no significant difference between the groups with regard to adverse effects. Compared to patients with postoperative flurbiprofen axetil, however, preoperative flurbiprofen axetil resulted in decreased pain score only at 2 h after operation. Preoperative use of flurbiprofen axetil will result in significantly lower postoperative pain scores, but no difference in nausea, vomiting, and opioid consumption compared to those who did not receive flurbiprofen axetil. However, more homogeneous and well-designed clinical studies are necessary to determine whether preoperative flurbiprofen axetil administration has more efficacy than that given at the end of surgery.

Formulation and evaluation of flurbiprofen microemulsion.

PubMed

Ambade, K W; Jadhav, S L; Gambhire, M N; Kurmi, S D; Kadam, V J; Jadhav, K R

2008-01-01

The purpose of the present study was to investigate the microemulsion formulations for topical delivery of Flurbiprofen (FP) in order to by pass its gastrointestinal adverse effects. The pseudoternary phase diagrams were developed and various microemulsion formulations were prepared using Isopropyl Myristate (IPM), Ethyl Oleate (EO) as oils, Aerosol OT as surfactant and Sorbitan Monooleate as cosurfactant. The transdermal permeability of flurbiprofen from microemulsions containing IPM and EO as two different oil phases was analyzed using Keshary-Chien diffusion cell through excised rat skin. Flurbiprofen showed higher in vitro permeation from IPM as compared to that of from EO microemulsion. Thus microemulsion containing IPM as oil phase were selected for optimization. The optimization was carried out using 2(3) factorial design. The optimized formula was then subjected to in vivo anti-inflammatory study and the performance of flurbiprofen from optimized formulation was compared with that of gel cream. Flurbiprofen from optimized microemulsion formulation was found to be more effective as compared to gel cream in inhibiting the carrageenan induced rat paw edema at all time intervals. Histopathological investigation of rat skin revealed the safety of microemulsion formulation for topical use. Thus the present study indicates that, microemulsion can be a promising vehicle for the topical delivery of flurbiprofen.

Effects of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen in Korean subjects.

PubMed

Lee, Yun-Jeong; Byeon, Ji-Yeong; Kim, Young-Hoon; Kim, Se-Hyung; Choi, Chang-Ik; Bae, Jung-Woo; Sohn, Uy-Dong; Jang, Choon-Gon; Lee, Jeongmi; Lee, Seok-Yong

2015-06-01

The aim of this study was to investigate the impact of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen and its metabolite. The CYP2C9 genotypes were determined with the use of polymerase chain reaction and restriction fragment and DNA sequencing analysis in 358 healthy Koreans. Among them, twenty individuals with CYP2C9*1/*1 (n = 12) or CYP2C9*1/*3 (n = 8) genotypes received a single 40 mg oral dose of flurbiprofen. The plasma concentrations of flurbiprofen and its metabolite, 4'-hydroxyflurbiprofen were measured by HPLC. AUCinf of flurbiprofen was significantly higher and its clearance was significantly lower in the CYP2C9*1/*3 individuals than in those with CYP2C9*1/*1. The AUC ratio of 4'-hydroxyflurbiprofen to flurbiprofen was significantly lower in the CYP2C9*1/*3 individuals than in those with CYP2C9*1/*1. These results indicate that the individuals carrying of CYP2C9*3 have significant reduction in flurbiprofen metabolism. The clinical use of this information may allow for more efficient personalized pharmacotherapy.

Solubilization of flurbiprofen within non-ionic Tween 20 surfactant micelles: a 19F and 1H NMR study.

PubMed

Saveyn, Pieter; Cocquyt, Ellen; Zhu, Wuxin; Sinnaeve, Davy; Haustraete, Katrien; Martins, José C; Van der Meeren, Paul

2009-07-14

The solubilization of the poorly water soluble anti-inflammatory drug flurbiprofen in non-ionic Tween 20 surfactant micellar solutions was studied by both (19)F and (1)H NMR spectroscopy in an acidic environment. These non-destructive techniques allowed us to investigate the effect of temperature cycling in situ. Using (19)F NMR, an increased solubilisation capacity was observed as the temperature increased. This effect became more pronounced above the cloud point, which was reduced by more than 30 degrees C in the presence of an excess of flurbiprofen. Upon clouding, peak splitting was observed in the (19)F spectrum, which indicates that two pools of solubilised flurbiprofen exist that are in slow exchange on the NMR frequency timescale. The clouding and solubilization processes were found to be reversible, albeit with slow kinetics. Based on chemical shift differences of both Tween 20 and flurbiprofen, as well as NOESY experiments, the flurbiprofen was found to be accumulated within the palisade layer of the Tween 20 micelles.

Meaningful relief with flurbiprofen 8.75 mg spray in patients with sore throat due to upper respiratory tract infection.

PubMed

de Looze, Ferdinandus; Russo, Marc; Bloch, Mark; Montgomery, Barney; Shephard, Adrian; DeVito, Robert

2018-03-01

Evaluate the efficacy of flurbiprofen 8.75 mg spray for sore throat relief. Randomized, double-blind study in adults with sore throat due to upper respiratory tract infection who took flurbiprofen (n = 249) or placebo spray (n = 256). Pain relief was assessed using the Sore Throat Relief Rating Scale. Flurbiprofen spray provided significantly greater relief versus placebo from 20 min to 6 h (p < 0.0001; maximum difference: 75 min). Sore throat severity was reduced ≥-2.2 on the Sore Throat Scale from 75 min to 6 h, indicating meaningful relief. Significantly more patients taking flurbiprofen spray reported ≥30 min of 'at least moderate' relief versus placebo over 6 h (p < 0.0001). Most adverse events were mild. Flurbiprofen spray provides rapid, long-lasting and clinically meaningful relief from sore throat (ANZCTR: ACTRN12612000457842).

Spectroscopic and DFT studies of flurbiprofen as dimer and its Cu(II) and Hg(II) complexes

NASA Astrophysics Data System (ADS)

Sagdinc, Seda; Pir, Hacer

2009-07-01

The vibrational study in the solid state of flurbiprofen and its Cu(II) and Hg(II) complexes was performed by IR and Raman spectroscopy. The changes observed between the IR and Raman spectra of the ligand and of the complexes allowed us to establish the coordination mode of the metal in both complexes. The comparative vibrational analysis of the free ligand and its complexes gave evidence that flurbiprofen binds metal (II) through the carboxylate oxygen. The fully optimized equilibrium structure of flurbiprofen and its metal complexes was obtained by density functional B3LYP method by using LanL2DZ and 6-31 G(d,p) basis sets. The harmonic vibrational frequencies, infrared intensities and Raman scattering activities of flurbiprofen were calculated by density functional B3LYP methods by using 6-31G(d,p) basis set. The scaled theoretical wavenumbers showed very good agreement with the experimental values. The electronic properties of the free molecule and its complexes were also performed at B3LYP/6-31G(d,p) level of theory. Detailed interpretations of the infrared and Raman spectra of flurbiprofen are reported. The UV-vis spectra of flurbiprofen and its metal complexes were also investigated in organic solvents.

Influence of the oral dissolution time on the absorption rate of locally administered solid formulations for oromucosal use: the flurbiprofen lozenges paradigm.

PubMed

Imberti, Roberto; De Gregori, Simona; Lisi, Lucia; Navarra, Pierluigi

2014-01-01

Flurbiprofen is a nonsteroidal anti-inflammatory agent preferentially used for local oromucosal treatment of painful and/or inflammatory conditions of the oropharynx such as gingivitis, stomatitis, periodontitis, pharyngitis and laryngitis. In this study, we have investigated the bioavailability of a new generic formulation of flurbiprofen lozenges developed by Epifarma Srl, compared to the originator Benactiv Gola® taken as reference. Within the framework of a formal bioequivalence study, we investigated in particular the putative influence of oral dissolution time (i.e. the time spent suckling the lozenge from its intake to complete dissolution) on the absorption rate, and the contribution of this factor to the total variability of plasma flurbiprofen during absorption. We found that the amount of flurbiprofen absorbed into the systemic circulation is not significantly higher for the test drug compared to that of the reference product. We observed that the length of oral dissolution time is inversely correlated to 10-min flurbiprofen plasma levels in the test but not in the reference formulation. We estimated that oral dissolution time accounts for about 14% of overall variability in flurbiprofen plasma 10 min after test drug administration. © 2014 S. Karger AG, Basel.

R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

PubMed Central

Marian, Claudiu; Häussler, Annett; Wijnvoord, Nina; Ziebell, Simone; Metzner, Julia; Koch, Marco; Myrczek, Thekla; Bechmann, Ingo; Kuner, Rohini; Costigan, Michael; Dehghani, Faramarz; Geisslinger, Gerd; Tegeder, Irmgard

2010-01-01

Background R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. Methodology/Principal Findings We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB), which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH) and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARγ and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. Conclusion Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain. PMID:20498712

Prolonged Preservation of Human Platelets for Combat Casualty Care.

DTIC Science & Technology

1994-04-15

membrane fluidity. 5) Flurbiprofen : Flurbiprofen is an inhibitor of the cyclooxygenase enzyme and thus blocks this arm of the arachidonic acid cascade...were previously demonstrated individually to effectively block agonist stimulated activation. These agents are quinacrine, flurbiprofen and...1 0 02 1 Quinacrine 0 0 25 13 0 67 28 5nM 0 25 38 0 67 56 50nM 0 25 37 0 44 61 .5M 0 6 25 0 38 28 Flurbiprofen 0 0 6 0 0 63 13 10nM 0 6 0 0 56 19 .lM

Transdermal delivery of flurbiprofen from surfactant-based vesicles: particle characterization and the effect of water on in vitro transport.

PubMed

Uchino, Tomonobu; Matsumoto, Yuiko; Murata, Akiko; Oka, Toshihiko; Miyazaki, Yasunori; Kagawa, Yoshiyuki

2014-04-10

Flurbiprofen loaded rigid and elastic vesicles comprising the bilayer-forming surfactant sucrose-ester laurate were prepared by the film rehydration and extrusion method. The charge-inducing agent sodium dodecyl sulfate, and the micelle-forming surfactants, sorbitan monolaurate, polyethylene glycol monolaurate, and polysorbate 20, were used to enhance elasticity. Vesicle formulations were evaluated for size, zeta potential, (1)H and (19)F nuclear magnetic resonance (NMR) spectra, and in vitro skin permeation across Yucatan micropig (YMP) skin. Vesicle formulations were stable for 2 weeks and their mean sizes were 95-135 nm. NMR spectroscopy showed that flurbiprofen molecular mobility was restricted by interaction with vesicle components because of entrapment in vesicle bilayers. Moreover, sorbitan monolaurate-containing vesicles strongly retained flurbiprofen molecules. After non-occlusive application to YMP skin, flurbiprofen transport from all vesicle formulations was superior to that of flurbiprofen alone and remarkably decreased after water vaporization. Polarization microscopy and small-angle X-ray diffraction analysis showed that the vesicle formulation was transferred to liquid crystalline state. Suppression of vesicle transition to the liquid crystalline state was observed with applications of both large quantities and diluted samples. The presence of water in the formulations was associated with maintenance of the vesicle structure and greater flurbiprofen transport across YMP skin. Copyright © 2014 Elsevier B.V. All rights reserved.

Prolonged Cholestatic Jaundice Associated With Flurbiprofen.

PubMed

Dogan, Serkan; Celikbilek, Mehmet; Demirkan, Kutay; Yilmaz, Semih; Deniz, Kemal; Gursoy, Sebnem; Yucesoy, Mehmet

2014-08-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed drugs throughout the world for pain relief. Although the adverse effects of NSAIDs to the liver are well known, flurbiprofen-induced liver cholestasis is extremely rare. Herein, we present a patient with prolonged icterus that is associated with the use of flurbiprofen without causing ductopenia. © The Author(s) 2013.

Flurbiprofen and intraocular pressure.

PubMed

Gieser, D K; Hodapp, E; Goldberg, I; Kass, M A; Becker, B

1981-07-01

Systemic or topical administration of corticosteroids may produce a rise in intraocular pressure (IOP). Nonsteroidal anti-inflammatory drugs (NSAI drugs) are alternate therapy for ocular inflammatory disease. Flurbiprofen, a new NSAI drug, was tested in double-masked fashion to delineate its effect on IOP. Flurbiprofen did not alter IOP in known high corticosteroid responders nor did it block corticosteroid-induced ocular hypertension.

Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress

PubMed Central

Hosoi, Toru; Yamaguchi, Rie; Noji, Kikuko; Matsuo, Suguru; Baba, Sachiko; Toyoda, Keisuke; Suezawa, Takahiro; Kayano, Takaaki; Tanaka, Shinpei; Ozawa, Koichiro

2014-01-01

Endoplasmic reticulum (ER) stress, caused by the accumulation of unfolded proteins, is involved in the development of obesity. We demonstrated that flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), exhibited chaperone activity, which reduced protein aggregation and alleviated ER stress-induced leptin resistance, characterized by insensitivity to the actions of the anti-obesity hormone leptin. This result was further supported by flurbiprofen attenuating high-fat diet-induced obesity in mice. The other NSAIDs tested did not exhibit such effects, which suggested that this anti-obesity action is mediated independent of NSAIDs. Using ferriteglycidyl methacrylate beads, we identified aldehyde dehydrogenase as the target of flurbiprofen, but not of the other NSAIDs. These results suggest that flurbiprofen may have unique pharmacological properties that reduce the accumulation of unfolded proteins and may represent a new class of drug for the fundamental treatment of obesity. Subject Categories Metabolism; Pharmacology & Drug Discovery PMID:24421337

Flurbiprofen 8.75 mg lozenges for treating sore throat symptoms: a randomized, double-blind, placebo-controlled study.

PubMed

Schachtel, Bernard P; Shephard, Adrian; Shea, Timothy; Sanner, Kathleen; Savino, Laurie; Rezuke, Jeanne; Schachtel, Emily; Aspley, Sue

2016-11-01

This study assessed multiple doses of flurbiprofen 8.75 mg lozenges for the relief of three prominent symptoms of acute pharyngitis: pain intensity (primary end point), difficulty swallowing and swollen throat. A total of 204 patients (102 in each group) with confirmed pharyngitis (onset ≤4 days) were randomly assigned to take up to five flurbiprofen or placebo lozenges every 3-6 h, for 7 days. Using validated rating scales (sore throat pain intensity, difficulty swallowing and swollen throat) patients rated their symptoms for the duration of the study. Over the first 24 h, patients treated with flurbiprofen lozenges reported significantly greater reductions in sore throat pain (47%) as well as difficulty swallowing (66%) and swollen throat (40%) compared with placebo (all p < 0.05). Multiple doses of flurbiprofen lozenges provide effective relief of sore throat pain intensity as well as difficulty swallowing and swollen throat.

Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress.

PubMed

Hosoi, Toru; Yamaguchi, Rie; Noji, Kikuko; Matsuo, Suguru; Baba, Sachiko; Toyoda, Keisuke; Suezawa, Takahiro; Kayano, Takaaki; Tanaka, Shinpei; Ozawa, Koichiro

2014-03-01

Endoplasmic reticulum (ER) stress, caused by the accumulation of unfolded proteins, is involved in the development of obesity. We demonstrated that flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), exhibited chaperone activity, which reduced protein aggregation and alleviated ER stress-induced leptin resistance, characterized by insensitivity to the actions of the anti-obesity hormone leptin. This result was further supported by flurbiprofen attenuating high-fat diet-induced obesity in mice. The other NSAIDs tested did not exhibit such effects, which suggested that this anti-obesity action is mediated independent of NSAIDs. Using ferriteglycidyl methacrylate beads, we identified aldehyde dehydrogenase as the target of flurbiprofen, but not of the other NSAIDs. These results suggest that flurbiprofen may have unique pharmacological properties that reduce the accumulation of unfolded proteins and may represent a new class of drug for the fundamental treatment of obesity.

Study on the inclusion complex between β-cyclodextrin derivatives and flurbiprofen by spectrofluorometric

NASA Astrophysics Data System (ADS)

Miao, Jiabing; Guo, Zhaohua; Wang, Yongwang; Chen, Dong; Li, Yifan; Zhang, Feng

2017-08-01

The inclusion behavior between β-cyclodextrin derivatives (β-CDs) and flurbiprofen had been studied by fluorescence spectrophotometry. The effects of type and concentration of β-CDs; ionic strength; pH as well as temperature on inclusion behavior were investigated. And then the thermodynamic parameters ΔH/ΔS and ΔG of the inclusion complex of flurbiprofen and HP-β-CD were calculated, the driving force of the inclusion reaction had been also certified. The experimental results indicate, the fluorescence intensity (F) of flurbiprofen increases with the raising of β-CDs concentration, among the studied types of β-cyclodextrin derivatives, hydroxypropy l-β-cyclodextrin (HP-β-CD) has the most obvious enhancement, namely HP-β-CD has the strongest ability to complex with flurbiprofen. Plot of 1/ (F-F0) against 1/ [β-CD] yields a straight line, indicating 1:1 stoichiometric complex formed between β-CDs and flurbiprofen. Inclusion constant is enhanced with the increase in ionic strength of solution, whereas followes an opposite tendency with the rise of pH value. In the inclusive process, under normal temperature ΔG<0, it illustrates that this process is spontaneous, and the driving force is the change of enthalpy.

A pH-independent instantaneous release of flurbiprofen: a study of the preparation of complexes, their characterization and in vitro/in vivo evaluation.

PubMed

Wang, Han-Bing; Yang, Fei-Fei; Gai, Xiu-Mei; Cheng, Bing-Chao; Li, Jin-Yu; Pan, Hao; Yang, Xing-Gang; Pan, Wei-San

2017-09-01

In this study, furbiprofen/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes were prepared to improve the drug dissolution and facilitate its application in hydrophilic gels. Inclusion complexes were prepared using a supercritical fluid processing and a conventional optimized co-lypholization method was employed as a reference. The entrapment efficacy and drug loading of both methods were investigated. Evaluation of drug dissolution enhancement was conducted in deionized water as well as buffer solutions of different pH. Carbopol 940 gels of both flurbiprofen and flurbiprofen/HPβCD inclusion complexes, with or without penetration enhancers, were prepared and percutaneous permeation studies were performed using rat abdominal skin samples. Formation of flurbiprofen/HPβCD inclusion complexes was confirmed by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The results obtained showed that SCF processing produced a higher EE (81.91 ± 1.54%) and DL (6.96 ± 0.17%) compared with OCL with values of 69.11 ± 2.23% and 4.00 ± 1.01%, respectively. A marked instantaneous release of flurbiprofen/HPβCD inclusion complexes prepared by SCF processing (103.04 ± 2.66% cumulative release within 5 min, a 10-fold increase in comparison with flurbiprofen alone) was observed. In addition, this improvement in dissolution was shown to be pH-independent (the percentage cumulative release at pH 1.2, 4.5, 6.8 and 7.4 at 5 min was 95.19 ± 1.71, 101.75 ± 1.44, 105.37 ± 4.58 and 96.84 ± 0.56, respectively). Percutaneous permeability of flurbiprofen-in-HPβCD-in-gels could be significantly accelerated by turpentine oil and was related to the water content in the system. An in vivo pharmacokinetic study showed a 2-fold increase in C max and a shortened T max as well as a comparable relative bioavailability when compared with the commercial flurbiprofen Cataplasms (Zepolas ® ). With their superior dissolution, these flurbiprofen/HPβCD inclusion complexes prepared by SCF processing could provide improved applications for flurbiprofen.

Oral Flurbiprofen Spray for Posttonsillectomy Pain.

PubMed

Muderris, Togay; Gul, Fatih; Yalciner, Gokhan; Babademez, Mehmet Ali; Bercin, Sami; Kiris, Muzaffer

2016-07-01

Tonsillectomy is still one of the most common surgical procedures, but there exists no standard guideline for pain management after tonsillectomy. Our aim is to determine whether oral spray of flurbiprofen reduces pain and has an influence on other morbid outcomes following tonsillectomy. Prospective, double-blind, randomized, placebo controlled. Patients at Ataturk Training and Research Hospital, Ankara, Turkey. This study was performed on 84 patients (45 in flurbiprofen group, 39 in placebo group) who underwent tonsillectomy. The patients were randomly chosen, and each used oral spray of flurbiprofen 3 times daily or placebo solution at the same regimen. Efficacy was assessed by changes in Numeric Pain Rating Scale. Data were collected at postoperative days 1, 3, 5, and 7 for pain, bleeding, and healing. Data for Mallampati scores were also collected. There were no significant difference between groups with respect to the demographic data. The flurbiprofen group had statistically significant lower pain scores at days 1, 3, 5, and 7 (P = .000, P = .002, P = .001, P = .000, respectively). On days 3 and 7, pain scores were significantly different between different Mallampati groups (P = .049, P = .015, respectively). The flurbiprofen group required less analgesic than the placebo group during the study period on days 1, 3, 5, and 7 (P = .001, P = .001, P = .03, P = .001, respectively). Healing and side effects were not significantly different between the groups. In this study, topical use of flurbiprofen may reduce posttonsillectomy pain without any evidence of additional complications. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

Direct resolution and quantitative analysis of flurbiprofen enantiomers using microcrystalline cellulose triacetate plates: applications to the enantiomeric purity control and optical isomer determination in widely consumed drugs.

PubMed

Del Bubba, M; Checchini, L; Ciofi, L; Furlanetto, S; Lepri, L

2014-01-01

Flurbiprofen enantiomers have very different pharmacological properties, since the (S)-(+) form has a much higher anti-inflammatory activity than the (R)-(-) isomer, the latter being responsible for very undesirable side effects, such as gastrointestinal irritation. Based on the different biological properties of flurbiprofen enantiomers, the development of chiral chromatographic methods for the control of the enantiomeric purity is a very important topic. In this study the separation of flurbiprofen enantiomers was achieved using for the first time noncommercial MCTA layers with polyvinyl alcohol as binder, which gives to these plates a mechanical stability equivalent to that of marketed ones. Baseline resolution (α = 1.31; RS = 2.0) was obtained with ethanol-acetic acid solution (pH 3.0 ± 0.1; 60:40, v/v) as eluent and a migration distance of about 14.5 cm. Under these experimental conditions, the thin-layer chromatography determination of the enantiomeric purity of the pharmacologically active (S)-(+)-flurbiprofen in the presence of 1% of the undesired (R)-(-) form was demonstrated. Moreover, the quantitative analysis of flurbiprofen enantiomers was achieved, obtaining quantification limits and detection limits of 50 and 25 ng of each enantiomer applied to the plate, respectively. The method was succesfully applied to the enantiomer determination in widely consumed drugs, obtaining results consistent with the flurbiprofen content declared in the drug facts. Copyright © 2013 John Wiley & Sons, Ltd.

Comparison of topically applied flurbiprofen or bromfenac ophthalmic solution on post-operative ocular hypertension in canine patients following cataract surgery.

PubMed

Lu, Jennifer; English, Robert; Nadelstein, Brad; Weigt, Anne; Berdoulay, Andrew; Binder, Dan; Ngan, Esther

2017-03-01

To compare the prevalence and kinetics of ocular hypertension after routine cataract extraction when using a predominately COX-2 inhibitor (bromfenac) versus a predominately COX-1 inhibitor (flurbiprofen) in combination with a topical corticosteroid. Patients undergoing unilateral or bilateral cataract surgery were randomly assigned to receive flurbiprofen or bromfenac at the day of surgery and continued for 6 weeks postoperatively, along with topical neo poly dexamethasone. No systemic nonsteroidal anti-inflammatory medications were administered before or after surgery. Intraocular pressure was monitored pre and postoperatively. When an IOP of >25 mmHg was detected, therapeutic intervention was performed. Eyes in both treatment groups showed a similar IOP profile with the highest mean IOP occurring two hours postsurgery and slowly declining during the next 6 weeks. However, eyes receiving bromfenac had a higher mean IOP at 2 h post-op (22.1 mmHg) than eyes receiving flurbiprofen (18.8 mmHg) and a slower decrease in IOP in the weeks after surgery. Over the course of the study, a higher percentage of eyes receiving bromfenac had therapy discontinued over concerns of elevated IOP compared to eyes receiving flurbiprofen (bromfenac 23.1% and flurbiprofen 9.8%). On average, the risk of having elevated intraocular pressure with bromfenac is 1.04 times higher than with flurbiprofen. Elevated postoperative IOP was observed in both treatment groups; however, bromfenac-treated eyes were more likely to require intervention for elevated IOP. © 2016 American College of Veterinary Ophthalmologists.

Enantioseparation of Racemic Flurbiprofen by Aqueous Two-Phase Extraction With Binary Chiral Selectors of L-dioctyl Tartrate and L-tryptophan.

PubMed

Chen, Zhi; Zhang, Wei; Wang, Liping; Fan, Huajun; Wan, Qiang; Wu, Xuehao; Tang, Xunyou; Tang, James Z

2015-09-01

A novel method for chiral separation of flurbiprofen enantiomers was developed using aqueous two-phase extraction (ATPE) coupled with biphasic recognition chiral extraction (BRCE). An aqueous two-phase system (ATPS) was used as an extracting solvent which was composed of ethanol (35.0% w/w) and ammonium sulfate (18.0% w/w). The chiral selectors in ATPS for BRCE consideration were L-dioctyl tartrate and L-tryptophan, which were screened from amino acids, β-cyclodextrin derivatives, and L-tartrate esters. Factors such as the amounts of L-dioctyl tartrate and L-tryptophan, pH, flurbiprofen concentration, and the operation temperature were investigated in terms of chiral separation of flurbiprofen enantiomers. The optimum conditions were as follows: L-dioctyl tartrate, 80 mg; L-tryptophan, 40 mg; pH, 4.0; flurbiprofen concentration, 0.10 mmol/L; and temperature, 25 °C. The maximum separation factor α for flurbiprofen enantiomers could reach 2.34. The mechanism of chiral separation of flurbiprofen enantiomers is discussed and studied. The results showed that synergistic extraction has been established by L-dioctyl tartrate and L-tryptophan, which enantioselectively recognized R- and S-enantiomers in top and bottom phases, respectively. Compared to conventional liquid-liquid extraction, ATPE coupled with BRCE possessed higher separation efficiency and enantioselectivity without the use of any other organic solvents. The proposed method is a potential and powerful alternative to conventional extraction for separation of various enantiomers. © 2015 Wiley Periodicals, Inc.

An examination of the thermodynamics of fusion, vaporization, and sublimation of (R,S)- and (R)-flurbiprofen by correlation gas chromatography.

PubMed

Umnahanant, Patamaporn; Hasty, Darrell; Chickos, James

2012-06-01

The vaporization, fusion, and sublimation enthalpies of (R,S)- and (R)-flurbiprofen at T = 298.15 K are reported and compared with literature values when available. Correlation gas chromatography experiments were first performed to identify appropriate standards that could be used for materials containing a single fluorine substituent. Subsequent correlations resulted in a vaporization enthalpy for (R,S)-flurbiprofen and (R)-flurbiprofen, ΔH(vap) (298.15 K), of (127.5 ± 5.5) and (127.4 ± 4.7) kJ mol, respectively. Fusion enthalpies, ΔH(fus) (387 K), of (28.2 ± and, ΔH(fus) (381 K), (22.8 ± kJ mol(-1) were also measured by differential scanning calorimetry for the racemic and chiral forms of flurbiprofen. Adjusted to T = 298.15 K and combined with the vaporization enthalpy resulted in sublimation enthalpies, ΔH(sub) (298.15 K), of (155.6 ± 5.8) and (145.1 ± 5.7) kJ mol(-1) for (R,S)- and (R)-flurbiprofen, respectively. The fusion enthalpy measured for the racemic form was in excellent agreement with the literature value, while the sublimation enthalpy varies substantially from previous work. Two weak solid-solid phase transitions were also observed for (R)-flurbiprofen at T = 353.9 K (0.30 ± 0.1) and 363.2 K (0.21 ± 0.03) kJ · mol(-1). Copyright © 2012 Wiley Periodicals, Inc.

Microcirculatory Impairment Following Focal and Global Cerebral Ischemia in the Rat.

DTIC Science & Technology

1982-02-08

THI 4 AGE (Won Dal. BIer SECURITY CLASSIFICATION OF THIS PAGE (When Data Entered) anti-inflammatory drugs (indomethacin, ibuprofen, flurbiprofen ...ibuprofen, flurbiprofen ), prostacyclin, antiserum against presumptive factor- Vill antigen, glass-wool filtration of blood, and alteration of arterial...used in these studies were indomethacin (WSD L-590, 226), ibuprofen (Upjohn U-IS, 573), flurbiprofen (Upjohn U-27, 182), and prostacyclin (Upjohn U

Cell Cycle Target-Based Therapy of Ovarian Cancer

DTIC Science & Technology

2008-03-01

inducers of apoptosis included flufenamic acid, flurbiprofen, celebrex and finasteride , whereas treatment with ibuprofen in low levels of apoptosis...Ibuprofen, Exisulind, Acetaminophen, Naproxen, NS-398, Celecoxib, Diclofenac, Finasteride , Flufenamic acid, Meloxican, Ebselen and Flurbiprofen was...Diclofenac, 50µM Finasteride , 200µM Flufenamic acid, 40µM Meloxican, 50µM Ebselen, 20nM Flurbiprofen or 50µM Sulindac sulfide. Apoptosis was measured 24

Improvement in bioavailability of transdermally applied flurbiprofen using tulsi (Ocimum sanctum) and turpentine oil.

PubMed

Charoo, Naseem Ahmad; Shamsher, Areeg Anwer Ali; Kohli, Kanchan; Pillai, Krishna; Rahman, Ziyaur

2008-09-01

Penetration enhancing potential of tulsi and turpentine oil on transdermal delivery of flurbiprofen, a potent non-steroidal anti-inflammatory agent, was investigated. The transdermal permeation rate of flurbiprofen across the rat abdominal skin from binary solvent mixture composition of propylene glycol (PG):isopropyl alcohol (IPA) (30:70%, v/v) was 98.88 microg/cm(2)/h, significantly higher than other binary solvent mixtures. The corresponding steady state plasma concentration, 0.71 microg/ml, was much lower than required steady state plasma concentration of 3-5 microg/ml. Hence influence of tulsi and turpentine oil in the optimized binary solvent mixture along with the increased drug load on the flurbiprofen permeation was evaluated. The magnitude of the flux enhancement factor with turpentine oil and tulsi oil was 2.4 and 2.0 respectively at 5% (v/v) concentration beyond which there was no significant increase in the flux. Addition of 2% (w/v) hydroxypropyl methylcellulose (HPMC), as a thickening agent, resulted in desired consistency for the fabrication of patch with insignificant effect on permeation rate of flurbiprofen. The reservoir type of transdermal patch formulation, fabricated by encapsulating the flurbiprofen reservoir solution within a shallow compartment moulded from polyester backing film and microporous ethyl vinyl acetate membrane, did not modulate the skin permeation of flurbiprofen through rat skin in case of turpentine formulations whereas flux of formulations with tulsi oil was significantly altered. The influence of penetration enhancer and solvents on the anatomical structure of the rat skin was studied. Enhancement properties exhibited by turpentine oil and tulsi oil in optimized binary solvent mixture were superior as compared to solvent treated and normal control groups with negligible skin irritation. The fabricated transdermal patches were found to be stable. The bioavailability of flurbiprofen with reference to orally administered flurbiprofen in albino rats was found to increase by 2.97, 3.80 and 5.56 times with transdermal patch formulation without enhancer, tulsi and turpentine oil formulations, respectively. The results were confirmed by pharmacodynamic studies in rat edema inflammation model.

Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

PubMed

Karlsson, Jessica; Fowler, Christopher J

2014-01-01

In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

Physicochemical, in vitro and in vivo evaluation of flurbiprofen microemulsion.

PubMed

Naeem, Muhammad; Ur Rahman, Nisar; Tavares, Guilherme D; Barbosa, Sávio F; Chacra, Nádia B; Löbenberg, Raimar; Sarfraz, Muhammad K

2015-09-01

Flurbiprofen, a potent nonsteroidal anti-inflammatory drug, is widely used for relief of pain in patients suffering from rheumatic diseases, migraine, sore throat and primary dysmenorrheal. However, this drug has many gastrointestinal side effects produced by its oral administration, such as gastric bleeding and peptic ulcer. These effects were responsible for non-compliance among patients, which ultimately results in treatment failure. The physicochemical properties of flurbiprofen, make it a suitable candidate for transdermal drug delivery, which can overcome the drawbacks of oral administration. In this sense, microemulsions have been proved to increase the cutaneous absorption of lipophilic drugs when compared to conventional drug delivery systems. The purpose of this study was to formulate and characterize gel based microemulsions, for topical delivery of flurbiprofen. Different gel bases, containing microemulsion and hydro-alcoholic solution of flurbiprofen, were developed and compared. In vitro study showed that gels containing microemulsion had a higher permeation rate than those containing hydro-alcoholic solutions. Additionally, formulation of Carbopol-I (microemulsion) showed higher percent of inhibition of inflammation than others bases. Further, skin irritation study demonstrated that Carbopol-I was none irritating. Flurbiprofen microemulsion incorporated on Carbopol-I showed physicochemical, in vitro and in vivo characteristics suitable for the development of alternative transdermal delivery formulation.

Stability-Indicating HPTLC Method for Simultaneous Estimation of Flurbiprofen and Chloramphenicol in Ophthalmic Solution.

PubMed

Sadakwala, Vaishnavi M; Chauhan, Renu S; Shah, Shailesh A; Shah, Dinesh R

2016-01-01

A specific, accurate and reproducible stability-indicating high performance thin layer chromatography (HPTLC) method was developed for the estimation of flurbiprofen and chloramphenicol in the presence of their degradation products. Degradation studies of both the drugs were carried out in acidic, alkaline, neutral, oxidative, photolytic and thermal stress conditions. Separation was performed on thin layer chromatography plate precoated with silica gel 60 F254 using ethyl acetate : n-hexane : methanol : tri-ethyl amine (5 : 4 : 2 : 0.5, v/v/v/v). Spots at retention factor 0.29 and 0.62 were recognized as flurbiprofen and chloramphenicol, respectively, and were quantified through densitometric measurements at wavelength 267 nm. Method was found to be linear over the concentration range 12-60 ng/spot with correlation coefficient of 0.9997 for flurbiprofen and 200-1,000 ng/spot with correlation coefficient of 0.9977 for chloramphenicol. The proposed method was applied to the estimation of flurbiprofen and chloramphenicol in commercial ophthalmic formulation. The developed HPTLC method can be applied for routine analysis of flurbiprofen and chloramphenicol in the presence of their degradation products in their individual as well as combined pharmaceutical formulations. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Akt/GSK-3β pathway mediates flurbiprofen-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rats.

PubMed

Sun, Baozhu; Chen, Lin; Wei, Xinbing; Xiang, Yanxiao; Liu, Xiaoqian; Zhang, Xiumei

2011-06-17

Apoptosis is one of the major mechanisms of cell death during cerebral ischemia and reperfusion injury. Flurbiprofen has been shown to reduce cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanism remains unclear. This study aimed to investigate the potential association between the neuroprotective effect of flurbiprofen and the apoptosis inhibiting signaling pathways, in particularly the Akt/GSK-3β pathway. A focal cerebral ischemia rat model was subjected to middle cerebral artery occlusion (MCAO) for 120 min and then treated with flurbiprofen at the onset of reperfusion. The infarct volume and the neurological deficit scores were evaluated at 24h after reperfusion. Cell apoptosis, apoptosis-related proteins and the levels of p-Akt and p-GSK-3β in ischemic penumbra were measured using TUNEL and western blot. The results showed that administration of flurbiprofen at the doses of 5 and 10mg/kg significantly attenuated brain ischemia/reperfusion injury, as shown by a reduction in the infarct volume, neurological deficit scores and cell apoptosis. Moreover, flurbiprofen not only inhibited the expression of Bax protein and p-GSK-3β, but also increased the expression of Bcl-2 protein, the ratio of Bcl-2/Bax as well as the P-Akt level. Taken together, these results suggest that flurbiprofen protects the brain from ischemia/reperfusion injury by reducing apoptosis and this neuroprotective effect may be partly due to the activation of Akt/GSK-3β signaling pathway. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo

PubMed Central

Eriksen, Jason L.; Sagi, Sarah A.; Smith, Tawnya E.; Weggen, Sascha; Das, Pritam; McLendon, D.C.; Ozols, Victor V.; Jessing, Kevin W.; Zavitz, Kenton H.; Koo, Edward H.; Golde, Todd E.

2003-01-01

Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid β protein (Aβ42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid β protein precursor (APP) transgenic mice, and plasma and brain levels of Aβ and the drug were evaluated. These studies show that (a) eight FDA-approved NSAIDs lower Aβ42 in vivo, (b) the ability of an NSAID to lower Aβ42 levels in cell culture is highly predicative of its in vivo activity, (c) in vivo Aβ42 lowering in mice occurs at drug levels achievable in humans, and (d) there is a significant correlation between Aβ42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Aβ42 levels in broken cell γ-secretase assays, indicating that these compounds directly target the γ-secretase complex that generates Aβ from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Aβ42 levels to the greatest extent. Because R-flurbiprofen reduces Aβ42 levels by targeting γ-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Aβ42 lowering agent. PMID:12897211

Evaluation of systemic absorption and renal effects of topical ophthalmic flurbiprofen and diclofenac in healthy cats.

PubMed

Lanuza, Rick; Rankin, Amy J; KuKanich, Butch; Meekins, Jessica M

2016-07-01

To investigate systemic absorption and renal effects of topically applied ophthalmic flurbiprofen and diclofenac in healthy cats. Twelve domestic shorthair cats. Cats were randomly assigned to two treatment groups (n = 6) and administered one drop (approximately 40 μL) of either flurbiprofen 0.03% or diclofenac 0.1% in both eyes four times daily (6 am, 12 pm, 6 pm, and 12 am) for 14 days. Blood samples were collected on days 0, 4, 8, 14, 16, and 17 and analyzed by liquid chromatography and mass spectrometry for flurbiprofen and diclofenac plasma concentrations. A complete blood count (CBC), serum chemistry, and urinalysis were analyzed at the beginning of the study (Day 0) and at the end of topical drug administration (Day 15). Both drugs demonstrated systemic absorption. Flurbiprofen was detected (mean ± SD) at day 4 (237 ± 65 ng/mL), day 8 (396 ± 91 ng/mL), day 14 (423 ± 56 ng/mL), day 16 (350 ± 66 ng/mL), and day 17 (270 ± 62 ng/mL), and diclofenac was detected (mean ± SD) at day 4 (130 ± 44 ng/mL), day 8 (131 ± 25 ng/mL), day 14 (150 ± 36 ng/mL), and sporadically on day 16 [corrected]. Flurbiprofen plasma concentration decreased slowly over 48 h after the last dose. No clinically significant abnormalities were noted in the serum blood urea nitrogen, creatinine, or urine specific gravity at the end of topical drug administration compared to the beginning of the study. Flurbiprofen and diclofenac were systemically absorbed after topical administration four times daily to both eyes of healthy cats. Flurbiprofen reached higher plasma concentrations compared to diclofenac. © 2015 American College of Veterinary Ophthalmologists.

Single dose oral flurbiprofen for acute postoperative pain in adults

PubMed Central

Sultan, Asquad; McQuay, Henry J; Moore, R Andrew; Derry, Sheena

2014-01-01

Background Flurbiprofen is a non-selective non-steroidal anti-inflammatory drug (NSAID), related to ibuprofen and naproxen, used to treat acute and chronic painful conditions. There is no systematic review of its use in acute postoperative pain. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral flurbiprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to January 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered flurbiprofen in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk (RR) and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Eleven studies compared flurbiprofen (699 participants) with placebo (362 participants) in studies lasting 6 to 12 hours. Studies were of adequate reporting quality, and most participants had pain following dental extractions. The dose of flurbiprofen used was 25 mg to 100 mg, with most information for 50 mg and 100 mg. The NNT for at least 50% pain relief over 4 to 6 hours for flurbiprofen 50 mg compared with placebo (692 participants) was 2.7 (2.3 to 3.3) and for 100 mg (416 participants) it was 2.5 (2.0 to 3.1). With flurbiprofen 50 mg and 100 mg 65% to 70% of participants experienced at least 50% pain relief, compared with 25% to 30% with placebo. Rescue medication was used by 25% and 16% of participants with flurbiprofen 50 mg and 100 mg over 6 hours, compared with almost 70% with placebo. Adverse events were uncommon, and not significantly different from placebo. Authors’ conclusions Flurbiprofen at doses of 50 mg and 100 mg is an effective analgesic in moderate to severe acute postoperative pain. The NNT for at least 50% pain relief is similar to that of commonly used NSAIDs such as ibuprofen and naproxen at usual doses. Use of rescue medication indicates a duration of action exceeding 6 hours. PMID:19588427

Growth and shrinkage of pluronic micelles by uptake and release of flurbiprofen: variation of pH.

PubMed

Alexander, Shirin; de Vos, Wiebe M; Castle, Thomas C; Cosgrove, Terence; Prescott, Stuart W

2012-04-24

The micellization of Pluronic triblock copolymers (P103, P123, and L43) in the presence of flurbiprofen at different pH was studied by small-angle neutron scattering (SANS), pulsed-field gradient stimulated-echo nuclear magnetic resonance (PFGSE-NMR), and surface tension measurements. Addition of flurbiprofen to the Pluronic at low pH leads to an increase in the fraction of micellization, aggregation number, and the core radius of the micelles. However, changing the pH to above the pKa of flurbiprofen in an ethanol/water mixture (∼6.5) reduces the fraction of micellization and results in a weaker interaction between the drug and micelles due to the increased drug solubility in aqueous solution.

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study.

PubMed

Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Schachtel, Emily

2014-07-03

The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Adults (n=198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n=101) or matching placebo lozenges (n=97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P<0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P<0.01). There were no serious adverse events. Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010.

Solid-state flurbiprofen and methyl-β-cyclodextrin inclusion complexes prepared using a single-step, organic solvent-free supercritical fluid process.

PubMed

Rudrangi, Shashi Ravi Suman; Kaialy, Waseem; Ghori, Muhammad U; Trivedi, Vivek; Snowden, Martin J; Alexander, Bruce David

2016-07-01

The aim of this study was to enhance the apparent solubility and dissolution properties of flurbiprofen through inclusion complexation with cyclodextrins. Especially, the efficacy of supercritical fluid technology as a preparative technique for the preparation of flurbiprofen-methyl-β-cyclodextrin inclusion complexes was evaluated. The complexes were prepared by supercritical carbon dioxide processing and were evaluated by solubility, differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, practical yield, drug content estimation and in vitro dissolution studies. Computational molecular docking studies were conducted to study the possibility of molecular arrangement of inclusion complexes between flurbiprofen and methyl-β-cyclodextrin. The studies support the formation of stable molecular inclusion complexes between the drug and cyclodextrin in a 1:1 stoichiometry. In vitro dissolution studies showed that the dissolution properties of flurbiprofen were significantly enhanced by the binary mixtures prepared by supercritical carbon dioxide processing. The amount of flurbiprofen dissolved into solution alone was very low with 1.11±0.09% dissolving at the end of 60min, while the binary mixtures processed by supercritical carbon dioxide at 45°C and 200bar released 99.39±2.34% of the drug at the end of 30min. All the binary mixtures processed by supercritical carbon dioxide at 45°C exhibited a drug release of more than 80% within the first 10min irrespective of the pressure employed. The study demonstrated the single step, organic solvent-free supercritical carbon dioxide process as a promising approach for the preparation of inclusion complexes between flurbiprofen and methyl-β-cyclodextrin in solid-state. Copyright © 2016 Elsevier B.V. All rights reserved.

THE INVESTIGATION OF EFFECT OF FLURBIPROFEN AXETIL ON THE TISSUE GROWTH AND THE CONTENT OF PGE2 IN CERVICAL CANCER.

PubMed

Lu, Jing; Wang, Shenggang; Chen, Guiying; Sun, Xiaofeng; Li, Kezhong

2016-11-01

The aim of this study was to investigate whether flurbiprofen axetil can inhibit the tissue growth and the content of PGE2 in cervical cancer or not. Fifty female BALB/c nude mice were randomly divided into control group (C), tumor + saline group (T), tumor + flurbiprofen axetil 10 mg/kg (Cfl0) group, tumor + flurbiprofen axetil 25 mg/kg (Cf25) group, tumor + flurbiprofen axetil tumor 50 mg/kg (Cf50), so that each group had 10 animals. Then, the animal model of human cervical carcinoma was established, and the relative tumor volume (RTV), relative tumor proliferation rate (T/C) and tumor inhibition rate were measured. The content of PGE2 in tumor tissue was determined by using enzyme-linked immunosorbent assay. There was no tumor formation in group C, and the time of tumor growth in other groups was non-statistically different. The RVT in Cf50 group was lower than in other groups. It was evident from the curve of tumor growth that the tumor weight in T group was evidently higher than that of administration groups (p < 0.01). The tumor inhibition rates of Cf10, Cf25 and Cf50 groups were 16.8, 19.6 and 36%, respectively, and the relative tumor proliferation rate were 85, 91 and 72%, respectively. The PGE, level of Cf50 was statistically (p < 0.01) lower than that of Cfl0 and Cf25 groups. Flurbiprofen axetil can inhibit the growth of cervical cancer transplanted tumor in nude mice and this inhibitory effect was maximal in Cf50 group. Flurbiprofen axetil can inhibit the production of PGE2 in tumor tissue of cervical carcinoma in nude mice.

Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect.

PubMed

Sonvico, Fabio; Conti, Chiara; Colombo, Gaia; Buttini, Francesca; Colombo, Paolo; Bettini, Ruggero; Barchielli, Marco; Leoni, Barbara; Loprete, Luca; Rossi, Alessandra

2017-09-28

In this work, a fixed-dose combination of gabapentin and flurbiprofen formulated as multilayer tablets has been designed, developed and studied in vitro and in vivo. The aim was to construct a single dosage form of the two drugs, able to perform a therapeutic program involving three release kinetics and two delivery sites, i.e., immediate release of gabapentin, intra-gastric prolonged release of gabapentin and intestinal (delayed) release of flurbiprofen. An oblong three-layer tablet was manufactured having as top layer a floating hydrophilic polymeric matrix for gastric release of gabapentin, as middle layer a disintegrating formulation for immediate release of a gabapentin loading dose and as bottom layer, an uncoated hydrophilic polymeric matrix, swellable but insoluble in gastric fluids, for delayed and prolonged release of flurbiprofen in intestinal environment. The formulations were studied in vitro and in vivo in healthy volunteers. The in vitro release rate assessment confirmed the programmed delivery design. A significant higher bioavailability of gabapentin administered 30min after meal, compared to fasting conditions or to dose administration 10min before meal, argued in favor of the gastro-retention of gabapentin prolonged release layer. The two drugs were delivered at different anatomical sites, since the food presence prolonged the gastric absorption of gabapentin from the floating layer and delayed the flurbiprofen absorption. The attainment of a successful delayed release of flurbiprofen was realized by a matrix based on a polymers' combination. The combined use of three hydrophilic polymers with different pH sensitivity provided the dosage form layer containing flurbiprofen with gastro-resistant characteristics without the use of film coating. Copyright © 2017 Elsevier B.V. All rights reserved.

Flurbiprofen in the symptomatic management of rheumatoid arthritis: a valuable alternative.

PubMed

Richy, F; Rabenda, V; Mawet, A; Reginster, J-Y

2007-08-01

The withdrawal of certain cyclooxygenase-2 selective drugs and the availability of over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) have increased the pressure for researching and prescribing conventional NSAIDs with a favourable efficacy/tolerance ratio in inflammatory diseases, particularly rheumatoid arthritis. The aim of this comprehensive meta-analysis was to evaluate the absolute and relative efficacy and safety of flurbiprofen in the management of rheumatoid arthritis. A systematic and exhaustive bibliographic research of published literature has been performed. The inclusion criteria are summarised as follows: randomised trial and rheumatoid arthritis and flurbiprofen and oral administration and anti-inflammatory doses from 100 to 300 mg and (placebo or aspirin or indomethacin or naproxen or ibuprofen or ketoprofen) and (articular pain or stiffness or swelling or mobility or patient/physician reported efficacy or tolerance or gastrointestinal (GI) tolerance). Studies were conducted from January 1975 to January 2006. Analyses have been stratified by comparisons and outcomes. Publication bias and robustness have been extensively investigated. Fourteen studies, accounting for 1103 patient-years, have been included in the quantitative review. The mean daily doses administrated were 200 mg flurbiprofen, 4000 mg aspirin, 150 indomethacin, 750 mg naproxen and 1800 mg ibuprofen. Flurbiprofen was superior to placebo for all outcomes, and superior to three of four other NSAIDs in terms of formal symptomatic measures (pain, stiffness and swelling). Several patients or physicians reported the efficacy of flurbiprofen as superior to indomethacin and naproxen, while its safety, and particularly its GI tolerance were better compared with aspirin and indomethacin. Sensitivity analyses have reported a sufficient robustness against systematic publication bias assumptions. This meta-analysis has shown that flurbiprofen is an interesting alternative to commonly prescribed NSAIDs in the symptomatic management of rheumatoid arthritis, especially given its favourable efficacy/tolerance ratio.

Induction of the p75NTR by Aryl Propionic Acids in Prostate Cancer Cells

DTIC Science & Technology

2007-12-01

among others. Long term ibuprofen use is associated with a decreased risk of prostate cancer (9-10). Treatment with the enantiomer R-flurbiprofen...cancer cell lines, PC-3 and DU-145. Of those tested, the enantiomer R-flurbiprofen and ibuprofen were the most effective. These drugs were also...Treatment of T24 bladder cancer cells and HCT-116 colon cancer cells with ibuprofen or the enantiomer R-flurbiprofen, which lacks COX inhibitory

Combination therapy in a transgenic model of Alzheimer’s disease

PubMed Central

Aytan, Nurgul; Choi, Ji-Kyung; Carreras, Isabel; Kowall, Neil W.

2013-01-01

The pathological accumulation of the β-amyloid protein (Aβ) has been closely associated with synaptic loss and neurotoxicity contributing to cognitive dysfunction in Alzheimer’s disease (AD). Oligomers of Aβ42 appear to be the most neurotoxic form. Two of the most promising attempts to reduce Aβ accumulation have been with scyllo-inositol, an inositol steroisomer, that stabilizes Aβ42 peptide and prevents it from progressing to oligomers and fibrils and R-flurbiprofen, a purified enantiomer of the classical racemic non-steroidal anti-inflammatory drugs (NSAID), flurbiprofen, that retains the ability to specifically lower Aβ42. In the present study we evaluated the effects of scyllo-inositol and the combination treatment of scyllo-inositol + R-flurbiprofen on amyloid pathology and hippocampal-dependent memory function in 5XFAD mice, a model of Aβ pathology characterized by an enormous production of Aβ42. Our expectations were that the combination treatment of scylloinositol + R-flurbiprofen would have an additive effect in preventing Aβ accumulation and that cognition would be improved. Mice treated with scyllo-inositol exhibit 41 and 35% reduction in the deposition of the amyloid plaques stained by antibody against Aβ42 and Aβ40 respectively. Scyllo-inositol was not more effective when combined with R-flurbiprofen for the measures tested. Scyllo-inositol treated mice performed significantly better at the radial arm water maze (RAWM) task than untreated and scyllo-inositol + R-flurbiprofen treated mice. PMID:24120437

Inhibition of Endocannabinoid Metabolism by the Metabolites of Ibuprofen and Flurbiprofen

PubMed Central

Karlsson, Jessica; Fowler, Christopher J.

2014-01-01

Background In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. Methodology/Principal Findings COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4′-hydroxyflurbiprofen and possibly also 3′-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. Conclusions/Significance It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo. PMID:25061885

Effects of flurbiprofen axetil on postoperative serum IL-2 and IL-6 levels in patients with colorectal cancer.

PubMed

Jiang, W W; Wang, Q H; Peng, P; Liao, Y J; Duan, H X; Xu, M; Li, Y; Zhang, P B

2015-12-09

We explored the effects of flurbiprofen axetil on interleukin (IL)-2 and IL-6 levels in postoperative patients with colorectal cancer. A total of 120 patients (American Society of Anesthesiologists I and II) scheduled to undergo colorectal cancer surgery were randomly divided into 3 groups (N = 40 in each group): flurbiprofen axetil group (group F), morphine group (group M), and tramadol group (group T). Group M received 0.1 mg/kg morphine, group T received 1.5 mg/kg tramadol, and group F received 1.5 mg/kg flurbiprofen axetil. Patients in the 3 groups were administered treatments through intravenous injection 10 min before surgery. Serum IL-2 and IL-6 levels were detected. Postoperative adverse reactions were recorded, such as nausea, vomiting, and pruritus. The serum IL-6 level of the 3 groups increased 3 h after surgery. Compared with group M, IL-6 level was higher in group T and group F at 1 day after the surgery, and the differences between group M and the other groups were significant (P < 0.05). Moreover, the incidence of adverse reactions was significantly different among 3 groups (P < 0.05). Flurbiprofen axetil promoted the secretion of IL-2 and inhibited IL-6; additionally, flurbiprofen axetil may have a lower incidence of adverse reactions compared to other treatments.

Topical flurbiprofen toxicosis in a cat.

PubMed

Yi, Elizabeth M; Leech, Elizabeth

2017-11-01

To describe the clinical presentation and treatment of a cat with flurbiprofen toxicosis due to topical cream exposure. A 3-year-old castrated male domestic shorthair cat presented to an emergency and referral center for acute lethargy, hematemesis, and anemia. Severe azotemia was observed on serum biochemistry panel. The patient's anemia was treated with packed RBC transfusion, and treatment with crystalloid fluids, famotidine, pantoprazole, ampicillin, and sucralfate were begun on presentation. Anemia became intractable and the patient received multiple packed RBC and whole blood transfusions. Severe gastric ulcerations and duodenal perforation were confirmed via gastroduodenoscopy, and the patient was treated with surgical excision and repair of duodenal perforation. Azotemia resolved with IV fluid therapy, and anemia resolved following surgery. The patient recovered and was discharged after 9 days of hospitalization. The patient had likely been exposed to the owner's compounded pain relief cream containing 10% flurbiprofen. There was confirmation of flurbiprofen exposure via acid extraction urine analysis at a university toxicology laboratory. This is the first described case of flurbiprofen toxicosis due to topical cream exposure in a cat. © Veterinary Emergency and Critical Care Society 2017.

Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration

PubMed Central

Kai, Shuken; Kondo, Eiji; Kawaguchi, Yasuyuki; Kitamura, Nobuto; Yasuda, Kazunori

2013-01-01

Aim To compare tissue concentrations of flurbiprofen resulting from topical application and oral administration according to the regulatory approved dosing guidelines. Method Sixteen patients were included in this study. Each patient was randomly assigned to the topical application or oral administration group. In each group, a pair of tapes or a tablet, containing a total of 40 mg flurbiprofen, was administered twice at 16 and 2 h before the surgery. Results The flurbiprofen concentration in the fat, tendon, muscle and periosteum tissues was significantly higher (P < 0.0330) after topical application (992 ng g−1 [95% CI 482, 1503], 944 [95% CI 481, 1407], 492 [95% CI 248, 735], and 455 [95% CI 153, 756], respectively) than after oral administration (150 ng g−1 [95% CI 84, 217], 186 [95% CI 118, 254], 82 [95% CI 49, 116],and 221 [95% CI, 135, 307], respectively). Conclusion Topical application is an effective method to deliver flurbiprofen to the human body, particularly to soft tissues near the body surface. PMID:22822928

Topical flurbiprofen or prednisolone. Effect on corneal wound healing in rabbits.

PubMed

Miller, D; Gruenberg, P; Miller, R; Bergamini, M V

1981-04-01

Flurbiprofen is a nonsteroidal anti-inflammatory (NSAI) agent currently undergoing clinical investigation. Anti-inflammatory steroids have long been known to delay the healing of corneal stromal wounds. This was designed to compare the effects of equipotent anti-inflammatory doses of flurbiprofen and of prednisolone acetate on the inflammation and the healing (as measured by the wound bursting pressure) or 4-mm through-and-through incisions treated four times a day for ten postoperative days. The results suggest that flurbiprofen and prednisolone are not different in their effect on both postoperative inflammation and postoperative wound healing. Since NSAI agents and steroids inhibit prostaglandin formation at different enzymatic steps, it is possible that prostaglandins not only are responsible for postoperative inflammation but also are required for postoperative wound healing.

The effects of aspirin, flurbiprofen, and NO-donating acetylsalicylic acid (NCX 4016) on mice models of endotoxic and septic shock.

PubMed

Ulu, Nadir; Iskit, Alper Bektaş; Sökmensüer, Cenk; Güç, Mustafa Oğuz

2015-01-01

Nitric oxide-donating nonsteroidal antiinflammatory drugs (NO-NSAIDs) are a promising new class of antiinflammatory agents, which are obtained by adding NO-donating moieties to the existing conventional NSAID molecules. The aim of this study was to investigate the effects of aspirin, flurbiprofen, and NO-donating acetylsalicylic acid (NCX 4016) on cecal ligation and puncture (CLP) and endotoxin-induced septic shock (LPS) models in mice. Overall survival and spleen and liver weights were monitored in LPS and CLP models. Histopathological examinations of liver and spleen were performed at the end of the experimental protocols. NCX 4016 was able to reverse the increased spleen weight in CLP-operated animals, whereas aspirin or flurbiprofen did not. Similar to the results of the CLP model, none of the drugs modified the survival rates in the LPS model. Flurbiprofen in particular produced significant histopathological damage in spleens and livers, which was less significant with aspirin. NCX 4016 did not cause any liver damage. NCX 4016 has the potential to be used in septic states, while special attention has to be paid to the effects of aspirin and flurbiprofen on the liver and spleen.

2D SMARTCyp Reactivity-Based Site of Metabolism Prediction for Major Drug-Metabolizing Cytochrome P450 Enzymes

DTIC Science & Technology

2012-05-25

3. (A) X-ray structure of human CYP2C9 cocrystallized with flurbiprofen showing hydrogen bonding interactions between the anionic carboxyl group with...Figure 3 shows the X-ray crystal structure of human CYP2C9 cocrystallized with flurbiprofen . The structure indicates that the carboxyl group of... flurbiprofen forms hydrogen bonding interactions with the Arg108 and Asn204 side chains of the protein.35 Since the Arg108 and Asn204 side chains are at the

Onset of action of a lozenge containing flurbiprofen 8.75 mg: a randomized, double-blind, placebo-controlled trial with a new method for measuring onset of analgesic activity.

PubMed

Schachtel, Bernard; Aspley, Sue; Shephard, Adrian; Shea, Timothy; Smith, Gary; Sanner, Kathleen; Savino, Laurie; Rezuke, Jeanne; Schachtel, Emily

2014-02-01

A new onset-of-action model was utilized to distinguish the pharmacologic activity of flurbiprofen 8.75mg delivered in a lozenge from the demulcent effect of the lozenge base. In a randomized, double-blind, placebo-controlled trial, patients with sore throat rated pain on a Sore Throat Pain Intensity Scale before taking one flurbiprofen or placebo lozenge and at frequent (2-minute) intervals over the first hour after treatment. Further ratings of the Sore Throat Pain Intensity Scale and other patient-reported outcomes (difficulty swallowing, swollen throat, pain relief) were obtained at varying intervals over 6 hours. Onset of pharmacologic activity was defined as the median time of first perceived pain reduction if a patient reported clinically meaningful (at least moderate) relief. The conventional method of comparing mean treatment responses at each time point was also implemented. Demulcent action was detected at the first 2-minute assessment. By the new method, 102 flurbiprofen-treated patients were identified as first perceiving pain relief at 12 minutes, compared with >120 minutes by 102 patients using placebo (P<0.001). By the conventional method, mean percentage pain reduction for flurbiprofen 8.75 mg was first significantly differentiated from placebo at 26 minutes (P<0.05). Efficacy of flurbiprofen lozenge was demonstrated for 3.5-4hours on the 4 patient-reported outcomes (all P<0.05 compared with placebo). There were no serious adverse events. This patient-centered onset-of-action model identifies the initiation of pain relief in patients who are definite drug responders, here demonstrating that a flurbiprofen 8.75-mg lozenge provides early relief of sore throat. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Randomised, double-blind, placebo-controlled studies on flurbiprofen 8.75 mg lozenges in patients with/without group A or C streptococcal throat infection, with an assessment of clinicians' prediction of 'strep throat'.

PubMed

Shephard, A; Smith, G; Aspley, S; Schachtel, B P

2015-01-01

Diagnosing group A streptococcus (Strep A) throat infection by clinical examination is difficult, and misdiagnosis may lead to inappropriate antibiotic use. Most patients with sore throat seek symptom relief rather than antibiotics, therefore, therapies that relieve symptoms should be recommended to patients. We report two clinical trials on the efficacy and safety of flurbiprofen 8.75 mg lozenge in patients with and without streptococcal sore throat. The studies enrolled adults with moderate-to-severe throat symptoms (sore throat pain, difficulty swallowing and swollen throat) and a diagnosis of pharyngitis. The practitioner assessed the likelihood of Strep A infection based on historical and clinical findings. Patients were randomised to flurbiprofen 8.75 mg or placebo lozenges under double-blind conditions and reported the three throat symptoms at baseline and at regular intervals over 24 h. A total of 402 patients received study medication (n = 203 flurbiprofen, n = 199 placebo). Throat culture identified Strep A in 10.0% of patients and group C streptococcus (Strep C) in a further 14.0%. The practitioners' assessments correctly diagnosed Strep A in 11/40 cases (sensitivity 27.5%, and specificity 79.7%). A single flurbiprofen lozenge provided significantly greater relief than placebo for all three throat symptoms, lasting 3-4 h for patients with and without Strep A/C. Multiple doses of flurbiprofen lozenges over 24 h also led to symptom relief, although not statistically significant in the Strep A/C group. There were no serious adverse events. The results highlight the challenge of identifying Strep A based on clinical features. With the growing problem of antibiotic resistance, non-antibiotic treatments should be considered. As demonstrated here, flurbiprofen 8.75 mg lozenges are an effective therapeutic option, providing immediate and long-lasting symptom relief in patients with and without Strep A/C infection. © 2014 John Wiley & Sons Ltd.

Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study

PubMed Central

2014-01-01

Background The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Methods Adults (n = 198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n = 101) or matching placebo lozenges (n = 97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Results Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P <0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P <0.01). There were no serious adverse events. Conclusions Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. Trial registration This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010. PMID:24988909

Flurbiprofen-antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling.

PubMed

Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

2016-01-01

Flurbiprofen-antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (-COOH) was temporarily masked by esterification with phenolic -OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001) reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-yl)propanoate (4b) showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer's yeast-induced pyrexia model, and significant (P<0.001) reduction in rectal temperature was shown by all prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug.

Flurbiprofen microgranules for relief of sore throat: a randomised, double-blind trial

PubMed Central

Russo, Marc; Bloch, Mark; de Looze, Fred; Morris, Christopher; Shephard, Adrian

2013-01-01

Background Many people with sore throat seek, and are often inappropriately prescribed, antibiotics. Aim The objective of this study was to determine the analgesic efficacy of flurbiprofen 8.75 mg microgranules versus placebo. These microgranules are a possible alternative treatment for patients with sore throat due to upper respiratory tract infection (URTI). Design and setting Randomised, double-blind, placebo-controlled, multiple-dose study conducted at eight primary care sites in Australia. Method Participants with sore throat of onset within the past 4 days received either flurbiprofen 8.75 mg microgranules or non-medicated placebo microgranules. Throat soreness, difficulty in swallowing, sore throat pain intensity, sore throat relief, oral temperature, and treatment benefits were all assessed at regular intervals. Result Of 373 patients from eight centres, 186 received flurbiprofen 8.75 mg microgranules and 187 received placebo microgranules (intent-to-treat population). Throat soreness was significantly reduced over the first 2 hours after the first dose. Reductions in difficulty in swallowing were observed at all time points from 5 to 360 minutes after the first dose, after taking flurbiprofen microgranules versus placebo. Sore throat relief was also evident at 1 minute and lasted for at least 6 hours. The multiple-dose efficacy results showed reduction of difficulty in swallowing at the end of days 1–3 and sore throat relief at the end of day 1. Conclusion Microgranules containing flurbiprofen 8.75 mg provided fast and effective relief from sore throat due to URTI and represent an alternative treatment option to antibiotic therapy. PMID:23561694

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

PubMed Central

Kukar, Thomas; Prescott, Sonya; Eriksen, Jason L; Holloway, Vallie; Murphy, M Paul; Koo, Edward H; Golde, Todd E; Nicolle, Michelle M

2007-01-01

Background Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice. Results A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning. Conclusion We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Aβ42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of R-flurbiprofen as an AD therapeutic and its possible mechanisms of action. PMID:17650315

Intravenous flurbiprofen axetil can increase analgesic effect in refractory cancer pain

PubMed Central

Wu, Hongyang; Chen, Zhendong; Sun, Guoping; Gu, Kangsheng; Pan, Yueyin; Hao, Jiqing; Du, Yingying; Ning, Jie

2009-01-01

Background The aim of this study was to investigate the analgesic effects of intravenous flurbiprofen axetil for the refractory pain in cancer patients. Methods 2109 patients were screened from the department of medical oncology, the first affiliated hospital of Anhui medical university in China between October of 2007 and October of 2008. Thirty-seven cases of cancer patients who had bad effect from anaesthetic drugs were received administration of intravenous flurbiprofen axetil with dose of 50 mg/5 ml/day. The pain score was evaluated for pre- and post- treatment by Pain Faces Scale criteria, and the side effects were also observed. Results Intravenous flurbiprofen axetil increased the analgesic effects. The total effective rate was 92%. The side effects, such as abdominal pain, alimentary tract bleeding which were found in using NSAIDs or constipation, nausea, vomit, sleepiness which were found in using opioid drugs did not be found. Conclusion Intravenous flurbiprofen axetil could provide better analgesia effects and few side effects to patients with refractory cancer pain. It could also increase analgesia effects when combining with anesthetic drugs in treatment of moderate or severe pain, especially breakthrough pain, and suit to patients who can not take oral drugs for the reason of constipation and psychosomatic symptoms. PMID:19267934

High enantioselective Novozym 435-catalyzed esterification of (R,S)-flurbiprofen monitored with a chiral stationary phase.

PubMed

Siódmiak, Tomasz; Mangelings, Debby; Vander Heyden, Yvan; Ziegler-Borowska, Marta; Marszałł, Michał Piotr

2015-03-01

Lipases form Candida rugosa and Candida antarctica were tested for their application in the enzymatic kinetic resolution of (R,S)-flurbiprofen by enantioselective esterification. Successful chromatographic separation with well-resolved peaks of (R)- and (S)-flurbiprofen and their esters was achieved in one run on chiral stationary phases by high-performance liquid chromatography (HPLC). In this study screening of enzymes was performed, and Novozym 435 was selected as an optimal catalyst for obtaining products with high enantiopurity. Additionally, the influence of organic solvents (dichloromethane, dichloroethane, dichloropropane, and methyl tert-butyl ether), primary alcohols (methanol, ethanol, n-propanol, and n-butanol), reaction time, and temperature on the enantiomeric ratio and conversion was tested. The high values of enantiomeric ratio (E in the range of 51.3-90.5) of the esterification of (R,S)-flurbiprofen were obtained for all tested alcohols using Novozym 435, which have a great significance in the field of biotechnological synthesis of drugs. The optimal temperature range for the performed reactions was from 37 to 45 °C. As a result of the optimization, (R)-flurbiprofen methyl ester was obtained with a high optical purity, eep = 96.3 %, after 96 h of incubation. The enantiomeric ratio of the reaction was E = 90.5 and conversion was C = 35.7 %.

[The Influence of Flurbiprofen on the Frequency of Postoperative Shivering].

PubMed

Urabe, Tomoaki; Nakanuno, Ryuichi; Hayase, Kazuma; Takata, Nanako; Senami, Masaki

2015-10-01

Many methods to prevent postoperative shivering (POS) has been reported. However, there are few reports demonstrating the effect of flurbiprofen on POS which affects the set point in the thermocenter of the hypothalamus. One hundred and forty six patients undergoing lung lobectomy or segmentectomy under video-assisted thoracic surgery were divided into a flurbiprofen-treated group (Group F) and a non-treated group (Group N). We retrospectively investigated the incidence of POS associated with total intravenous anesthesia with epidural anesthesia compared with or without flurbiprofen. We weighed the incidence of POS against age, body mass index, the effective site concentration of fentanyl on extubation, the mean dose of remifentanil, the minimum rectal temperature, the surgical duration and total hemorrhage volume based on the anesthetic chart Chi-square and Student t-test were used for statistical analysis. Although the surgical duration in Group F was shorter than that in Group N (223±83 vs. 165±80 (min), P<0.01), the incidence of POS in Group F was higher than that in Group N (1/32 vs. 28/114, P<0.01). There were no significant differences in another items between the two groups. The results of the study indicates that flurbiprofen has a possible beneficial effect in preventing POS.

Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers

PubMed Central

Hanley, Michael J; Masse, Gina; Harmatz, Jerold S; Cancalon, Paul F; Dolnikowski, Gregory G; Court, Michael H; Greenblatt, David J

2013-01-01

Aim The present study evaluated the possibility of drug interactions involving blueberry juice (BBJ) and substrate drugs whose clearance is dependent on cytochromes P4503A (CYP3A) and P4502C9 (CYP2C9). Methods A 50:50 mixture of lowbush and highbush BBJ was evaluated in vitro as an inhibitor of CYP3A activity (hydroxylation of triazolam and dealkylation of buspirone) and of CYP2C9 activity (flurbiprofen hydroxylation) using human liver microsomes. In clinical studies, clearance of oral buspirone and oral flurbiprofen was studied in healthy volunteers with and without co-treatment with BBJ. Results BBJ inhibited CYP3A and CYP2C9 activity in vitro, with 50% inhibitory concentrations (IC50) of less than 2%, but without evidence of mechanism-based (irreversible) inhibition. Grapefruit juice (GFJ) also inhibited CYP3A activity, but inhibitory potency was increased by pre-incubation, consistent with mechanism-based inhibition. In clinical studies, GFJ significantly increased area under the plasma concentration−time curve (AUC) for the CYP3A substrate buspirone. The geometric mean ratio (GMR = AUC with GFJ divided by AUC with water) was 2.12. In contrast, the effect of BBJ (GMR = 1.39) was not significant. In the study of flurbiprofen (CYP2C9 substrate), the positive control inhibitor fluconazole significantly increased flurbiprofen AUC (GMR = 1.71), but BBJ had no significant effect (GMR = 1.03). Conclusion The increased buspirone AUC associated with BBJ is quantitatively small and could have occurred by chance. BBJ has no effect on flurbiprofen AUC. The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9. PMID:22943633

Flurbiprofen in rapid eye movement sleep deprivation induced hyperalgesia.

PubMed

Gürel, Elif Ezgi; Ural, Keremcan; Öztürk, Gülnur; Öztürk, Levent

2014-04-10

Rapid eye movement (REM) sleep deprivation induces hyperalgesia in healthy rats. Here, we evaluated the effects of flurbiprofen, an anti-inflammatory and neuroprotective agent, on the increased thermal responses observed in REM sleep deprived rats. Forty female rats were divided into four groups following 96-hour REM sleep deprivation: intraperitoneal injections of placebo, and flurbiprofen 5 mg/kg, 15 mg/kg and 40 mg/kg were made in CONT (n=10), FBP5, FBP15 and FBP40 groups respectively. Pain threshold measurements were performed three times at baseline (0.hour), at the end of REM sleep deprivation (96.hour) and at 1 h after injections (97.hour) by hot plate and tail-flick tests. REM sleep deprivation induced a significant decrease in pain thresholds of all rats (hotplate: 0.hour vs 96.hour, 9.75±2.85 vs 5.10±2.02, p<0.001; tail flick: 0.hour vs 96.hour, 11.92±4.62 vs 7.92±5.15, p<0.001). Flurbiprofen in 15 mg/kg and 40 mg/kg doses significantly improved pain tolerance measured by tail flick test (tail flick in FBP15 and FBP40 groups: 96.hour vs 97.hour, 7.01±4.97 vs 8.34±3.61 and 5.06±1.57 vs 7.04±2.49, p<0.05 for both). 96 h of REM sleep deprivation resulted in reduced pain thresholds in both hot plate and tail flick tests. Flurbiprofen was used for the first time in a rat model of REM sleep deprivation, and it provided anti-nociceptive effects in 15 mg/kg and 40 mg/kg doses. Flurbiprofen may have the potential for treatment of painful syndromes accompanying insomnia or sleep loss. Copyright © 2014 Elsevier Inc. All rights reserved.

Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies

PubMed Central

Bhaskar, Kesavan; Anbu, Jayaraman; Ravichandiran, Velayutham; Venkateswarlu, Vobalaboina; Rao, Yamsani Madhusudan

2009-01-01

The aim of the study is to prepare aqueous dispersions of lipid nanoparticles – flurbiprofen solid lipid nanoparticles (FLUSLN) and flurbiprofen nanostructured lipid carriers (FLUNLC) by hot homogenization followed by sonication technique and then incorporated into the freshly prepared hydrogels for transdermal delivery. They are characterized for particle size, for all the formulations, more than 50% of the particles were below 300 nm after 90 days of storage at RT. DSC analyses were performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by TEM which revealed fairly spherical shape of the formulations. Further they were evaluated for in vitro drug release characteristics, rheological behaviour, pharmacokinetic and pharmacodynamic studies. The pharmacokinetics of flurbiprofen in rats following application of SLN gel (A1) and NLC gel (B1) for 24 h were evaluated. The Cmax of the B1 formulation was 38.67 ± 2.77 μg/ml, which was significantly higher than the A1 formulation (Cmax = 21.79 ± 2.96 μg/ml). The Cmax and AUC of the B1 formulation were 1.8 and 2.5 times higher than the A1 gel formulation respectively. The bioavailability of flurbiprofen with reference to oral administration was found to increase by 4.4 times when gel formulations were applied. Anti-inflammatory effect in the Carrageenan-induced paw edema in rat was significantly higher for B1 and A1 formulation than the orally administered flurbiprofen. Both the SLN and NLC dispersions and gels enriched with SLN and NLC possessed a sustained drug release over period of 24 h but the sustained effect was more pronounced with the SLN and NLC gel PMID:19243632

Efficacy of flurbiprofen 8.75 mg spray in patients with sore throat due to an upper respiratory tract infection: A randomised controlled trial.

PubMed

de Looze, Ferdinandus; Russo, Marc; Bloch, Mark; Montgomery, Barney; Shephard, Adrian; Smith, Gary; Aspley, Sue

2016-06-01

Viral infections cause most cases of pharyngitis (sore throat); consequently, antibiotics are generally not warranted. However, a treatment targeting pain and inflammation, e.g. a topical non-steroidal anti-inflammatory spray, may be helpful for patients. To evaluate the efficacy and safety of flurbiprofen 8.75 mg spray. This randomised, double-blind, parallel group study was conducted at six community-based clinical research centres in Australia and two in New Zealand. Adults with sore throat due to upper respiratory tract infection (onset ≤ four days) took one dose of flurbiprofen (n = 249) or placebo spray (n = 256); after six hours, they could re-dose every three-six hours as required, for three days (max. five doses/day). The primary endpoint was the area under the change from baseline curve in throat soreness from zero-two hours (AUC0-2h). The change from baseline in other sore throat symptoms also assessed efficacy. The mean AUC0-2h for throat soreness was significantly greater with flurbiprofen spray (-1.82; 95% CI: -1.98 to 1.65) compared with placebo (-1.13; 95% CI: -1.27 to 0.99) (P < 0.0001). Significantly greater reductions from baseline were observed with flurbiprofen spray compared with placebo from the first time-points assessed (five minutes for throat soreness/difficulty swallowing, 20 minutes for sore throat pain intensity and 30 minutes for swollen throat) for up to six hours (P < 0.05 for all). There was no significant difference in adverse events between treatment groups during the three-day study. Flurbiprofen spray provides rapid and long-lasting relief from sore throat symptoms, and is well-tolerated over three days.

Evaluation of flurbiprofen urinary ratios as in vivo indices for CYP2C9 activity

PubMed Central

Zgheib, N K; Frye, R F; Tracy, T S; Romkes, M; Branch, R A

2007-01-01

Aims We investigated flurbiprofen pharmacokinetics in 12 volunteers to develop a phenotypic trait measure that correlates with the fractional clearance to 4′-hydroxyflurbiprofen. The effect of the CYP2C9 inhibitor fluconazole on flurbiprofen metabolism was also evaluated. Methods Flurbiprofen pharmacokinetics were evaluated before and after the first and seventh doses of fluconazole. The urinary recovery ratio was calculated as FLRR = 4′-OHF/ [4′-OHF + Ftot] and the urinary metabolic ratio was calculated as FLMR = 4′-OHF/Ftot, where 4′-OHF and Ftot represent total (conjugated and unconjugated) amounts recovered in urine. Results There was a statistically significant relationship between the 4′-OHF formation clearance (4OHCLf) and both the 8-h FLRR and the 8-h FLMR with and without administration of fluconazole. The flurbiprofen apparent oral clearance (CL/F) was decreased by 53% [90% confidence interval (CI) −58, −48] and 64% (90% CI −69, −59), respectively, after administration of one and seven doses of fluconazole when compared with administration of flurbiprofen alone; similarly, the 4OHCLf decreased by 69% (90% CI −74, −64) and 78% (90% CI −83, −73), the 8-h FLRR decreased by 35% (90% CI −41, −29) and 40% (90% CI −46, −35) and the 8-h FLMR decreased by 61% (90% CI −65, −58) and 67% (90% CI −70, −63). The magnitude of decrease in CL/F and 4OHCLf was greater after seven doses compared with after one dose of fluconazole (P < 0.005). Conclusions This study provides strong evidence that both the 8-h FLRR and the 8-h FLMR are suitable phenotypic indices for CYP2C9 activity. PMID:17054666

Synthesis of L-Ascorbyl Flurbiprofenate by Lipase-Catalyzed Esterification and Transesterification Reactions

PubMed Central

Sun, Li-rui; Wang, Yan; Xia, Chun-gu

2017-01-01

The synthesis of L-ascorbyl flurbiprofenate was achieved by esterification and transesterification in nonaqueous organic medium with Novozym 435 lipase as biocatalyst. The conversion was greatly influenced by the kinds of organic solvents, speed of agitation, catalyst loading amount, reaction time, and molar ratio of acyl donor to L-ascorbic acid. A series of solvents were investigated, and tert-butanol was found to be the most suitable from the standpoint of the substrate solubility and the conversion for both the esterification and transesterification. When flurbiprofen was used as acyl donor, 61.0% of L-ascorbic acid was converted against 46.4% in the presence of flurbiprofen methyl ester. The optimal conversion of L-ascorbic acid was obtained when the initial molar ratio of acyl donor to ascorbic acid was 5 : 1. kinetics parameters were solved by Lineweaver-Burk equation under nonsubstrate inhibition condition. Since transesterification has lower conversion, from the standpoint of productivity and the amount of steps required, esterification is a better method compared to transesterification. PMID:28421196

Therapeutic effects of flurbiprofen axetil on mesenteric traction syndrome: randomized clinical trial.

PubMed

Takahashi, Hidemasa; Shida, Dai; Tagawa, Kyoko; Iwamoto, Ryo; Arita, Makoto; Arai, Hiroyuki; Suzuki, Takeo

2017-08-11

This study aimed to reveal the appropriate timing for the intravenous administration of flurbiprofen axetil for preventing mesenteric traction syndrome (MTS), caused by prostacyclin release. In this prospective, randomized, clinical study, forty-five patients who were undergoing elective surgery for colorectal cancer via laparotomy were enrolled. Patients were randomly divided into 3 groups: a preoperative group (n = 16) receiving flurbiprofen axetil directly before surgery; a post-MTS group (n = 14) receiving following MTS onset; and a control group (n = 15) who were not administered flurbiprofen axetil. 6-keto-PGF1α, a stable metabolite of prostacyclin, levels were measured and mean blood pressures were recorded. In the preoperative group, 6-keto-PGF1α levels did not increase, blood pressure levels did not decrease, and no facial flushing was observed. In both the post-MTS and control groups, 6-keto-PGF1α levels increased markedly after mesenteric traction and blood pressure decreased significantly. The post-MTS group exhibited a faster decreasing trend in 6-keto-PGF1α levels and quick restore of the mean blood pressure, and the use of vasopressors and phenylephrine were lower than that in the control group. Even therapeutic administration of flurbiprofen axetil after the onset of MTS has also effects on MTS by suppressing prostacyclin production. Clinical trial number: UMIN000009111 . (Registered 14 October 2012).

Comparative bioavailability and pharmacokinetics of two oral formulations of flurbiprofen: a single-dose, randomized, open-label, two-period, crossover study in Pakistani subjects.

PubMed

Qayyum, Aisha; Najmi, Muzammil Hasan; Abbas, Mateen

2013-11-01

Comparative bioavailability studies are conducted to establish the bioequivalence of generic formulation with that of branded reference formulation, providing confidence to clinicians to use these products interchangeably. This study was carried out to compare a locally manufactured formulation of flurbiprofen with that of a branded product. Twenty two healthy male adults received a single dose of flurbiprofen (100mg) either generic or branded product according to randomization scheme on each of 2 periods. Blood samples were collected and plasma flurbiprofen concentration was determined by a validated HPLC method. Pharmacokinetic parameters like AUC(0-t), AUC(0-oo), Cmax, Tmax, t½, Vd and clearance were determined. The 90% CI for the ratio of geometric means of test to reference product's pharmacokinetic variables was calculated. Pharmacokinetic parameters for two formulations were comparable. Ratio of means of AUC(0-24), AUC(0-oo) and Cmax for test to reference products and 90% CI for these ratios were within the acceptable range. The p-values calculated by TOST were much less than the specified value (p-0.05). ANOVA gave p-values which were more than the specified value (p-0.05) for sequence, subject, period and formulation. Test formulation of flurbiprofen (tablet Flurso) was found to meet the criteria for bioequivalence to branded product (tablet Ansaid) based on pharmacokinetic parameters.

Controlled precipitation for enhanced dissolution rate of flurbiprofen: development of rapidly disintegrating tablets.

PubMed

Essa, Ebtessam A; Elmarakby, Amira O; Donia, Ahmed M A; El Maghraby, Gamal M

2017-09-01

The aim of this work was to investigate the potential of controlled precipitation of flurbiprofen on solid surface, in the presence or absence of hydrophilic polymers, as a tool for enhanced dissolution rate of the drug. The work was extended to develop rapidly disintegrated tablets. This strategy provides simple technique for dissolution enhancement of slowly dissolving drugs with high scaling up potential. Aerosil was dispersed in ethanolic solution of flurbiprofen in the presence and absence of hydrophilic polymers. Acidified water was added as antisolvent to produce controlled precipitation. The resultant particles were centrifuged and dried at ambient temperature before monitoring the dissolution pattern. The particles were also subjected to FTIR spectroscopic, X-ray diffraction and thermal analyses. The FTIR spectroscopy excluded any interaction between flurbiprofen and excipients. The thermal analysis reflected possible change in the crystalline structure and or crystal size of the drug after controlled precipitation in the presence of hydrophilic polymers. This was further confirmed by X-ray diffraction. The modulation in the crystalline structure and size was associated with a significant enhancement in the dissolution rate of flurbiprofen. Optimum formulations were successfully formulated as rapidly disintegrating tablet with subsequent fast dissolution. Precipitation on a large solid surface area is a promising strategy for enhanced dissolution rate with the presence of hydrophilic polymers during precipitation process improving the efficiency.

Intravenous flurbiprofen axetil enhances analgesic effect of opioids in patients with refractory cancer pain by increasing plasma β-endorphin.

PubMed

Wu, Ting-Ting; Wang, Zhi-Gang; Ou, Wu-Ling; Wang, Jun; Yao, Guo-Qing; Yang, Bo; Rao, Zhi-Guo; Gao, Jian-Fei; Zhang, Bi-Cheng

2014-01-01

The study aimed to investigate the analgesic effect of a combination of intravenous flurbiprofen axetil and opioids, and evaluate the relationship between refractory pain relief and plasma β-endorphin levels in cancer patients. A total of 120 cancer patients was randomly divided into two groups, 60 patients took orally morphine sulfate sustained-release tablets in group A, and another 60 patients receiving the combination treatment of intravenous flurbiprofen axetil and opioid drugs in group B. After 7 days, pain relief, quality of life improvement and side effects were evaluated. Furthermore, plasma β-endorphin levels were measured by radioimmunoassay. With the combination treatment of intravenous intravenous flurbiprofen axetil and opioids, the total effective rate of pain relief rose to 91.4%, as compared to 82.1% when morphine sulfate sustained-release tablet was used alone. Compared with that of group A, the analgesic effect increased in group B (p=0.031). Moreover, satisfactory pain relief was associated with a significant increase in plasma β-endorphin levels. After the treatment, plasma β-endorphin level in group B was 62.4±13.5 pg/ml, which was higher than that in group A (45.8±11.2 pg/ml) (p<0.05). Our results suggest the combination of intravenous flurbiprofen axetil and opioids can enhance the analgesic effect of opioid drugs by increasing plasma β-endorphin levels, which would offer a selected and reliable strategy for refractory cancer pain treatment.

Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin.

PubMed

Nath, Niharika; Liu, Xiaoping; Jacobs, Lloydine; Kashfi, Khosrow

2013-01-01

The Wnt/β-catenin/T cell factor (TCF) signaling pathway is important in the development of nonmelanoma skin cancers (NMSCs). Nitric-oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are chemopreventive agents consisting of a traditional NSAID attached to an NO-releasing moiety through a chemical spacer. Previously we showed that an aromatic spacer enhanced the potency of a particular NO-NSAID compared to an aliphatic spacer. We synthesized an NO-releasing NSAID with an aromatic spacer (flurbiprofen benzyl nitrate, NBS-242), and using the human skin cancer cell line A-431, we evaluated its effects on cell kinetics, Wnt/β-catenin, cyclin D1, and caspase-3. NBS-242 inhibited the growth of A-431 cancer cells, being ~15-fold more potent than flurbiprofen and up to 5-fold more potent than NO-flurbiprofen with an aliphatic spacer, the half maximal inhibitory concentrations (IC50) for growth inhibition being 60 ± 4 μM, 320 ± 20 μM, and 880 ± 65 μM for NBS-242, NO-flurbiprofen, and flurbiprofen, respectively. This effect was associated with inhibition of proliferation, accumulation of cells in the G0/G1 phase of the cell cycle, and an increase in apoptotic cell population. NBS-242 cleaved β-catenin both in the cytoplasm and the nucleus of A-431 cells. NBS-242 activated caspase-3 whose activation was reflected in the cleavage of procaspase-3. To test the functional consequence of β-catenin cleavage, we determined the expression of cyclin D1, a Wnt-response gene. NBS-242 reduced cyclin D1 levels in a concentration dependent manner. These findings establish a strong inhibitory effect of NBS-242 in A-431 human epidermoid carcinoma cells. NBS-242 modulates parameters that are important in determining cellular mass.

The fentanyl concentration required for immobility under propofol anesthesia is reduced by pre-treatment with flurbiprofen axetil.

PubMed

Kodaka, Mitsuharu; Tsukakoshi, Mikiko; Miyao, Hideki; Tsuzaki, Koichi; Ichikawa, Junko; Komori, Makiko

2013-12-01

We hypothesized that nonsteroidal anti-inflammatory drugs decrease the plasma fentanyl concentration required to produce immobility in 50% of patients in response to skin incision (Cp50incision) compared with placebo under target-controlled infusion (TCI) propofol anesthesia. Sixty-two unpremedicated patients scheduled to undergo gynecologic laparoscopy were randomly assigned to receive placebo (control group) or flurbiprofen axetil 1 mg·kg(-1) (flurbiprofen group) preoperatively. General anesthesia was induced with fentanyl and propofol, and intubation was performed after succinylcholine 1 mg·kg(-1). Propofol was administered via a target-controlled infusion (TCI) system (Diprifusor™) set at an effect-site concentration of 5 μg·mL(-1). Fentanyl was given by a TCI system using the STANPUMP software (Schafer model). The concentration for the first patient was set at 3 ng·mL(-1) and modified in each group according to the up-down method. Skin incision was performed after more than ten minutes equilibration time. Serum fentanyl concentration, bispectral index (BIS), and hemodynamic parameters were measured two minutes before and after skin incision. The Cp50incision of fentanyl was derived from the mean of the crossovers (i.e., the serum fentanyl concentrations of successive participants who responded and those who did not or vice versa). Ten and 11 independent crossover pairs were collected in the control and flurbiprofen groups, respectively, representing 42 of 62 enrolled patients. The mean (SD) fentanyl Cp50incision was less in the flurbiprofen group [0.84 (0.63) ng·mL(-1)] than in the control group [1.65 (1.15) ng·mL(-1)]; P = 0.007; however, there were no differences in BIS, blood pressure, or heart rate, between groups. Preoperative flurbiprofen axetil decreased the Cp50incision of fentanyl by 49% during propofol anesthesia without changing the BIS or hemodynamic variables.

Novel dual-reverse thermosensitive solid lipid nanoparticle-loaded hydrogel for rectal administration of flurbiprofen with improved bioavailability and reduced initial burst effect.

PubMed

Din, Fakhar Ud; Mustapha, Omer; Kim, Dong Wuk; Rashid, Rehmana; Park, Jong Hyuck; Choi, Ju Yeon; Ku, Sae Kwang; Yong, Chul Soon; Kim, Jong Oh; Choi, Han-Gon

2015-08-01

The purpose of this study was to develop novel solid lipid nanoparticle (SLN)-loaded dual-reverse thermosensitive hydrogel (DRTH) for rectal administration of flurbiprofen with improved bioavailability and reduced initial burst effect. The flurbiprofen-loaded SLNs were prepared by hot homogenisation technique, after optimising the amounts of lipid mixture (tricaprin and triethanolamine in 8:2 weight ratio), drug and surfactant. The flurbiprofen-loaded thermosensitive SLN composed of drug, lipid mixture and surfactant at a weight ratio of 10/15/1.3 was a solid at room temperature, and changed to liquid form at physiological temperature due to its melting point of about 32°C. This SLN gave the mean particle size of about 190nm and entrapment efficiency of around 90%. The DRTHs were prepared by adding this flurbiprofen-loaded thermosensitive SLN in various poloxamer solutions. Their rheological characterisation, release and stability were investigated while a morphological and pharmacokinetic study was performed after its rectal administration to rats compared with the drug and hydrogel. Poloxamer 188 and SLN decreased the gelation temperature and gelation time, but increased the viscosity at 25°C, gel strength and mucoadhesive force of DRTHs. In particular, the DRTH composed of [SLN/P 407/P 188 (10%/15%/25%)] with the gelation temperature of about 35°C existed as liquid at room temperature, but gelled at 30-36°C, leading to opposite reversible property of SLN. Thus, it was easy to administer rectally, and it gelled rapidly inside the body. This DRTH gave a significantly increased dissolution rate of the drug as compared to the flurbiprofen, but significantly retarded as compared to the hydrogel, including the initial dissolution rate. Moreover, this DRTH gave significantly higher plasma concentration and 7.5-fold AUC values compared to the drug, and lower initial plasma concentration and Cmax value compared to the hydrogel due to reduced initial burst effect. No damage in rectal mucosa was observed after the application of DRTH. Thus, this DRTH system with improved bioavailability and reduced initial burst effect would be recommended as an alternative for the flurbiprofen-loaded rectal pharmaceutical products. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of preemptive analgesia with flurbiprofen ester on lymphocytes and natural killer cells in patients undergoing esophagectomy: A randomized controlled pilot study

PubMed Central

Zhou, Yi; Huang, Jinxi; Bai, Yu; Li, Changsheng

2017-01-01

Background Tumors may induce systemic immune dysfunction, which can be aggravated by surgery and anesthesia/analgesia. Data on the effect of flurbiprofen preemptive analgesia on immune dysfunction is limited. The aim of this study was to investigate the effect of flurbiprofen preemptive analgesia on lymphocytes and natural killer (NK) cells in patients undergoing thoracotomy and thoracoscopy radical esophagectomy, and to explore the analgesic methods suitable for tumor patients. Methods This was a randomized controlled pilot study of 89 patients with esophageal cancer treated with surgery at the Henan Cancer Hospital between January 1, 2015 and December 31, 2016. The patients were divided into three groups: group 1, thoracotomy; group 2, thoracoscopy and laparoscopic surgery; and group 3, flurbiprofen, thoracoscopy, and laparoscopic surgery. CD3+, CD19+, NK, CD4+, and CD8+ cells in whole blood were measured by flow cytometry 30 minutes before surgery (T0), at the end of the thoracic section of the procedure (T1), and at the end of the operation (T2). Results There were no significant differences in CD3+, CD19+, CD8+, NK, and CD4+ cells between the three groups or regarding the time points during the procedure (all P > 0.05). Thoracotomy and thoracoscopy surgery resulted in similar immunological outcomes. Conclusion Flurbiprofen ester preemptive analgesia did not suppress the immune function in patients and could be a safe analgesic method for patients with esophageal cancer undergoing surgery. PMID:28892265

R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer's disease

PubMed Central

Carreras, Isabel; McKee, Ann C.; Choi, Ji-Kyung; Aytan, Nurgul; Kowall, Neil W.

2013-01-01

We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular Aß and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma-secretase modulator (GSM) and both activities have the potential to decrease Aß pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, Aß, tau, and the neurochemical profile of the hippocampus. Treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of Aß (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. Glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function. PMID:24161403

Effects of preemptive analgesia with flurbiprofen ester on lymphocytes and natural killer cells in patients undergoing esophagectomy: A randomized controlled pilot study.

PubMed

Zhou, Yi; Huang, Jinxi; Bai, Yu; Li, Changsheng; Lu, Xihua

2017-11-01

Tumors may induce systemic immune dysfunction, which can be aggravated by surgery and anesthesia/analgesia. Data on the effect of flurbiprofen preemptive analgesia on immune dysfunction is limited. The aim of this study was to investigate the effect of flurbiprofen preemptive analgesia on lymphocytes and natural killer (NK) cells in patients undergoing thoracotomy and thoracoscopy radical esophagectomy, and to explore the analgesic methods suitable for tumor patients. This was a randomized controlled pilot study of 89 patients with esophageal cancer treated with surgery at the Henan Cancer Hospital between January 1, 2015 and December 31, 2016. The patients were divided into three groups: group 1, thoracotomy; group 2, thoracoscopy and laparoscopic surgery; and group 3, flurbiprofen, thoracoscopy, and laparoscopic surgery. CD3+, CD19+, NK, CD4+, and CD8+ cells in whole blood were measured by flow cytometry 30 minutes before surgery (T0), at the end of the thoracic section of the procedure (T1), and at the end of the operation (T2). There were no significant differences in CD3+, CD19+, CD8+, NK, and CD4+ cells between the three groups or regarding the time points during the procedure (all P > 0.05). Thoracotomy and thoracoscopy surgery resulted in similar immunological outcomes. Flurbiprofen ester preemptive analgesia did not suppress the immune function in patients and could be a safe analgesic method for patients with esophageal cancer undergoing surgery. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Efficacy of flurbiprofen 8.75 mg lozenge in patients with a swollen and inflamed sore throat.

PubMed

Aspley, Sue; Shephard, Adrian; Schachtel, Emily; Sanner, Kathleen; Savino, Laurie; Schachtel, Bernard

2016-09-01

Sore throat is often over-treated with antibiotics, therefore there is a need for non-antibiotic treatments that provide effective relief. From the patient's point of view, symptoms of pharyngeal inflammation such as a "swollen" and "inflamed" throat are often considered the most bothersome; so, a non-steroidal anti-inflammatory drug could be an appropriate treatment. We investigated the efficacy and safety of flurbiprofen 8.75 mg lozenge in adults with a swollen and inflamed throat. We enrolled adults with moderate-to-severe sore throat and evidence of tonsillo-pharyngitis into a randomized, double-blind study. Patients received flurbiprofen 8.75 mg or placebo lozenges every 3-6 hours as needed (up to five lozenges in 24 hours) and rated their symptoms (sore throat pain, difficulty swallowing and the sensation of a swollen throat) on standard linear scales regularly over 24 hours. The efficacy of flurbiprofen lozenge was determined in patients reporting a swollen and inflamed throat at baseline, as well as those with relatively severe symptoms. ClinicalTrials.gov NCT01049334. The main outcome measures were the time-weighted summed differences in patient-reported sore throat pain, difficulty swallowing and swollen throat over 24 hours. Out of 204 patients, 124 (60.8%) described their throats as swollen and inflamed at baseline. Flurbiprofen lozenges provided greater relief than placebo over 24 hours: 79.8%, 99.6% and 69.3% (for sore throat pain, difficulty swallowing and swollen throat, respectively, all P ≤ 0.01). These outcomes were more substantial in patients with relatively severe symptoms. No serious or unexpected adverse events occurred. Flurbiprofen 8.75 mg lozenge appears to provide effective, well-tolerated relief of sore throat, difficulty swallowing and swollen throat in adults with a swollen and inflamed throat, as well as those with relatively severe symptoms. A limitation of these findings is that, while predetermined, these are secondary outcomes derived from a targeted sub-group of patients, not the entire study population.

Flurbiprofen improves dysfunction of T-lymphocyte subsets and natural killer cells in cancer patients receiving post-operative morphine analgesia.

PubMed

Shen, Jin-Chun; Sun, He-Liang; Zhang, Ming-Qiang; Liu, Xiao-Yu; Wang, Zhong- Yun; Yang, Jian-Jun

2014-08-01

Acute pain can lead to immune dysfunction, which can be partly ameliorated by successful pain management. Opioids, which are widely used for analgesia, can result in the deterioration of immune function. This study aimed to investigate the influence of morphine with or without flurbiprofen as post-operative analgesics on the immune systems of patients undergoing gastric cancer surgery. 60 patients undergoing gastric cancer surgery were equally randomized into two groups. They received post-operative patient-controlled intravenous (IV) analgesia using morphine either with or without flurbiprofen. Visual analogue scale (VAS) scores, Bruggemann comfort scale (BCS) scores, morphine consumption, time of first flatus, incidence of nausea/vomiting, and T-lymphocyte subsets (CD3⁺, CD4⁺, and CD8⁺) and natural killer cells (CD3⁻CD16⁺CD56⁺) were evaluated. No significant difference was observed in the VAS scores, BCS scores, and nausea/vomiting incidence between groups. Less morphine was consumed and the time of first flatus was earlier in patients receiving morphine with flurbiprofen than morphine alone. The expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ decreased at 2 hours after incision and, except for CD3⁻CD16⁺CD56⁺, returned to baseline at 120 hours after surgery. Moreover, the expression of CD3⁻CD16⁺CD56⁺ at 2 hours after incision and the expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ at 24 hours after surgery were higher in patients receiving morphine with flurbiprofen than morphine alone. The combination of morphine and flurbiprofen ameliorates the immune depression in Tlymphocyte subsets and natural killer cells and provides a similar analgesic efficacy to morphine alone in patients undergoing gastric cancer surgery.

Improvements in throat function and qualities of sore throat from locally applied flurbiprofen 8.75 mg in spray or lozenge format: findings from a randomized trial of patients with upper respiratory tract infection in the Russian Federation

PubMed Central

Burova, Natalia; Bychkova, Valeria; Shephard, Adrian

2018-01-01

Objective To assess the speed of relief provided by flurbiprofen 8.75 mg spray and lozenge and their effect on many of the different qualities and characteristics of throat pain and discomfort, and the many articulations of the broad term “sore throat” (ST). Patients and methods Four hundred and forty adults with recent-onset, moderate-to-severe ST due to upper respiratory tract infection (URTI) were randomized to a single dose of either flurbiprofen 8.75 mg spray (n=218) or flurbiprofen 8.75 mg lozenge (n=222). Throat swabs for bacterial culture were taken at baseline. ST relief was assessed at 1 minute, 1 and 2 hours post-dose using the Sore Throat Relief Rating Scale. The change from baseline at 1 and 2 hours post-dose in difficulty swallowing and swollen throat was assessed using the difficulty swallowing scale and the swollen throat scale, respectively. Patients’ experience of URTI symptoms was assessed using a URTI questionnaire at baseline and 2 hours post-dose. The change in Qualities of Sore Throat Index, a 10-item index of qualities of ST, from baseline at 2 hours post-dose was also measured. Results ST relief was evident in the spray and the lozenge treatment groups at 1 minute, 1 and 2 hours post-dose (P>0.05). In both groups, scores for difficulty swallowing and swollen throat significantly improved at 1 and 2 hours post-dose compared with baseline. At 2 hours post-dose, the number of patients experiencing URTI symptoms that can be attributed to or associated with ST decreased relative to baseline. The mean change from baseline to 2 hours post-dose for each individual score on the Qualities of Sore Throat Index showed significant improvements for flurbiprofen spray and lozenge (all P<0.0001). Conclusion Non-inferiority was established, and flurbiprofen spray and lozenge provided effective relief from ST pain and many of the other commonly reported qualities of ST.

Improvements in throat function and qualities of sore throat from locally applied flurbiprofen 8.75 mg in spray or lozenge format: findings from a randomized trial of patients with upper respiratory tract infection in the Russian Federation.

PubMed

Burova, Natalia; Bychkova, Valeria; Shephard, Adrian

2018-01-01

To assess the speed of relief provided by flurbiprofen 8.75 mg spray and lozenge and their effect on many of the different qualities and characteristics of throat pain and discomfort, and the many articulations of the broad term "sore throat" (ST). Four hundred and forty adults with recent-onset, moderate-to-severe ST due to upper respiratory tract infection (URTI) were randomized to a single dose of either flurbiprofen 8.75 mg spray (n=218) or flurbiprofen 8.75 mg lozenge (n=222). Throat swabs for bacterial culture were taken at baseline. ST relief was assessed at 1 minute, 1 and 2 hours post-dose using the Sore Throat Relief Rating Scale. The change from baseline at 1 and 2 hours post-dose in difficulty swallowing and swollen throat was assessed using the difficulty swallowing scale and the swollen throat scale, respectively. Patients' experience of URTI symptoms was assessed using a URTI questionnaire at baseline and 2 hours post-dose. The change in Qualities of Sore Throat Index, a 10-item index of qualities of ST, from baseline at 2 hours post-dose was also measured. ST relief was evident in the spray and the lozenge treatment groups at 1 minute, 1 and 2 hours post-dose ( P >0.05). In both groups, scores for difficulty swallowing and swollen throat significantly improved at 1 and 2 hours post-dose compared with baseline. At 2 hours post-dose, the number of patients experiencing URTI symptoms that can be attributed to or associated with ST decreased relative to baseline. The mean change from baseline to 2 hours post-dose for each individual score on the Qualities of Sore Throat Index showed significant improvements for flurbiprofen spray and lozenge (all P <0.0001). Non-inferiority was established, and flurbiprofen spray and lozenge provided effective relief from ST pain and many of the other commonly reported qualities of ST.

R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer's disease.

PubMed

Carreras, Isabel; McKee, Ann C; Choi, Ji-Kyung; Aytan, Nurgul; Kowall, Neil W; Jenkins, Bruce G; Dedeoglu, Alpaslan

2013-12-06

We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular Aß and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma-secretase modulator (GSM) and both activities have the potential to decrease Aß pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, Aß, tau, and the neurochemical profile of the hippocampus. Treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of Aß (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. Glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function. © 2013 Published by Elsevier B.V.

The effects of topical diclofenac, topical flurbiprofen, and humidity on corneal sensitivity in normal dogs.

PubMed

Dorbandt, Daniel M; Labelle, Amber L; Mitchell, Mark A; Hamor, Ralph E

2017-03-01

To determine the immediate and chronic effects of topical 0.1% diclofenac and 0.03% flurbiprofen on corneal sensitivity in normal canine eyes. Eighteen normal, nonbrachycephalic dogs. A prospective, randomized, masked, crossover study was performed. To determine the immediate effects associated with treatment, the study drug was instilled into the eye every 5 min for five doses, and corneal sensitivity of treated and untreated eyes was obtained prior to treatment and every 15 min post-treatment for 60 min. To determine the chronic effects, the study drug was instilled every 12 h for 30 days, and corneal sensitivity of treated and untreated eyes was obtained prior to treatment on days 0 and 30. A washout period of at least 30 days occurred between drug crossover. Ambient temperature and humidity were measured throughout the study. After multiple instillations, there was no difference in corneal sensitivity between eyes over time for diclofenac (P = 0.67) or flurbiprofen (P = 0.54), with a median sensitivity of 25 mm (1.8 g/mm 2 ). After chronic dosing, there was no difference in corneal sensitivity between eyes over time for diclofenac (P = 0.82) or flurbiprofen (P = 0.56), with a median sensitivity of 35 mm (1.0 g/mm 2 ). Decreasing ambient humidity was associated with an increase in sensitivity measurements (P = 0.0001). Neither diclofenac nor flurbiprofen had an effect on corneal sensitivity after multiple-drops or twice-daily dosing for 30 days. Ambient humidity may have an effect on corneal sensitivity measurements, with a longer filament length eliciting a blink response at lower humidity. © 2016 American College of Veterinary Ophthalmologists.

Aging Enables Ca2+ Overload and Apoptosis Induced by Amyloid-β Oligomers in Rat Hippocampal Neurons: Neuroprotection by Non-Steroidal Anti-Inflammatory Drugs and R-Flurbiprofen in Aging Neurons.

PubMed

Calvo-Rodríguez, María; García-Durillo, Mónica; Villalobos, Carlos; Núñez, Lucía

2016-07-22

The most important risk factor for Alzheimer's disease (AD) is aging. Neurotoxicity in AD has been linked to dyshomeostasis of intracellular Ca2+ induced by small aggregates of the amyloid-β peptide 1-42 (Aβ42 oligomers). However, how aging influences susceptibility to neurotoxicity induced by Aβ42 oligomers is unknown. In this study, we used long-term cultures of rat hippocampal neurons, a model of neuronal in vitro aging, to investigate the contribution of aging to Ca2+ dishomeostasis and neuron cell death induced by Aβ42 oligomers. In addition, we tested whether non-steroidal anti-inflammatory drugs (NSAIDs) and R-flurbiprofen prevent apoptosis acting on subcellular Ca2+ in aged neurons. We found that Aβ42 oligomers have no effect on young hippocampal neurons cultured for 2 days in vitro (2 DIV). However, they promoted apoptosis modestly in mature neurons (8 DIV) and these effects increased dramatically after 13 DIV, when neurons display many hallmarks of in vivo aging. Consistently, cytosolic and mitochondrial Ca2+ responses induced by Aβ42 oligomers increased dramatically with culture age. At low concentrations, NSAIDs and the enantiomer R-flurbiprofen lacking anti-inflammatory activity prevent Ca2+ overload and neuron cell death induced by Aβ42 oligomers in aged neurons. However, at high concentrations R-flurbiprofen induces apoptosis. Thus, Aβ42 oligomers promote Ca2+ overload and neuron cell death only in aged rat hippocampal neurons. These effects are prevented by low concentrations of NSAIDs and R-flurbiprofen acting on mitochondrial Ca2+ overload.

CYP2C9 genotype vs. metabolic phenotype for individual drug dosing--a correlation analysis using flurbiprofen as probe drug.

PubMed

Vogl, Silvia; Lutz, Roman W; Schönfelder, Gilbert; Lutz, Werner K

2015-01-01

Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects), correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinary metabolic ratio MR (concentration of CYP2C9-dependent metabolite divided by concentration of flurbiprofen) determined two hours after flurbiprofen (8.75 mg) administration served as phenotyping metric. Linear statistical models correlating genotype and phenotype provided highly significant allele-specific MR estimates of 0.596 for the wild type allele CYP2C9*1, 0.405 for CYP2C9*2 (68 % of wild type), and 0.113 for CYP2C9*3 (19 % of wild type). If these estimates were used for flurbiprofen dose adjustment, taking 100 % for genotype *1/*1, an average reduction to 84 %, 60 %, 68 %, 43 %, and 19 % would result for genotype *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Due to the large individual variation within genotypes with coefficients of variation ≥ 20 % and supposing the normal distribution, one in three individuals would be out of the average optimum dose by more than 20 %, one in 20 would be 40 % off. Whether this problem also applies to other CYPs and other drugs has to be investigated case by case. Our data for the given example, however, puts the benefit of individual drug dosing to question, if it is exclusively based on genotype.

Cell Cycle Target-based Therapy for Ovarian Cancer

DTIC Science & Technology

2008-09-01

induces apoptosis in quiescent ovarian cancer cells. Strong inducers of apoptosis included flufenamic acid, flurbiprofen, celebrex and finasteride ...Thus, a whole panel of NSAIDs including Aspirin, Ibuprofen, Exisulind, Acetaminophen, Naproxen, NS-398, Celecoxib, Diclofenac, Finasteride ...Naproxen, 200µM NS-398, 50µM Celecoxib, 200µM Diclofenac, 50µM Finasteride , 200µM Flufenamic acid, 40µM Meloxican, 50µM Ebselen, 20nM Flurbiprofen or

Comparison of preoperative nepafenac (0.1%) and flurbiprofen (0.03%) eye drops in maintaining mydriasis during small incision cataract surgery in patients with senile cataract: A randomized, double-blind study.

PubMed

Sarkar, Saumya; Mondal, Kanchan Kumar; Roy, Sukalyan Saha; Gayen, Sharmistha; Ghosh, Abhishek; De, Radha Raman

2015-01-01

This study compared the effectiveness of prophylactic administration of topical flurbiprofen 0.03% and nepafenac 0.1% in maintaining mydriasis during small incision cataract surgery (SICS). This study was a prospective, randomized, double-blind comparative study in adult cataract patients given topical flurbiprofen or nepafenac prior to SICS and capsular bag intraocular lens (IOL) implantation at a tertiary care hospital. Horizontal and vertical diameters of pupil were measured at the beginning and end of surgery, and the mean values were compared across the two groups. Unpaired t-test and Fisher's exact test were used to analyse the results. A total of 70 eyes of cataract surgery patients, 33 males and 37 females, with a mean age of 58.5 ± 11.24 years, were included in the study. The mean horizontal and vertical diameters of the two groups were similar at the start of surgery. Significant differences were seen after IOL implantation, with the nepafenac group having the larger mean diameters in both horizontal (P = 0.03) and vertical (P = 0.04) pupillary measurements. Topical nepafenac has been shown to be a more effective inhibitor of meiosis during SICS and provides a more stable mydriatic effect compared to topical flurbiprofen.

Pharmacokinetics of colon-specific pH and time-dependent flurbiprofen tablets.

PubMed

Vemula, Sateesh Kumar; Veerareddy, Prabhakar Reddy; Devadasu, Venkat Ratnam

2015-09-01

Present research deals with the development of compression-coated flurbiprofen colon-targeted tablets to retard the drug release in the upper gastro intestinal system, but progressively release the drug in the colon. Flurbiprofen core tablets were prepared by direct compression method and were compression coated using sodium alginate and Eudragit S100. The formulation is optimized based on the in vitro drug release study and further evaluated by X-ray imaging and pharmacokinetic studies in healthy humans for colonic delivery. The optimized formulation showed negligible drug release (4.33 ± 0.06 %) in the initial lag period followed by progressive release (100.78 ± 0.64 %) for 24 h. The X-ray imaging in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. The C max of colon-targeted tablets was 12,374.67 ng/ml at T max 10 h, where as in case of immediate release tablets the C max was 15,677.52 ng/ml at T max 3 h, that signifies the ability of compression-coated tablets to target the colon. Development of compression-coated tablets using combination of time-dependent and pH-sensitive approaches was suitable to target the flurbiprofen to colon.

Development of an ANN optimized mucoadhesive buccal tablet containing flurbiprofen and lidocaine for dental pain.

PubMed

Hussain, Amjad; Syed, Muhammad Ali; Abbas, Nasir; Hanif, Sana; Arshad, Muhammad Sohail; Bukhari, Nadeem Irfan; Hussain, Khalid; Akhlaq, Muhammad; Ahmad, Zeeshan

2016-06-01

A novel mucoadhesive buccal tablet containing flurbiprofen (FLB) and lidocaine HCl (LID) was prepared to relieve dental pain. Tablet formulations (F1-F9) were prepared using variable quantities of mucoadhesive agents, hydroxypropyl methyl cellulose (HPMC) and sodium alginate (SA). The formulations were evaluated for their physicochemical properties, mucoadhesive strength and mucoadhesion time, swellability index and in vitro release of active agents. Release of both drugs depended on the relative ratio of HPMC:SA. However, mucoadhesive strength and mucoadhesion time were better in formulations, containing higher proportions of HPMC compared to SA. An artificial neural network (ANN) approach was applied to optimise formulations based on known effective parameters (i.e., mucoadhesive strength, mucoadhesion time and drug release), which proved valuable. This study indicates that an effective buccal tablet formulation of flurbiprofen and lidocaine can be prepared via an optimized ANN approach.

Effect of oxycodone hydrochloride combined with flurbiprofen axetil for intravenous patient-controlled analgesia in lower abdominal patients: A randomized trial.

PubMed

Xiang, Xiaobing; Yuan, Xiaohong; Lian, Yanhong; Fang, Jun; Wu, Yingli

2018-02-01

Problems like postoperative pain are still common phenomena after general anesthesia. Oxycodone hydrochloride is a semisynthetic opioid with a safe and excellent therapeutic effect on visceral pain. Flurbiprofen axetil has the efficacy of targeted analgesia. We hypothesize that different doses of oxycodone hydrochloride combined with flurbiprofen axetil would generate great results on postoperative intravenous analgesia in lower abdominal patients. In the clinical trial, 90 American Society of Anesthesiologists I or II patients scheduled for elective general anesthesia were randomly divided into 3 groups, 30 cases in each group. Group I: oxycodone hydrochloride 0.5 mg/kg + flurbiprofen axetil 150 mg, group II: oxycodone hydrochloride 0.75 mg/kg + flurbiprofen axetil 150 mg, group III: oxycodone hydrochloride 1.0 mg/kg + flurbiprofen axetil 150 mg. Dilute them with 0.9% saline to 150 mL, respectively, with the background dose of 2 mL/h, patient-controlled analgesia 2 mL per time, with an interval of 10 min, and the loading dose of 0.1 mL/kg. Record the preoperative situation, 24 h (T0) before surgery, postoperative situation, 1 h (T1), 4 h (T2), 8 h (T3), 12 h (T4), 24 h (T5), 48 h (T6), 72 h (T7) after the surgery, including the mean arterial pressure, heart rate, saturation of pulse oximetry, static and dynamic pain rating (NRS) and Ramsay sedation score, effective pressing and total pressing ratio (referred to as the pressing ratio), patient satisfaction, and occurrence of adverse reactions. There was no significant statistic difference in mean arterial blood pressure, heart rate, arterial oxygen saturation, and adverse reactions among the 2 groups at each time point (P > .05). Compared with group I, the static NRS rating in group II and group III were significantly lower than that in group I (P < .05) from T1 to T5. The dynamic NRS rating of group II from T1 to T4 and that of group III from T1 to T5 were significantly lower (P < .05). The effective pressing and total pressing ratio was significantly higher (P < .05). There was no significant statistic difference between group II and group III in NRS rating and the effective pressing and total pressing ratio (P > .05). Compared with group III, the Ramsay sedation scores of group I and group II were significantly lower from T1 to T4 (P < .05). The dose of 0.75 mg/kg oxycodone hydrochloride combined with flurbiprofen axetil can provide safe and effective postoperative analgesia for lower abdominal patients, with fewer adverse reactions.

Induction of the p75NTR by Aryl Propionic Acids in Prostate Cancer Cells

DTIC Science & Technology

2008-12-01

and ketoprofen among others. Long term ibuprofen use is associated with a decreased risk of prostate cancer (9-10). Treatment with the enantiomer R...different metastatic hormone-refractory prostate cancer cell lines, PC-3 and DU-145. Of those tested, the enantiomer R-flurbiprofen and ibuprofen were...class of NSAIDs. Treatment of T24 bladder cancer cells and HCT-116 colon cancer cells with ibuprofen or the enantiomer R- flurbiprofen, which lacks COX

Colon Targeted Guar Gum Compression Coated Tablets of Flurbiprofen: Formulation, Development, and Pharmacokinetics

PubMed Central

Bontha, Vijaya Kumar

2013-01-01

The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4) showed almost complete drug release in the colon (99.86%) within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period). The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The C max of colon targeted tablets was 11956.15 ng/mL at T max of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen. PMID:24260738

Colon targeted guar gum compression coated tablets of flurbiprofen: formulation, development, and pharmacokinetics.

PubMed

Vemula, Sateesh Kumar; Bontha, Vijaya Kumar

2013-01-01

The rationale of the present study is to formulate flurbiprofen colon targeted compression coated tablets using guar gum to improve the therapeutic efficacy by increasing drug levels in colon, and also to reduce the side effects in upper gastrointestinal tract. Direct compression method was used to prepare flurbiprofen core tablets, and they were compression coated with guar gum. Then the tablets were optimized with the support of in vitro dissolution studies, and further it was proved by pharmacokinetic studies. The optimized formulation (F4) showed almost complete drug release in the colon (99.86%) within 24 h without drug loss in the initial lag period of 5 h (only 6.84% drug release was observed during this period). The pharmacokinetic estimations proved the capability of guar gum compression coated tablets to achieve colon targeting. The C(max) of colon targeted tablets was 11956.15 ng/mL at T max of 10 h whereas it was 15677.52 ng/mL at 3 h in case of immediate release tablets. The area under the curve for the immediate release and compression coated tablets was 40385.78 and 78214.50 ng-h/mL and the mean resident time was 3.49 and 10.78 h, respectively. In conclusion, formulation of guar gum compression coated tablets was appropriate for colon targeting of flurbiprofen.

Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract surgery

PubMed Central

Halder, Sujash; Mondal, Kanchan Kumar; Biswas, Supreeti; Mandal, Tapan Kumar; Dutta, Bakul Kumar; Haldar, Mithilesh

2013-01-01

Objectives: To determine the aqueous and plasma concentrations of moxifloxacin administered topically alone and with flurbiprofen in patients undergoing cataract surgery. Materials and Methods: A total of 50 subjects scheduled for routine cataract surgery were randomly allocated to two groups (n = 25 each). Group-1 patients were treated with topical moxifloxacin alone: One drop 6 times/day for 3 days before surgery and one drop 4 times on the day of surgery: Group-2 patients were treated with topical moxifloxacin as in Group-1 and with topical flurbiprofen: One drop 4 times/day for 3 days before and on the day of surgery. The interval between two drugs was 30 min for last 3 days and 15 min on the day of surgery. Last dose was administered 1 h before aqueous humor and blood sampling for both the groups. The antibiotic concentration in aqueous humor and plasma were determined by using high performance liquid chromatography. Results: The mean concentration of moxifloxacin in aqueous humor was 1.71 ± 0.82 mg/ml in Group-1 and 2.39 ± 1.34 mg/ml in Group-2. Concentrations of moxifloxacin in aqueous humor were significantly higher in Group-2 than that of Group-1. Conclusion: Flurbiprofen may increase the concentration of moxifloxacin in aqueous humor. PMID:23833362

Enhancement of skin permeation of flurbiprofen via its transdermal patches using isopulegol decanoate (ISO-C10) as an absorption enhancer: pharmacokinetic and pharmacodynamic evaluation.

PubMed

Chen, Yang; Quan, Peng; Liu, Xiaochang; Guo, Wenjia; Song, Wenting; Cun, Dongmei; Wang, Zhongyan; Fang, Liang

2015-09-01

The study aimed to prepare a transdermal patch for flurbiprofen using isopulegol decanoate (ISO-C10) as a permeation enhancer, and to evaluate the in-vitro and in-vivo percutaneous permeation of the drug, as well as the pharmacodynamic efficacy of the formulation. The permeation experiments were conducted on rabbit skin, and the pharmacokinetic profiles and synovial fluid drug concentration were measured after in-vivo transdermal administration. A deconvolution approach was employed to analyse the correlation between the in-vitro and in-vivo drug permeation. The anti-inflammatory and analgesic effects were, respectively, assessed using the adjuvant arthritis model and the acetic acid induced pain model. ISO-C10 could increase the in-vitro permeation of flurbiprofen from 46.22 ± 5.65 μg/cm(2) to 101.07 ± 10.85 μg/cm(2) . The in-vivo absorption of the drug was also improved by the enhancer, and a good linear correlation was observed between the in-vitro and in-vivo drug permeation. Meanwhile, the ISO-C10 contained patches increased the drug disposition in synovial fluid and enhanced the pharmacodynamic efficacy of the formulation. ISO-C10 would be a promising permeation enhancer for improving the in-vitro and in-vivo delivery of flurbiprofen from its transdermal patches. © 2015 Royal Pharmaceutical Society.

Comparison of the Characteristics and Performance of Flurbiprofen 8.75 mg Spray for Sore Throat.

PubMed

Veale, David; Shephard, Adrian; Adams, Verity; Lidster, Charlotte

2017-01-01

Sore throat sprays provide targeted relief by delivering the active ingredient directly to the site of pain. Different sprays vary in characteristics, thus affecting delivery of the active ingredient to the throat, which can impact compliance. The characteristics and performance of FLURBIPROFEN 8.75 mg SPRAY were compared with 12 other sprays. Parameters assessed included spray angle and pattern, droplet size distribution, shot weight uniformity and shot weight throughout life. Among all sprays tested WICK Sulagil Halsspray had the smallest spray angle (46°) and also the smallest diameter spray pattern (X=32.8 mm; Y=34.4 mm). Thiovalone® Buccal Spray Suspension had both the largest spray angle (82°) and largest diameter spray pattern (X=62.6 mm; Y=78.0 mm). Hasco Sept® Aerosol Spray had the smallest droplet size (Dv90=118.4 μm) whereas OKi infiammazione e dolore® 0.16% spray had the largest (Dv90=214.34 μm). In terms of shot weight uniformity, TANTUM® VERDE GOLA 0.25% spray showed the least variation (2% RSD) between shots and UNIBEN Aerosol Spray the most (23.4% RSD). Shot weight throughout life studies showed that FLURBIPROFEN 8.75 mg SPRAY had the least deviation from shot weight (1.77%) whereas OKi infiammazione e dolore® 0.16% spray deviated the most (44.9%). FLURBIPROFEN 8.75 mg SPRAY had the second smallest spray angle/pattern and droplet size distribution and also the least variation in shot weight. Different sore throat sprays vary in different attributes, affecting delivery of the active ingredient. FLURBIPROFEN 8.75 mg SPRAY performed well overall, ranking first among all sprays tested, and providing a dose which is targeted and uniformly delivered throughout the life of the bottle. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

CYP2C9 Genotype vs. Metabolic Phenotype for Individual Drug Dosing—A Correlation Analysis Using Flurbiprofen as Probe Drug

PubMed Central

Vogl, Silvia; Lutz, Roman W.; Schönfelder, Gilbert; Lutz, Werner K.

2015-01-01

Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects), correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinary metabolic ratio MR (concentration of CYP2C9-dependent metabolite divided by concentration of flurbiprofen) determined two hours after flurbiprofen (8.75 mg) administration served as phenotyping metric. Linear statistical models correlating genotype and phenotype provided highly significant allele-specific MR estimates of 0.596 for the wild type allele CYP2C9*1, 0.405 for CYP2C9*2 (68 % of wild type), and 0.113 for CYP2C9*3 (19 % of wild type). If these estimates were used for flurbiprofen dose adjustment, taking 100 % for genotype *1/*1, an average reduction to 84 %, 60 %, 68 %, 43 %, and 19 % would result for genotype *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Due to the large individual variation within genotypes with coefficients of variation ≥ 20 % and supposing the normal distribution, one in three individuals would be out of the average optimum dose by more than 20 %, one in 20 would be 40 % off. Whether this problem also applies to other CYPs and other drugs has to be investigated case by case. Our data for the given example, however, puts the benefit of individual drug dosing to question, if it is exclusively based on genotype. PMID:25775139

Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

PubMed Central

Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

2016-01-01

Flurbiprofen–antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (–COOH) was temporarily masked by esterification with phenolic –OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001) reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-yl)propanoate (4b) showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer’s yeast-induced pyrexia model, and significant (P<0.001) reduction in rectal temperature was shown by all prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with reduced GI adverse effects than the parent drug. PMID:27555750

Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth.

PubMed Central

Tutton, P. J.; Barkla, D. H.

1980-01-01

The influence of two prostaglandin (PG) analogues, 16,16-dimethyl PG E2 and 16,16-dimethyl PG F2 alpha and of the cyclo-oxygenase inhibitor, flurbiprofen, on epithelial cell proliferation was assessed using a stathmokinetic technique. The epithelia examined were those of the jejunal crypts, the colonic crypts and that of dimethylhydrazine-induced adenocarcinomas of rat colon. The influence of the two prostaglandin analogues, and of flurbiprofen, on the growth of a human colorectal tumour propagated as xenografts in immune-deprived mice was also assessed. The PG E2 analogue transiently inhibited xenograft growth, but was without effect on the mitotic rate in the rat tissues. The PG F2 alpha analogue was also found to inhibit xenograft growth but, unlike the PG E2 analogue, it was found to be a strong inhibitor of cell proliferation in rat colonic tumours, and an accelerator of proliferation in jejunal-crypt cells. The only statistically significant effect of flurbiprofen was to accelerate cell division in the rat colonic tumours. PMID:7362778

Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth.

PubMed

Tutton, P J; Barkla, D H

1980-01-01

The influence of two prostaglandin (PG) analogues, 16,16-dimethyl PG E2 and 16,16-dimethyl PG F2 alpha and of the cyclo-oxygenase inhibitor, flurbiprofen, on epithelial cell proliferation was assessed using a stathmokinetic technique. The epithelia examined were those of the jejunal crypts, the colonic crypts and that of dimethylhydrazine-induced adenocarcinomas of rat colon. The influence of the two prostaglandin analogues, and of flurbiprofen, on the growth of a human colorectal tumour propagated as xenografts in immune-deprived mice was also assessed. The PG E2 analogue transiently inhibited xenograft growth, but was without effect on the mitotic rate in the rat tissues. The PG F2 alpha analogue was also found to inhibit xenograft growth but, unlike the PG E2 analogue, it was found to be a strong inhibitor of cell proliferation in rat colonic tumours, and an accelerator of proliferation in jejunal-crypt cells. The only statistically significant effect of flurbiprofen was to accelerate cell division in the rat colonic tumours.

Intravenous flurbiprofen axetil can stabilize the hemodynamic instability due to mesenteric traction syndrome--evaluation with continuous measurement of the systemic vascular resistance index using a FloTrac® sensor.

PubMed

Takada, Motoshi; Taruishi, Chieko; Sudani, Tomoko; Suzuki, Akira; Iida, Hiroki

2013-08-01

Evaluation of the stabilizing effect of intravenous flurbiprofen axetil against hemodynamic instability due to mesenteric traction syndrome (MTS) by continuous measurement of systemic vascular resistance index (SVRI) using a FloTrac(®) sensor was evaluated. Prospective randomized trial. A single-center study performed in an educational hospital. Two prospective studies were carried out, each with 40 patients scheduled for elective open abdominal surgery. Twenty patients received 50 mg of flurbiprofen axetil after the recognition of MTS by the anesthesiologist (group FT). The remaining patients served as controls (groups CP and CT). SVRI data was collected every 20 seconds for 1 hour after starting the laparotomy. The average SVRI prior to skin incision was taken as the baseline. Following 3 values were devised to evaluate MTS: the S-value (sum total of changes in SVRI from baseline), the T-value (period during which SVRI remained 20% or more below baseline), and the M-value (maximum change in SVRI from baseline). In group FP, decrease in SVRI was smaller than in group CP, and statistical differences in the 3 values were found. In group FT, SVRI recovered earlier than in group CT, and statistical differences were found in S-value and T-value. However, the M-value had no statistical differences. Intravenous flurbiprofen axetil can stabilize the hemodynamic instability due to MTS. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparison of the Effects of Daily Single-Dose Use of Flurbiprofen, Diclofenac Sodium, and Tenoxicam on Postoperative Pain, Swelling, and Trismus: A Randomized Double-Blind Study.

PubMed

Kaplan, Volkan; Eroğlu, Cennet Neslihan

2016-10-01

The aim of the present study was to compare the effects of daily single-dose use of flurbiprofen, diclofenac sodium, and tenoxicam on pain, swelling, and trismus that occur after surgical extraction of impacted wisdom teeth using local anesthesia. The present study included 3 groups with 30 patients in each group. Those volunteering to participate in this double-blind randomized study (n = 90) were selected from a patient population with an indication for extraction of impacted wisdom teeth. Group 1 patients received 200 mg flurbiprofen, group 2 patients received 100 mg diclofenac sodium, and group 3 patients received 20 mg tenoxicam. All doses were once a day, starting preoperatively. Pain was evaluated postoperatively at 1, 2, 3, 6, 8, and 24 hours and at 2 and 7 days using a visual analog scale (VAS). For comparison with the preoperative measurements, the patients were invited to postoperative follow-up visits 2 and 7 days after extraction to evaluate for swelling and trismus. The statistical analysis was performed using descriptive statistics in SAS, version 9.4 (SAS Institute, Cary, NC), software. Statistical analysis of the pain, swelling, and trismus data was performed using the Kruskal-Wallis, Dunn, and Wilcoxon-Mann-Whitney U tests. The statistical level of significance was accepted at P = .05 and power of 0.80. Clinically, tenoxicam showed better analgesic and anti-inflammatory efficacy compared with diclofenac sodium and, in particular, flurbiprofen. Although the VAS scores in the evaluation of pain showed statistically significant differences at 2 days, no statistically significant difference was found for swelling and trismus. Our study evaluated the analgesic and anti-inflammatory effects with a daily single dose of flurbiprofen, diclofenac sodium, and tenoxicam. Daily 20 mg tenoxicam can be accepted as an adequate and safe option for patients after a surgical procedure. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Flurbiprofen and hypertension but not hydroxyethyl starch are associated with post-craniotomy intracranial haematoma requiring surgery.

PubMed

Jian, M; Li, X; Wang, A; Zhang, L; Han, R; Gelb, A W

2014-11-01

Post-craniotomy intracranial haematoma is one of the most serious complications after neurosurgery. We examined whether post-craniotomy intracranial haematoma requiring surgery is associated with the non-steroidal anti-inflammatory drugs flurbiprofen, hypertension, or hydroxyethyl starch (HES). A case-control study was conducted among 42 359 patients who underwent elective craniotomy procedures at Beijing Tiantan Hospital between January 2006 and December 2011. A one-to-one control group without post-craniotomy intracranial haematoma was selected matched by age, pathologic diagnosis, tumour location, and surgeon. Perioperative blood pressure records up to the diagnosis of haematoma, the use of flurbiprofen and HES were examined. The incidence of post-craniotomy intracranial haematoma and the odds ratios for the risk factors were determined. A total of 202 patients suffered post-craniotomy intracranial haematoma during the study period, for an incidence of 0.48% (95% CI=0.41-0.55). Haematoma requiring surgery was associated with an intraoperative systolic blood pressure of >160 mm Hg (OR=2.618, 95% CI=2.084-2.723, P=0.007), an intraoperative mean blood pressure of >110 mm Hg (OR=2.600, 95% CI=2.312-3.098, P=0.037), a postoperative systolic blood pressure of >160 mm Hg (OR=2.060, 95% CI= 1.763-2.642, P=0.022), a postoperative mean blood pressure of >110 mm Hg (OR=3.600, 95% CI= 3.226-4.057, P=0.001), and the use of flurbiprofen during but not after the surgery (OR=2.256, 95% CI=2.004-2.598, P=0.005). The intraoperative infusion of HES showed no significant difference between patients who had a haematoma and those who did not. Intraoperative and postoperative hypertension and the use of flurbiprofen during surgery are risk factors for post-craniotomy intracranial haematoma requiring surgery. The intraoperative infusion of HES was not associated with a higher incidence of haematoma. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Clinical Analysis of Analgesics and Steroids Use for Extraction of Teeth in Patients with Intellectual Disability Under General Anesthesia.

PubMed

Maeda, Shigeru; Honda, Yuka; Tanimura, Hiroshi; Tomoyasu, Yumiko; Higuchi, Hitoshi; Murata, Naomichi; Egusa, Masahiko; Miyawaki, Takuya

2017-01-01

The extraction of lower wisdom teeth is often performed under general anesthesia in patients with intellectual disabilities. However, the choice of analgesics has not yet been investigated. To analyze the use of analgesics during general anesthesia for extraction including lower wisdom teeth in patients with intellectual disabilities. This research is a retrospective observational study. The study population was composed of all patients presenting for extraction of lower wisdom teeth under ambulatory general anesthesia in the clinic of Special Needs Dentistry in Okayama University Hospital from April 2011 to March 2016. The distribution of the combination of analgesics and the relationship between the use of analgesics and the type of extraction were investigated. One hundred and twelve cases were enrolled in this study. Intravenous injections of flurbiprofen, acetaminophen and betamethasone were used in 96 (85.7%), 12 (10.7%) and 26 cases (23.2%), respectively. Flurbiprofen is a non-steroid anti-inflammatory drugs (NSAIDs). Acetaminophen is an old analgesic, but an injection of acetaminophen is new, which was released in 2013 in Japan. And betamethasone is not an analgesic, but a steroid. Betamethasone was used in combination with other analgesics, and was used at a higher dose in a case in which four wisdom teeth were extracted. Flurbiprofen was the main analgesic used for extraction of wisdom teeth under general anesthesia in patients with intellectual disabilities. Betamethasone was used to support flurbiprofen or acetaminophen for extractions of multiple wisdom teeth, with the aim of controlling swelling rather than relieving pain.

Liquid chromatography-tandem mass spectrometry for the quantification of flurbiprofen in human plasma and its application in a study of bioequivalence.

PubMed

Mei, Chenghan; Li, Bin; Yin, Qiangfeng; Jin, Jing; Xiong, Ting; He, Wenjuan; Gao, Xiujuan; Xu, Rong; Zhou, Piqi; Zheng, Heng; Chen, Hui

2015-07-01

A simple, quick and accurate LC-MS/MS method for the quantification of flurbiprofen in human plasma with indomethacin as internal standard (IS) was developed and validated. Samples were treated with methanol to precipitate proteins, then separated on a Ultimate C18 column (5μm, 2.1×50mm) with a gradient elusion process. Mobile phase A was comprised of water and formic acid, mobile phase B was comprised of acetonitrile and formic acid. Multi reaction monitoring (MRM) signals were saved on a negative ionization electrospray mass spectrometer. The calibration curve showed good linearity in the range of 40.00-10000.00μg/L (r(2)=0.998). Intra-day RE was 0.2-2.2%. Inter-day RE was 0.5-3.4%. The samples showed good stability under the study conditions. No significant matrix effect was observed. The established method was then applied to a bioequivalence study of a flurbiprofen axetil formulation. Copyright © 2015 Elsevier B.V. All rights reserved.

[Clinical observation of propofol combined with flurbiprofen axetil for induced abortion anesthesia].

PubMed

Yang, Hong-wei; Xie, Yong-qiu; Guo, Qu-lian

2006-10-01

To observe the effect of propofol combined with flurbiprofen axetil for abortion anesthesia. Eighty ASA I - II induced abortion patients were randomly divided into 4 groups. Group I was administrated 1 microg/kg with tramadol first, after 10 minutes with 2 mg/kg propofol. Group II was administrated with 1 mg/kg tramadol first, after 10 minutes with 2 mg/kg propofol. Group III was administrated flurbiprofen axetil 50 mg first, after 10 minutes 2 mg/kg propofol. Group IV was administrated propofol 2 mg/kg. The speed of intravenous injection of propofol was 100 mg/min in all groups. Induction time, recovery time, propofol dosage, HR, BP, SpO2, and side effect were recorded. The anesthesia effect was judged by operation doctors. Propofol consumption and awaken time in Group IV was more than those of other groups. The number of patients in Group I with minimum value of SpO2 in the operation (85% - 90% or SpO2<85%) was higher than that of other groups (P<0.05). The number of patients in Group I and II with the tongue falling backwards during anesthesia, with post-anesthesia nausea and vomit was higher than that of other groups (P<0.05). Incidences of post-anesthesia excitement or delirium were higher than other groups. Fewer patients in Group IV showed a good level anesthesia effect than other groups. The post-operative hypogastric pain of VAS score (0 - 2) in Group III was better than others. Propofol combined with flurbiprofen axetil gives more efficient anesthesia for induced abortion patients in gynecology department. It can not only have satisfactory anesthesia effect, but also decrease adverse effects and obtain better depression effects to the post-operative hypogastric pain.

Comparison of fructus agni casti and flurbiprofen in the treatment of cyclic mastalgia in premenopausal women.

PubMed

Dinç, Tolga; Coşkun, Faruk

2014-01-01

Cyclic mastalgia is described as a diffuse, periodic and bilateral breast pain that can not be localized. Although there are several methods of treatment, the most efficient treatment method is still controversial. The aim of this study is to determine, compare and discuss the results of the patients under 40 years old age with a complaint of cyclic mastalgia and without any clinical signs, family history and ultrasonography finding, treated with fructus agni casti extract or flurbiprofen. One hundred and fourteen premenapousal patients younger than 40 years old with a complaint of cyclic mastalgia and without any clinical, family or ultrasonography findings were analyzed prospectively. Fructus agni casti extract (Group 1) or flurbiprofen (Group 2) were administered to the patients. VAS scores were accepted as full recovery whit a score of zero, as significant healing when the score improved more than 50%, as mild-moderate healing when the improvement was less than 50% and as no healing in case of no improvement. The mean age in group 1 was 28.29±5.81, and in group 2 was 29.09±4.49. The mean number of days with pain was 6.0±1.70 days in group 1, and was 6.3±1.63 in group 2. There was no significant difference in VAS scores between the two groups after treatment. Fructus agni casti extract and flurbiprofen are commonly used medications in the treatment of cyclic mastalgia. Both of these medications significantly reduce the complaints and have acceptable side-effects. There is no proven superiority over each other. Further clinical and laboratory studies are necessary to determine the ideal medication fort he treatment of cyclic mastalgia.

Plasma pharmacokinetics and synovial concentrations of S-flurbiprofen plaster in humans.

PubMed

Yataba, Ikuko; Otsuka, Noboru; Matsushita, Isao; Kamezawa, Miho; Yamada, Ichimaro; Sasaki, Sigeru; Uebaba, Kazuo; Matsumoto, Hideo; Hoshino, Yuichi

2016-01-01

The purpose of this study is to investigate the pharmacokinetics and deep tissue penetration capability of the newly developed S-flurbiprofen plaster (SFPP) in humans. Study 1: SFPP tape-type patch (2-60 mg) was applied to the lower back for 24 h in healthy adult volunteers. S-flurbiprofen (SFP) plasma concentration was measured over time to examine SFP pharmacokinetics. Study 2: SFPP (20 mg) was applied for 12 h to the affected knee of osteoarthritis (OA) patients who were scheduled for total knee arthroplasty. Deep tissues (synovial tissue and synovial fluid) were collected during surgery to compare SFP concentrations after application of SFPP or a commercially available flurbiprofen (FP) gel-type patch. Study 1: The plasma concentration of SFP was sustained during 24-h topical application of the SFPP, showing a high percutaneous absorption ratio of 51.4-72.2 %. Cmax and AUC0-∞ were dose-proportional. Study 2: After application of the SFPP for 12 h, SFP concentrations in the synovial tissue and synovial fluid were 14.8-fold (p = 0.002) and 32.7-fold (p < 0.001) higher, respectively, than those achieved by the FP patch. Sustained plasma concentration of SFP and high percutaneous absorption ratio was observed after 24-h topical application of the SFPP. Compared to the FP patch, the SFPP showed superior percutaneous absorption and greater tissue penetration of SFP into the synovial tissue. Greater tissue penetration of the SFPP seemed to be primarily due to its formulation. Thus, SFPP is expected to show higher efficacy for the treatment of knee OA.

Comparison of the analgesic effect of intravenous acetaminophen with that of flurbiprofen axetil on post-breast surgery pain: a randomized controlled trial.

PubMed

Nonaka, Takahiro; Hara, Marie; Miyamoto, Chisato; Sugita, Michiko; Yamamoto, Tatsuo

2016-06-01

Acetaminophen is known to be a relatively weak analgesic with fewer side effects than nonsteroidal anti-inflammatory drugs (NSAIDs). This study aimed to determine whether intravenous (iv) acetaminophen produces comparable analgesic effects to those of flurbiprofen (positive control drug), an intravenously injectable NSAID, after partial mastectomies. The primary outcome assessed was pain intensity during the first 24 h after the operation, and the secondary outcome was the satisfaction rating at discharge. After obtaining Institutional Ethics Committee approval, a series of 40 consecutive female patients who were scheduled for partial mastectomies were enrolled. Participants were randomly divided into two groups: an acetaminophen (1000 mg × 3) group (group A) and a flurbiprofen (50 mg × 3) group (group F). Each drug was administered 15 min before the end of surgery, and at 6 and 12 h after the operation. Postoperative pain was evaluated using a 100-mm visual analog scale (VAS) at 3, 6, and 24 h postoperatively. Satisfaction rating was evaluated on a 5-point scale (very good, good, well, bad, and very bad). VAS scores (mm) with movement in groups A and F at 3, 6, and 24 h after the surgery were 22 vs. 28, 14 vs. 24, and 12 vs. 20.5 (median), respectively, with no significant differences between the two groups. Eighteen of 20 patients in group A and 20 of 20 patients in group F expressed a satisfaction rating of greater than good. Acetaminophen produces an equivalent analgesic effect to flurbiprofen in post-partial mastectomy patients.

The effect of flurbiprofen on the development of anencephaly in early stage chicken embryos.

PubMed

Özeren, Ersin; Er, Uygur; Güvenç, Yahya; Demirci, Adnan; Arıkök, Ata Türker; Şenveli, Engin; Ergün, Rüçhan Behzat

2015-04-01

The study investigated the effect of flurbiprofen on the development of anencephaly in early stage chicken embryos. We looked at four groups with a total of 36 embryos. There was a control group, a normal saline group, a normal-dose group and a high-dose group with ten, ten, eight and eight eggs with embryo respectively. Two embryos in the control group, studied with light microscopy at 48 h, were consistent with 28-29 hours' incubation in the Hamburger-Hamilton System. They had open neural tubes. The other embryos in this group were considered normal. One embryo in the normal saline group was on the occlusion stage at 48 h. One embryo showed an open neural tube. They were compatible with 28-29 hours' incubation in the Hamburger-Hamilton system. The remaining eight embryos showed normal development. In the normal dose group, one embryo showed underdevelopment of the embryonic disc and the embryo was dead. In four embryos, the neural tubes were open. One cranial malformation was found that was complicated with anencephaly in one embryo. In two embryos the neural tubes were closed, as they showed normal development, and they reached their expected stages according to the Hamburger-Hamilton classification. There was no malformation or growth retardation. Four experimental embryos were anencephalic in the high dose group, and three embryos had open neural tubes. One embryo exhibited both anencephaly and a neural tube closure defect. None of the embryos in this group showed normal development. Even the usual therapeutic doses of flurbiprofen increased the risk of neural tube defect. Flurbiprofen was found to significantly increase the risk of anencephaly. The provision of improved technical materials and studies with larger sample sizes will reveal the stage of morphological disruption during the development of embryos.

Flurbiprofen Axetil Provides Effective Analgesia Without Changing the Pregnancy Rate in Ultrasound-Guided Transvaginal Oocyte Retrieval: A Double-Blind Randomized Controlled Trial.

PubMed

Zhao, Hong; Feng, Yi; Jiang, Yan; Lu, Qun

2017-10-01

In this prospective double-blind randomized study, we evaluated the analgesic effect and potential effect on pregnancy rate of the nonsteroidal anti-inflammatory drug flurbiprofen axetil in patients undergoing ultrasound-guided transvaginal oocyte retrieval under propofol-remifentanil anesthesia. A total of 200 patients scheduled to undergo ultrasound-guided transvaginal oocyte retrieval were randomly allocated to receive 1.5 mg/kg of flurbiprofen axetil (FA group) or placebo (control group) 30 minutes before the procedure. Postoperative pain scores, embryo implantation rate, and pregnancy rate were recorded. Neuroendocrine biomarkers and prostaglandin E2 levels in follicular fluid were tested after oocyte retrieval. Patients in the FA group awakened earlier after surgery than patients in the control group (3.3 ± 2.6 vs 5.3 ± 3.4 minutes, P < .05) and had lower pain scores than patients in the control group (2.0 [0.0, 2.8] vs 5.0 [3.0, 5.0], P< .001). The difference in pregnancy rates between the 2 groups (44%-44%) was 0% (conventional 2-sided 95% confidence interval, -13.8% to 13.8%). The lower limit of the 90% 1-sided confidence interval for this difference was -9.0%, which was within the predefined noninferiority margin of -15.0%. The concentration of prostaglandin E2 in follicular fluid was decreased in the FA group (24.51 ± 1.52 vs 25.15 ± 1.49 pg/mL, P = .039), although the difference does not appear to be clinically important. Flurbiprofen axetil given before ultrasound-guided transvaginal oocyte retrieval for patients under propofol-remifentanil general anesthesia relieves pain without any detrimental effect on clinical pregnancy rate.

On-Demand Drug Delivery System Using Micro-organogels with Gold Nanorods

PubMed Central

2016-01-01

In this study, we designed a biocompatible drug carrier: micro-organogels prepared by emulsification using vegetable oils and self-assembled gelator fibers. Flurbiprofen was chosen as a hydrophobic model drug and is classified as a nonsteroidal anti-inflammatory drug. In the absence of NIR light, flurbiprofen encapsulated in micro-organogels with gold nanorods (GNRs) was released slowly, while release was accelerated in the presence of NIR light due to the increase in the temperature surrounding the GNRs that transforms the gels into liquid. These results suggest that our system can be efficiently used as a versatile scaffold for on-demand drug delivery systems. PMID:27994743

The dispersion releaser technology is an effective method for testing drug release from nanosized drug carriers.

PubMed

Janas, Christine; Mast, Marc-Phillip; Kirsamer, Li; Angioni, Carlo; Gao, Fiona; Mäntele, Werner; Dressman, Jennifer; Wacker, Matthias G

2017-06-01

The dispersion releaser (DR) is a dialysis-based setup for the analysis of the drug release from nanosized drug carriers. It is mounted into dissolution apparatus2 of the United States Pharmacopoeia. The present study evaluated the DR technique investigating the drug release of the model compound flurbiprofen from drug solution and from nanoformulations composed of the drug and the polymer materials poly (lactic acid), poly (lactic-co-glycolic acid) or Eudragit®RSPO. The drug loaded nanocarriers ranged in size between 185.9 and 273.6nm and were characterized by a monomodal size distribution (PDI<0.1). The membrane permeability constants of flurbiprofen were calculated and mathematical modeling was applied to obtain the normalized drug release profiles. For comparing the sensitivities of the DR and the dialysis bag technique, the differences in the membrane permeation rates were calculated. Finally, different formulation designs of flurbiprofen were sensitively discriminated using the DR technology. The mechanism of drug release from the nanosized carriers was analyzed by applying two mathematical models described previously, the reciprocal powered time model and the three parameter model. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations.

PubMed

Zheng, Dan; Shuai, Xiao; Li, Yanping; Zhou, Peng; Gong, Tao; Sun, Xun; Zhang, Zhirong

2016-09-01

Tarenflurbil (R-flurbiprofen) was acknowledged as a promising candidate in Alzheimer's disease (AD) therapy. However, the Phase III study of tarenflurbil was extremely restricted by its poor delivery efficiency to the brain. To tackle this problem, the novel carriers for tarenflurbil, racemic flurbiprofen (FLU) derivatives (FLU-D1 and FLU-D2) modified by N,N-dimethylethanolamine-related structures were synthesized and characterized. These derivatives showed good safety level in vitro and they possessed much higher cellular uptake efficiency in brain endothelial cells than FLU did. More importantly, the uptake experiments suggested that they were internalized via active transport mechanisms. Biodistribution studies in rats also illustrated a remarkably enhanced accumulation of these derivatives in the brain. FLU-D2, the ester linkage form of these derivatives, achieved a higher brain-targeting efficiency. Its C max and AUC 0- t were enhanced by 12.09-fold and 4.61-fold, respectively compared with those of FLU. Additionally, it could be hydrolyzed by esterase in the brain to release the parent FLU, which might facilitate its therapeutic effect. These in vitro and in vivo results highlighted the improvement of the brain-targeted delivery of FLU by making use of N,N-dimethylethanolamine ligand, with which an active transport mechanism was involved.

A Comparison of Fentanyl and Flurbiprofen Axetil on Serum VEGF-C, TNF-α, and IL-1ß Concentrations in Women Undergoing Surgery for Breast Cancer.

PubMed

Wen, Yiyun; Wang, Mingde; Yang, Jinfeng; Wang, Yichun; Sun, Huiping; Zhao, Jianghong; Liu, Weizhen; Zhou, Zhengyu; Deng, Hongwu; Castillo-Pedraza, Catalina; Zhang, Yi; Candiotti, Keith A

2015-07-01

Vascular endothelial growth factor-C (VEGF-C), tumor necrosis factor-α (TNF-α), and interleukin-1ß(IL-1ß) have been shown to be associated with the recurrence and metastasis of breast cancer after surgery. This study tested the hypothesis that patients undergoing surgery for breast cancer, who received postoperative analgesia with flurbiprofen axetil combined with small doses of fentanyl (FA), exhibited reduced levels of VEGF-C, TNF-α, and IL-1ß compared with those patients receiving fentanyl alone (F). Forty-women with primary breast cancer undergoing a modified radical mastectomy were randomized to receive postoperative analgesia with flurbiprofen axetil combined with fentanyl or fentanyl alone. Venous blood was sampled before anesthesia, at the end of surgery, and at 48 hours after surgery, and the serum was analyzed. The primary endpoint was changes in the VEGF-C concentrations in serum. Group FA patients reported similar analgesic effects as group F patients at 2, 24, and 48 hours. At 48 hours, mean postoperative concentrations of VEGF-C in group F patients were higher than in group FA patients, 730.9 versus. 354.1 pg/mL (P = 0.003), respectively. The mean postoperative concentrations of TNF-α in group F patients were also higher compared with group FA patients 27.1 vs. 15.8 pg/mL (P = 0.005). Finally, the mean postoperative concentrations of IL-1ß in group F were also significantly higher than in group FA 497.5 vs. 197.7 pg/mL (P = 0.001). In patients undergoing a mastectomy, postoperative analgesia with flurbiprofen axetil, combined with fentanyl, were associated with decreases in serum concentrations of VEGF-C, TNF-α, and IL-1ß compared with patients receiving doses of only fentanyl. © 2014 World Institute of Pain.

Changes in mechanical, chemical, and thermal sensitivity of the cornea after topical application of nonsteroidal anti-inflammatory drugs.

PubMed

Acosta, M Carmen; Berenguer-Ruiz, Leticia; García-Gálvez, Alberto; Perea-Tortosa, David; Gallar, Juana; Belmonte, Carlos

2005-01-01

In addition to their well-known anti-inflammatory actions, some of the nonsteroidal anti-inflammatory drugs (NSAIDs) appear to have an analgesic effect. In human subjects, the changes in threshold and intensity of sensations evoked by mechanical, chemical, and thermal stimulation of the cornea induced by topical administration of two commercial NSAIDs, diclofenac sodium (Voltaren; Novartis, Basel, Switzerland) and flurbiprofen (Ocuflur; Allergan, Irvine, CA), were studied. Corneal sensitivity was measured in 10 young, healthy subjects with a gas esthesiometer. Chemical (10%-70% CO2 in air), mechanical (0-264 mL/min), and thermal (corneal temperature changes between -4.5 degrees C and +3 degrees C around the normal value) stimuli were applied to the center of the cornea. The intensity and perceived magnitude of the psychophysical attributes of the evoked sensation were scored at the end of the pulse in a 10-cm, continuous visual analog scale (VAS). The threshold was expressed as the stimulus intensity that evoked a VAS score >0.5. Sensitivity was measured in both eyes of each subject on two separate days, one without treatment and the other 30 minutes after topical application of 0.03% flurbiprofen (seven subjects) or 0.1% diclofenac sodium (six subjects). Diclofenac attenuated significantly all the sensation parameters evoked by high-intensity mechanical, chemical, and thermal stimuli. Flurbiprofen produced a slight reduction of the sensations evoked by mechanical and chemical stimulation that became significant only for the irritation caused by chemical stimuli of maximum intensity (70% CO2). None of the drugs modified significantly the detection threshold of the different stimuli. Flurbiprofen had a very limited effect on sensations evoked by corneal stimulation, whereas diclofenac reduced the intensity of sensations evoked by stimuli of different modality, suggesting a mild local anesthetic effect of this drug on all types of corneal sensory fibers. Such anesthetic action could explain the analgesic effect that has been reported after topical application of diclofenac in inflamed human eyes.

Effect of guest drug character encapsulated in the cavity and intermolecular spaces of γ-cyclodextrins on the dissolution property of ternary γ-cyclodextrin complex.

PubMed

Liu, Nan; Higashi, Kenjirou; Ueda, Keisuke; Moribe, Kunikazu

2017-10-15

Various ternary Guest 2/(Guest 1/γ-cyclodextrin (CD)) complexes were prepared using a cogrinding and subsequent heating method, wherein Guest 1 was incorporated in the cavity of γ-CD and Guest 2 was incorporated into the intermolecular spaces between γ-CD columns. Dissolution fluxes of Guest 1 and Guest 2 from all ternary complexes were almost identical. The dissolution flux of flurbiprofen (Guest 1) from the ternary complexes depended on the solubility of Guest 2 drugs (naproxen

Efficacy of S-flurbiprofen plaster in knee osteoarthritis treatment: Results from a phase III, randomized, active-controlled, adequate, and well-controlled trial.

PubMed

Yataba, Ikuko; Otsuka, Noboru; Matsushita, Isao; Matsumoto, Hideo; Hoshino, Yuichi

2017-01-01

S-flurbiprofen plaster (SFPP) is a novel non-steroidal anti-inflammatory drug (NSAID) patch, intended for topical treatment for musculoskeletal diseases. This trial was conducted to examine the effectiveness of SFPP using active comparator, flurbiprofen (FP) patch, on knee osteoarthritis (OA) symptoms. This was a phase III, multi-center, randomized, adequate, and well-controlled trial, both investigators and patients were blinded to the assigned treatment. Enrolled 633 knee OA patients were treated with either SFPP or FP patch for two weeks. The primary endpoint was improvement in knee pain on rising from the chair as assessed by visual analogue scale (rVAS). Safety was evaluated through adverse events (AEs). The change in rVAS was 40.9 mm in SFPP group and 30.6 mm in FP patch group (p < 0.001). The incidence of drug-related AEs at the application site was 9.5% (32 AEs, 29 mild and 3 moderate) in SFPP and 1.6% in FP patch (p < 0.001). Withdrawals due to AE were five in SFPP and one in FP patch. The superiority of SFPP in efficacy was demonstrated. Most of AEs were mild and few AEs led to treatment discontinuation. Therefore, SFPP provides an additional option for knee OA therapy.

Factors affecting the formation of eutectic solid dispersions and their dissolution behavior.

PubMed

Vippagunta, Sudha R; Wang, Zeren; Hornung, Stefanie; Krill, Steven L

2007-02-01

The objective of this work was to obtain a fundamental understanding of the factors, specifically the properties of poorly water-soluble drugs and water-soluble carriers, which influence predominantly, the formation of eutectic or monotectic crystalline solid dispersion and their dissolution behavior. A theoretical model was applied on five poorly water-soluble drugs (fenofibrate, flurbiprofen, griseofulvin, naproxen, and ibuprofen) having diverse physicochemical properties and water-soluble carrier (polyethylene glycol (PEG) 8000) for the evaluation of these factors. Of these, two drugs, fenofibrate and flurbiprofen, and PEG of different molecular weights (3350, 8000, and 20000), were chosen as model drugs and carriers for further investigation. Experimental phase diagrams were constructed and dissolution testing was performed to assess the performance of the systems. The theoretical model predicted the formation of eutectic or monotectic solid dispersions of fenofibrate, griseofulvin, ibuprofen, and naproxen with PEG, holding the contribution of specific intermolecular interactions between compound and carrier to zero. In the case of the flurbiprofen-PEG eutectic system, intermolecular interactions between drug and polymer needed to be taken into consideration to predict the experimental phase diagram. The results of the current work suggest that the thermodynamic function of melting point and heat of fusion (as a measure of crystal energy of drug) plays a significant role in the formation of a eutectic system. Lipophilicity of the compound (as represented by cLog P) was also demonstrated to have an effect. Specific interactions between drug and carrier play a significant role in influencing the eutectic composition. Molar volume of the drug did not seem to have an impact on eutectic formation. The polymer molecular weight appeared to have an impact on the eutectic composition for flurbiprofen, which exhibits specific interactions with PEG, whereas no such impact of polymer molecular weight on eutectic composition was observed for fenofibrate, which does not exhibit specific interactions with PEG. The impact of polymer molecular weight on dissolution of systems where specific drug-polymer interactions are exhibited was also observed. The current work provides valuable insight into factors affecting formation and dissolution of eutectic systems, which can facilitate the rational selection of suitable water-soluble carriers. Copyright (c) 2006 Wiley-Liss, Inc.

3-aminopropyl functionalized magnesium phyllosilicate as an organoclay based drug carrier for improving the bioavailability of flurbiprofen.

PubMed

Yang, Liang; Choi, Soo-Kyung; Shin, Hyun-Jae; Han, Hyo-Kyung

2013-01-01

This study aimed to develop an oral delivery system using clay-based organic-inorganic hybrid materials to improve the bioavailability of the drug, flurbiprofen, which is poorly soluble in water. 3-aminopropyl functionalized magnesium phyllosilicate (AMP clay) was synthesized by a one-pot direct sol-gel method, and then flurbiprofen (FB) was incorporated into AMP clay (FB-AMP) at different drug/clay ratios. The structural characteristics of AMP and FB-AMP formulation were confirmed by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. Among tested formulations, FB-AMP(3), dramatically increased the dissolution of FB and achieved rapid and complete drug release within 2 hours. More than 60% of FB was released from FB-AMP(3) after 30 minutes; the drug was completely dissolved in the water within 2 hours. Under the acidic condition (pH 1.2), FB-AMP(3) also increased the dissolution of FB by up to 47.1% within 1 hour, which was three-fold higher than that of untreated FB. Furthermore, following an oral administration of FB-AMP(3) to Sprague-Dawley rats, the peak plasma concentration and area under the plasma concentration-time curve of FB increased two-fold, and the time to reach the peak plasma concentration was shortened compared with that in the untreated FB. This result suggests that the oral drug delivery system using clay-based organic-inorganic hybrid material might be useful to improve the bioavailability of FB.

3-aminopropyl functionalized magnesium phyllosilicate as an organoclay based drug carrier for improving the bioavailability of flurbiprofen

PubMed Central

Yang, Liang; Choi, Soo-Kyung; Shin, Hyun-Jae; Han, Hyo-Kyung

2013-01-01

This study aimed to develop an oral delivery system using clay-based organic–inorganic hybrid materials to improve the bioavailability of the drug, flurbiprofen, which is poorly soluble in water. 3-aminopropyl functionalized magnesium phyllosilicate (AMP clay) was synthesized by a one-pot direct sol-gel method, and then flurbiprofen (FB) was incorporated into AMP clay (FB-AMP) at different drug/clay ratios. The structural characteristics of AMP and FB-AMP formulation were confirmed by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. Among tested formulations, FB-AMP(3), dramatically increased the dissolution of FB and achieved rapid and complete drug release within 2 hours. More than 60% of FB was released from FB-AMP(3) after 30 minutes; the drug was completely dissolved in the water within 2 hours. Under the acidic condition (pH 1.2), FB-AMP(3) also increased the dissolution of FB by up to 47.1% within 1 hour, which was three-fold higher than that of untreated FB. Furthermore, following an oral administration of FB-AMP(3) to Sprague-Dawley rats, the peak plasma concentration and area under the plasma concentration-time curve of FB increased two-fold, and the time to reach the peak plasma concentration was shortened compared with that in the untreated FB. This result suggests that the oral drug delivery system using clay-based organic–inorganic hybrid material might be useful to improve the bioavailability of FB. PMID:24204143

Topical Anti-Inflammatory and Analgesic Effects of Multiple Applications of S(+)-Flurbiprofen Plaster (SFPP) in a Rat Adjuvant-Induced Arthritis Model.

PubMed

Sugimoto, Masanori; Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

2016-06-01

Preclinical Research The aim of this study was to evaluate the efficacy of multiple applications of S(+)-flurbiprofen plaster (SFPP), a novel Nonsteroidal anti-inflammatory drug (NSAID) patch, for the alleviation of inflammatory pain and edema in rat adjuvant-induced arthritis (AIA) model as compared to other NSAID patches. The AIA model was induced by the injection of Mycobacterium butyricum and rats were treated with a patch (1.0 cm × 0.88 cm) containing each NSAID (SFP, ketoprofen, loxoprofen, diclofenac, felbinac, flurbiprofen, or indomethacin) applied to the paw for 6 h per day for 5 days. The pain threshold was evaluated using a flexion test of the ankle joint, and the inflamed paw edema was evaluated using a plethysmometer. cyclooxygenase (COX)-1 and COX-2 inhibition was evaluated using human recombinant proteins. Multiple applications of SFPP exerted a significant analgesic effect from the first day of application as compared to the other NSAID patches. In terms of paw edema, SFPP decreased edema from the second day after application, Multiple applications of SFPP were superior to those of other NSAID patches, in terms of the analgesic effect with multiple applications. These results suggest that SFPP may be a beneficial patch for providing analgesic and anti-inflammatory effects clinically. Drug Dev Res 77 : 206-211, 2016. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc.

Topical Anti‐Inflammatory and Analgesic Effects of Multiple Applications of S(+)‐Flurbiprofen Plaster (SFPP) in a Rat Adjuvant‐Induced Arthritis Model

PubMed Central

Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

2016-01-01

Abstract Preclinical Research The aim of this study was to evaluate the efficacy of multiple applications of S(+)‐flurbiprofen plaster (SFPP), a novel Nonsteroidal anti‐inflammatory drug (NSAID) patch, for the alleviation of inflammatory pain and edema in rat adjuvant‐induced arthritis (AIA) model as compared to other NSAID patches. The AIA model was induced by the injection of Mycobacterium butyricum and rats were treated with a patch (1.0 cm × 0.88 cm) containing each NSAID (SFP, ketoprofen, loxoprofen, diclofenac, felbinac, flurbiprofen, or indomethacin) applied to the paw for 6 h per day for 5 days. The pain threshold was evaluated using a flexion test of the ankle joint, and the inflamed paw edema was evaluated using a plethysmometer. cyclooxygenase (COX)−1 and COX‐2 inhibition was evaluated using human recombinant proteins. Multiple applications of SFPP exerted a significant analgesic effect from the first day of application as compared to the other NSAID patches. In terms of paw edema, SFPP decreased edema from the second day after application, Multiple applications of SFPP were superior to those of other NSAID patches, in terms of the analgesic effect with multiple applications. These results suggest that SFPP may be a beneficial patch for providing analgesic and anti‐inflammatory effects clinically. Drug Dev Res 77 : 206–211, 2016. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc. PMID:27241582

Muscle shortening maneuver and not topical anti-inflammatory therapy is effective in reducing the width of subacromial-subdeltoid bursa in shoulder impingement syndrome

NASA Astrophysics Data System (ADS)

Melchiorre, Daniela; Lippi, Paolo; Marchi, Alberto; Maresca, Marco; Bravi, Riccardo; Eros, Quarta; Lazzerini, Patrizia; Bagni, Maria Angela

2018-04-01

Aim of the study was to compare the efficacy of a muscle shortening maneuver (MSM) with the efficacy of a topical NSAID (flurbiprofen) in patients with subacromial impingement syndrome (SIS). The effects of these therapies were evaluated by sonographic exam (US). SIS was diagnosed by US in 78 patients with painful shoulder. Thirty patients (first group) were treated with topical flurbiprofen for 15 days. Forty-eight patients (second group) were treated with MSM, which was performed once. The shoulder was analyzed in all patients by US before and after treatment. Before treatment and 15 days after treatment, pain by Visual Analogue Scale (VAS), range of motion (ROM) and Neer's Test were evaluated. Pain was decreased by both treatments. In only 8 patients of the first group, the encroachment of acromion into the rotator cuff was no more detectable by US after the treatment; ROM increased (> 45°) only in 11 patients (36%) and the width of subacromial-subdeltoid bursa (SSB) was not significantly reduced. At variance with the results obtained in the first group, in all patients of the second group the encroachment of acromion was no more detectable by US, ROM increased (> 45°) and the width of SSB was significantly reduced after the maneuver. Both topical flurbiprofen and MSM were helpful in pain control, but better results, with decrease of width of SSB assessed by US, were obtained by MSM.

Indomethacin and flurbiprofen speed recovery of rat bronchial epithelium after exposure to cigarette smoke.

PubMed

Rogers, D F; Jeffery, P K

1986-01-01

The cigarette smoke-induced rat model of chronic bronchitis was used to study the time course of the return of cigarette smoke-induced secretory cell hyperplasia to the normal and the capacity of two non-steroidal anti-inflammatory drugs to speed this recovery. Cigarette smoke alone significantly increased (P less than 0.05) the number of secretory cells in all of the eight airway levels studied to between 52-225% above control values. After cessation of exposure, recovery was complete by 9 days in the trachea, between 10-21 days in 'proximal' intrapulmonary airways and 43-84 days in distal bronchioli. Indomethacin and flurbiprofen, given by intraperitoneal injection at 4 mg/kg body weight for 21 days of the recovery period, significantly reduced the time taken for recovery to between 4 and 9 days in intrapulmonary airways but had no effect in the trachea.

Modulation of drug release from nanocarriers loaded with a poorly water soluble drug (flurbiprofen) comprising natural waxes.

PubMed

Baviskar, D T; Amritkar, A S; Chaudhari, H S; Jain, D K

2012-08-01

In this study, flurbiprofen (FLB) Solid Lipid Nanoparticles (SLN) composed from a mixture of beeswax and carnauba wax, Tween 80 and egg lecithin as emulsifiers have been prepared. FLB was incorporated as model lipophilic drug to assess the influence of matrix composition in the drug release profile. SLN were produced by microemulsion technique. In vitro studies were performed in Phosphate Buffered Saline (PBS). The FLB loaded SLN showed a mean particle size of 75 +/- 4 nm, a polydispersity index approximately 0.2 +/- 0.02 and an entrapment efficiency (EE) of more than 95%. Suspensions were stable, with zeta potential values in the range of -15 to -17 mV. DSC thermograms and UV analysis indicated the stability of nanoparticles with negligible drug leakage. Nanoparticles with higher beeswax content in their core exhibited faster drug release than those containing more carnauba wax.

Study of the solvent effects on the molecular structure and Cdbnd O stretching vibrations of flurbiprofen

NASA Astrophysics Data System (ADS)

Tekin, Nalan; Pir, Hacer; Sagdinc, Seda

2012-12-01

The effects of 15 solvents on the C=O stretching vibrational frequency of flurbiprofen (FBF) were determined to investigate solvent-solute interactions. Solvent effects on the geometry and C=O stretching vibrational frequency, ν(C=O), of FBF were studied theoretically at the DFT/B3LYP and HF level in combination with the polarizable continuum model and experimentally using attenuated total reflection infrared spectroscopy (ATR-IR). The calculated C=O stretching frequencies in the liquid phase are in agreement with experimental values. Moreover, the wavenumbers of ν(C=O) of FBF in different solvents have been obtained and correlated with the Kirkwood-Bauer-Magat equation (KBM), the solvent acceptor numbers (ANs), and the linear solvation energy relationships (LSERs). The solvent-induced stretching vibrational frequency shifts displayed a better correlation with the LSERs than with the ANs and KBM.

Qualities of Sore Throat Index (QuaSTI): measuring descriptors of sore throat in a randomized, placebo-controlled trial.

PubMed

Schachtel, Bernard; Shephard, Adrian; Schachtel, Emily; Lorton, Mary Beth; Shea, Tim; Aspley, Sue

2018-03-01

Patients with pharyngitis often describe various sensory, affective and evaluative pain qualities. Using an 11-word/phrase index, the Qualities of Sore Throat Index (QuaSTI), we characterized throat symptoms and evaluated changes in a randomized controlled trial (NCT01986361). Patients received a single flurbiprofen 8.75 mg (n = 101) or placebo (n = 21) lozenge and rated throat soreness at baseline and regular intervals over 3 h, and the QuaSTI at baseline, 1, 2 and 3 h post-treatment. The QuaSTI distinguished active drug from placebo and detected clinically important (≥2-point) changes over 3 h. Mean change from baseline over 3 h was significantly greater for flurbiprofen (154%) than placebo (p < 0.05). The QuaSTI is a sensitive instrument for measuring therapeutic effects in patients with pharyngitis.

Pluronic lecithin organogel as a topical drug delivery system.

PubMed

Pandey, Mohit; Belgamwar, Veena; Gattani, Surendra; Surana, Sanjay; Tekade, Avinash

2010-01-01

The objective of this study was to formulate and evaluate the pluronic lecithin organogel containing flurbiprofen for topical application. Different formulations of pluronic lecithin organogels were prepared by using pluronic F127, lecithin, flurbiprofen, isopropyl palmitate, water, sorbic acid, and potassium sorbate. To study the in vitro potential of these formulations, permeation studies were performed with Keshary-Chien diffusion cells. The results of the in vitro permeation studies found that release of flurbiprofen from dialysis membrane-70 was more than excised dorsal rat skin. Gelation temperature study was carried out to determine the temperature where sol-gel transformation takes place. The viscosities of different formulations were determined by using Brookfield Viscometer at 25°C, the viscosity of formulations increases as the lecithin concentration increases. Also the formulations were tested for appearance and feel psychorheologically, pH, and drug content. Interactions between the components of the gel have been investigated by differential scanning calorimetry and X-ray powder diffractometry. The optimized formulation subjected to differential scanning calorimetry shows no drug-polymer interaction. To investigate the in vivo performance of the formulations, a carrageenan-induced rat paw edema model and skin irritation study was used. The stability studies and freeze-thaw thermal cyclic test were carried out, showing no phase separation of gel, and representing gel stability. Statistical analysis of the data of animal study (anti-inflammatory activity) was done by using one way analysis of variance (ANOVA) followed by Dunnett's test. The formulation shows a statistically significant anti-inflammatory activity and is non-irritant to skin.

CYCLOOXYGENASE COMPETITIVE INHIBITORS ALTER TYROSYL RADICAL DYNAMICS IN PROSTAGLANDIN H SYNTHASE-2†

PubMed Central

Wu, Gang; Tsai, Ah-Lim; Kulmacz, Richard J.

2009-01-01

Reaction of prostaglandin H synthase (PGHS) isoforms 1 or 2 with peroxide forms a radical at Tyr385 that is required for cyclooxygenase catalysis, and another radical at Tyr504, whose function is unknown. Both tyrosyl radicals are transient and rapidly dissipated by reductants, suggesting that cyclooxygenase catalysis might be vulnerable to suppression by intracellular antioxidants. Our initial hypothesis was that the two radicals are in equilibrium and that their proportions and stability are altered upon binding of fatty acid substrate. As a test, we examined the effects of three competitive inhibitors (nimesulide, flurbiprofen and diclofenac) on the proportions and stability of the two radicals in PGHS-2 pretreated with peroxide. Adding nimesulide after ethyl peroxide led to some narrowing of the tyrosyl radical signal detected by EPR spectroscopy, consistent with a small increase in the proportion of the Tyr504 radical. Neither flurbiprofen nor diclofenac changed the EPR linewidth when added after peroxide. In contrast, the effects of cyclooxygenase inhibitors on the stability of the preformed tyrosyl radicals were dramatic. The half-life of total tyrosyl radical was 4.1 min in the control, >10 hr with added nimesulide, 48 min with flurbiprofen, and 0.8 min with diclofenac. Stabilization of the tyrosyl radicals was evident even at substoichiometric levels of nimesulide. Thus, the inhibitors had potent, structure-dependent, effects on the stability of both tyrosyl radicals. This dramatic modulation of tyrosyl radical stability by cyclooxygenase site ligands suggests a mechanism for regulating the reactivity of PGHS tyrosyl radicals with cellular antioxidants. PMID:19894761

Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance

PubMed Central

Ma, Li; del Soldato, Piero; Wallace, John L.

2002-01-01

Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet/serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib- or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti- and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro- and antiangiogenic growth factors. PMID:12232050

Flurbiprofen-loaded niosomes-in-gel system improves the ocular bioavailability of flurbiprofen in the aqueous humor.

PubMed

El-Sayed, Marwa M; Hussein, Amal K; Sarhan, Hatem A; Mansour, Heba F

2017-06-01

The present work aimed to prolong the contact time of flurbiprofen (FBP) in the ocular tissue to improve the drug anti-inflammatory activity. Different niosome systems were fabricated adopting thin-film hydration technique and using the nonionic surfactant Span 60. The morphology of the prepared niosomes was characterized by scanning electron microscopy (SEM). Physical characterization by differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy were conducted for the optimized formula (F5) that was selected on the basis of percent entrapment efficiency, vesicular size and total lipid content. F5 was formulated as 1% w/w Carpobol 934 gel. Pharmacokinetic parameters of FBP were investigated following ocular administration of F5-loaded gel system, F5 niosome dispersion or the corresponding FBP ocular drops to albino rabbits dispersion. Anti-inflamatory effect of F5-loaded carbopol gel was investigated by histopathological examination of the corneal tissue before and after the treatment of inflamed rabbit eye with the system. Results showed that cholesterol content, surfactant type. and total lipid contents had an apparent impact on the vesicle size of the formulated niosomes. Physical characterization revealed reduced drug crystallinity and incidence of interaction with other niosome contents. F5-loaded gel showed higher C max , area under the curve (AUC 0-12 ), and thus higher ocular bioavailability than those of the corresponding FBP ocular solution. F5-loaded gel showed a promising rapid anti-inflammatory effect in the inflamed rabbit eye. These findings will eradicate the necessity for frequent ocular drug instillation and thus, improve patient compliance.

A novel injection strategy of flurbiprofen axetil by inhibiting protein binding with 6-methoxy-2-naphthylacetic acid.

PubMed

Ogata, Kenji; Takamura, Norito; Tokunaga, Jin; Ikeda, Tetsuya; Setoguchi, Nao; Tanda, Kazuhiro; Yamasaki, Tetsuo; Nishio, Toyotaka; Kawai, Keiichi

2016-04-01

Flurbiprofen axetil (FPA) is an injection product and a prodrug of a non-steroidal anti-inflammatory drug (NSAID). After injection, it is rapidly hydrolyzed to the active form, flurbiprofen (FP). Since frequent injections of FPA can lead to abnormal physiology, an administration strategy is necessary to ensure there is enhancement of the analgesic efficiency of FP after a single dose and to reduce the total number of doses. FP strongly binds to site II of albumin, and thus the free (unbound) FP concentration is low. This study focused on 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone (a prodrug of NSAID). We performed ultrafiltration experiments and pharmacokinetics analysis in rats to investigate whether the inhibitory effect of 6-MNA on FP binding to albumin increased the free FP concentration in vitro and in vivo. Results indicated that 6-MNA inhibited the binding of FP to albumin competitively. When 6-MNA was injected in rats, there was a significant increase in the free FP concentration and the area under concentration-time curve (AUC) calculated from the free FP concentration, while there was a significant decrease in the total (bound + free) FP concentration and the AUC calculated from the total FP concentration. These findings indicate that 6-MNA inhibits the protein binding of FP in vivo. This suggests that the frequency of FPA injections can be reduced when administered with nabumetone, as there is increase in the free FP concentration associated with pharmacological effect.

Analgesic Effect of the Newly Developed S(+)-Flurbiprofen Plaster on Inflammatory Pain in a Rat Adjuvant-Induced Arthritis Model.

PubMed

Sugimoto, Masanori; Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Hirose, Takuya; Endo, Hiromi; Futaki, Nobuko; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

2016-02-01

Preclinical Research This article describes the properties of a novel topical NSAID (Nonsteroidal anti-inflammatory drug) patch, SFPP (S(+)-flurbiprofen plaster), containing the potent cyclooxygenase (COX) inhibitor, S(+)-flurbiprofen (SFP). The present studies were conducted to confirm human COX inhibition and absorption of SFP and to evaluate the analgesic efficacy of SFPP in a rat adjuvant-induced arthritis (AIA) model. COX inhibition by SFP, ketoprofen and loxoprofen was evaluated using human recombinant COX proteins. Absorption of SFPP, ketoprofen and loxoprofen from patches through rat skin was assessed 24 h after application. The AIA model was induced by injecting Mycobacterium tuberculosis followed 20 days later by the evaluation of the prostaglandin PGE2 content of the inflamed paw and the pain threshold. SFP exhibited more potent inhibitory activity against COX-1 (IC50  = 8.97 nM) and COX-2 (IC50  = 2.94 nM) than the other NSAIDs evaluated. Absorption of SFP was 92.9%, greater than that of ketoprofen and loxoprofen from their respective patches. Application of SFPP decreased PGE2 content from 15 min to 6 h and reduced paw hyperalgesia compared with the control, ketoprofen and loxoprofen patches. SFPP showed analgesic efficacy, and was superior to the ketoprofen and loxoprofen patches, which could be through the potent COX inhibitory activity of SFP and greater skin absorption. The results suggested SFPP can be expected to exert analgesic effect clinically. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc.

Analgesic Effect of the Newly Developed S(+)‐Flurbiprofen Plaster on Inflammatory Pain in a Rat Adjuvant‐Induced Arthritis Model

PubMed Central

Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Hirose, Takuya; Endo, Hiromi; Futaki, Nobuko; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

2016-01-01

ABSTRACT Preclinical Research This article describes the properties of a novel topical NSAID (Nonsteroidal anti‐inflammatory drug) patch, SFPP (S(+)‐flurbiprofen plaster), containing the potent cyclooxygenase (COX) inhibitor, S(+)‐flurbiprofen (SFP). The present studies were conducted to confirm human COX inhibition and absorption of SFP and to evaluate the analgesic efficacy of SFPP in a rat adjuvant‐induced arthritis (AIA) model. COX inhibition by SFP, ketoprofen and loxoprofen was evaluated using human recombinant COX proteins. Absorption of SFPP, ketoprofen and loxoprofen from patches through rat skin was assessed 24 h after application. The AIA model was induced by injecting Mycobacterium tuberculosis followed 20 days later by the evaluation of the prostaglandin PGE2 content of the inflamed paw and the pain threshold. SFP exhibited more potent inhibitory activity against COX‐1 (IC50 = 8.97 nM) and COX‐2 (IC50 = 2.94 nM) than the other NSAIDs evaluated. Absorption of SFP was 92.9%, greater than that of ketoprofen and loxoprofen from their respective patches. Application of SFPP decreased PGE2 content from 15 min to 6 h and reduced paw hyperalgesia compared with the control, ketoprofen and loxoprofen patches. SFPP showed analgesic efficacy, and was superior to the ketoprofen and loxoprofen patches, which could be through the potent COX inhibitory activity of SFP and greater skin absorption. The results suggested SFPP can be expected to exert analgesic effect clinically. Drug Dev Res 76 : 20–28, 2016. © 2016 Wiley Periodicals, Inc. PMID:26763139

Efficacy of flurbiprofen 8.75 mg delivered as a spray or lozenge in patients with sore throat due to upper respiratory tract infection: a randomized, non-inferiority trial in the Russian Federation

PubMed Central

Radkova, Eugenia; Burova, Natalia; Bychkova, Valeria; DeVito, Robert

2017-01-01

Objective To assess the efficacy of flurbiprofen 8.75 mg delivered as a spray or lozenge in patients with sore throat due to upper respiratory tract infection (URTI). Materials and methods This multicenter, double-blind, double-dummy, non-inferiority study randomized 440 adults with recent-onset, moderate-to-severe sore throat due to URTI to a single dose of either flurbiprofen 8.75 mg spray (n=218) or flurbiprofen 8.75 mg lozenge (n=222). The presence or absence of beta-hemolytic streptococci (A or C) was confirmed by culture tests (throat swab). The primary efficacy end point was the difference from baseline to 2 hours post-dose in sore throat pain intensity scale (STPIS pain intensity difference [PID] 2h), a validated 100 mm visual analog scale (from 0=“no pain” to 100=“severe pain”), with a non-inferiority margin of −6 mm. Secondary end points included STPIS PID at 1 hour (STPIS PID 1h) and over 2 hours (STPIS sum of sore throat pain intensity differences [SPID]0–2h) and ratings of patient satisfaction and investigator assessment of drug efficacy at 2 hours. Safety (adverse events [AEs]) was also assessed. Results Reductions in sore throat pain intensity at 2 hours (STPIS PID 2h) were similar for spray (least square mean −40.51) and lozenge (−40.10) (difference: 0.41, 95% confidence interval [95% CI] −3.20, 4.01), with non-inferiority demonstrated. Subgroup analyses showed similar efficacy (STPIS PID 2h) for patients testing positive or negative for Strep A or C. There was no significant difference between spray and lozenge in STPIS PID 1h or STPIS SPID0–2h, and patient satisfaction and investigators’ assessment of efficacy at 2 hours were similar for both groups. There were no significant differences in AEs between the two groups, with 17 drug-related events across both groups, all being mild and none being serious. Conclusion Both formulations demonstrated comparable efficacy and safety profiles and provide patients with two different treatment formats to choose from for effective symptomatic relief of sore throat, depending on their preference. PMID:28740426

Efficacy of flurbiprofen 8.75 mg delivered as a spray or lozenge in patients with sore throat due to upper respiratory tract infection: a randomized, non-inferiority trial in the Russian Federation.

PubMed

Radkova, Eugenia; Burova, Natalia; Bychkova, Valeria; DeVito, Robert

2017-01-01

To assess the efficacy of flurbiprofen 8.75 mg delivered as a spray or lozenge in patients with sore throat due to upper respiratory tract infection (URTI). This multicenter, double-blind, double-dummy, non-inferiority study randomized 440 adults with recent-onset, moderate-to-severe sore throat due to URTI to a single dose of either flurbiprofen 8.75 mg spray (n=218) or flurbiprofen 8.75 mg lozenge (n=222). The presence or absence of beta-hemolytic streptococci (A or C) was confirmed by culture tests (throat swab). The primary efficacy end point was the difference from baseline to 2 hours post-dose in sore throat pain intensity scale (STPIS pain intensity difference [PID] 2h), a validated 100 mm visual analog scale (from 0="no pain" to 100="severe pain"), with a non-inferiority margin of -6 mm. Secondary end points included STPIS PID at 1 hour (STPIS PID 1h) and over 2 hours (STPIS sum of sore throat pain intensity differences [SPID] 0-2h ) and ratings of patient satisfaction and investigator assessment of drug efficacy at 2 hours. Safety (adverse events [AEs]) was also assessed. Reductions in sore throat pain intensity at 2 hours (STPIS PID 2h) were similar for spray (least square mean -40.51) and lozenge (-40.10) (difference: 0.41, 95% confidence interval [95% CI] -3.20, 4.01), with non-inferiority demonstrated. Subgroup analyses showed similar efficacy (STPIS PID 2h) for patients testing positive or negative for Strep A or C. There was no significant difference between spray and lozenge in STPIS PID 1h or STPIS SPID 0-2h , and patient satisfaction and investigators' assessment of efficacy at 2 hours were similar for both groups. There were no significant differences in AEs between the two groups, with 17 drug-related events across both groups, all being mild and none being serious. Both formulations demonstrated comparable efficacy and safety profiles and provide patients with two different treatment formats to choose from for effective symptomatic relief of sore throat, depending on their preference.

Flurbiprofen Ophthalmic

MedlinePlus

... call your doctor immediately: bleeding within the eye sensitivity to light eye pain blurry, cloudy, or blocked areas of vision If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting ...

Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol

PubMed Central

Ramos Yacasi, Gladys Rosario; García López, María Luisa; Espina García, Marta; Parra Coca, Alexander; Calpena Campmany, Ana Cristina

2016-01-01

This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen’s egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman’s criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials. PMID:27601897

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers

PubMed Central

Volak, Laurie P; Hanley, Michael J; Masse, Gina; Hazarika, Suwagmani; Harmatz, Jerold S; Badmaev, Vladimir; Majeed, Muhammed; Greenblatt, David J; Court, Michael H

2013-01-01

Aims Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. Methods A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Results Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma Cmax, AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05–0.08 μm and 0.6 μm, respectively). Conclusion The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. PMID:22725836

Nitric oxide-releasing flurbiprofen reduces formation of proinflammatory hydrogen sulfide in lipopolysaccharide-treated rat

PubMed Central

Anuar, Farhana; Whiteman, Matthew; Siau, Jia Ling; Kwong, Shing Erl; Bhatia, Madhav; Moore, Philip K

2006-01-01

The biosynthesis of both nitric oxide (NO) and hydrogen sulfide (H2S) is increased in lipopolysaccharide (LPS)-injected mice and rats but their interaction in these models is not known. In this study we examined the effect of the NO donor, nitroflurbiprofen (and the parent molecule flurbiprofen) on NO and H2S metabolism in tissues from LPS-pretreated rats. Administration of LPS (10 mg kg−1, i.p.; 6 h) resulted in an increase (P<0.05) in plasma TNF-α, IL-1β and nitrate/nitrite (NOx) concentrations, liver H2S synthesis (from added cysteine), CSE mRNA, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO) activity (marker for neutrophil infiltration) and nuclear factor-kappa B (NF-κB) activation. Nitroflurbiprofen (3–30 mg kg−1, i.p.) administration resulted in a dose-dependent inhibition of the LPS-mediated increase in plasma TNF-α, IL-1β and NOx concentration, liver H2S synthesis (55.00±0.95 nmole mg protein−1, c.f. 62.38±0.47 nmole mg protein−1, n=5, P<0.05), CSE mRNA, iNOS, MPO activity and NF-κB activation. Flurbiprofen (21 mg kg−1, i.p.) was without effect. These results show for the first time that nitroflurbiprofen downregulates the biosynthesis of proinflammatory H2S and suggest that such an effect may contribute to the augmented anti-inflammatory activity of this compound. These data also highlight the existence of ‘crosstalk' between NO and H2S in this model of endotoxic shock. PMID:16491094

A Novel Approach to Flurbiprofen Pulsatile Colonic Release: Formulation and Pharmacokinetics of Double-Compression-Coated Mini-Tablets.

PubMed

Vemula, Sateesh Kumar

2015-12-01

A significant plan is executed in the present study to study the effect of double-compression coating on flurbiprofen core mini-tablets to achieve the pulsatile colonic delivery to deliver the drug at a specific time as per the patho-physiological need of the disease that results in improved therapeutic efficacy. In this study, pulsatile double-compression-coated tablets were prepared based on time-controlled hydroxypropyl methylcellulose K100M inner compression coat and pH-sensitive Eudragit S100 outer compression coat. Then, the tablets were evaluated for both physical evaluation and drug-release studies, and to prove these results, in vivo pharmacokinetic studies in human volunteers were conducted. From the in vitro drug-release studies, F6 tablets were considered as the best formulation, which retarded the drug release in the stomach and small intestine (3.42 ± 0.12% in 5 h) and progressively released to the colon (99.78 ± 0.74% in 24 h). The release process followed zero-order release kinetics, and from the stability studies, similarity factor between dissolution data before and after storage was found to be 88.86. From the pharmacokinetic evaluation, core mini-tablets producing peak plasma concentration (C max) was 14,677.51 ± 12.16 ng/ml at 3 h T max and pulsatile colonic tablets showed C max = 12,374.67 ± 16.72 ng/ml at 12 h T max. The area under the curve for the mini and pulsatile tablets was 41,238.52 and 72,369.24 ng-h/ml, and the mean resident time was 3.43 and 10.61 h, respectively. In conclusion, development of double-compression-coated tablets is a promising way to achieve the pulsatile colonic release of flurbiprofen.

Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.

PubMed

Ramos Yacasi, Gladys Rosario; García López, María Luisa; Espina García, Marta; Parra Coca, Alexander; Calpena Campmany, Ana Cristina

This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen's egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman's criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials.

The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice.

PubMed Central

Sheldon, P. W.; Clarke, C.; Dawson, K. B.

1984-01-01

Using a quantitative cytochemical technique for measuring beta-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic. Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective. Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse. Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour. PMID:6696821

In vitro investigations of α-amylase mediated hydrolysis of cyclodextrins in the presence of ibuprofen, flurbiprofen, or benzo[a]pyrene.

PubMed

Lumholdt, Ludmilla Riisager; Holm, René; Jørgensen, Erling Bonne; Larsen, Kim Lambertsen

2012-11-15

In vitro studies of α-amylase degradation of α-, β- and γ-cyclodextrins and 2-hydroxypropyl-β- and -γ-cyclodextrins were investigated spectrophotometrically by measuring the formation of reducing sugars, the reaction products of α-amylase degradation. This was done to evaluate potential degradation and thereby biological conversion of the cyclodextrins if dosed orally, as the intestinal tract contains α-amylase for digestive purposes. The results demonstrated that only γ- and 2-hydroxypropyl-γ-cyclodextrins can be degraded by α-amylase to a relevant extent, that is, γ- and 2-hydroxypropyl-γ-cyclodextrins have different biopharmaceutical behaviours than the other evaluated cyclodextrins. The rate of degradation was affected by the addition of the inclusion complex forming additives flurbiprofen, ibuprofen and benzo[a]pyrene. This effect between the degradation dynamics and the included additives was caused by a correlation between solubility of the additives and the stability of the complex. Copyright © 2012 Elsevier Ltd. All rights reserved.

Determination of ibuprofen and flurbiprofen in pharmaceuticals by capillary zone electrophoresis.

PubMed

Hamoudová, Rafifa; Pospísilová, Marie

2006-06-16

Capillary zone electrophoresis with spectrophotometric detection was used for the determination of ibuprofen (IB) and flurbiprofen (FL) in pharmaceuticals. The separation was carried out in a fused silica capillary (60 cm x 100 microm i.d. effective length 45 cm) at 30 kV with UV detection at 232 nm. The optimized background electrolyte was 20mM N-(2-acetamido)-2-aminoethanesulfonic acid (ACES) with 20mM imidazole and 10mM alpha-cyclodextrin of pH 7.3. 2-Naphthoxyacetic acid was used as internal standard. A single analysis took less than 5 min. Rectilinear calibration ranges were 2-500 mg l(-1) for IB and 1-60 mg l(-1) for FL. The relative standard deviations (R.S.D.) values (n=6) were 1.53% for IB and 1.29% for FL (for 200 mg l(-1) IB and 10 mg l(-1) FL). This validated method has been successfully applied for the routine analysis of 10 commercially available pharmaceutical preparations (syrup, tablets, cream and gel).

New Form Discovery for the Analgesics Flurbiprofen and Sulindac Facilitated by Polymer-Induced Heteronucleation

PubMed Central

GRZESIAK, ADAM L.; MATZGER, ADAM J.

2008-01-01

The selection and discovery of new crystalline forms is a longstanding issue in solid-state chemistry of critical importance because of the effect molecular packing arrangement exerts on materials properties. Polymer-induced heteronucleation has recently been developed as a powerful approach to discover and control the production of crystal modifications based on the insoluble polymer heteronucleant added to the crystallization solution. The selective nucleation and discovery of new crystal forms of the well-studied pharmaceuticals flurbiprofen (FBP) and sulindac (SUL) has been achieved utilizing this approach. For the first time, FBP form III was produced in bulk quantities and its crystal structure was also determined. Furthermore, a novel 3:2 FBP:H2O phase was discovered that nucleates selectively from only a few polymers. Crystallization of SUL in the presence of insoluble polymers facilitated the growth of form I single crystals suitable for structure determination. Additionally, a new SUL polymorph (form IV) was discovered by this method. The crystal forms of FBP and SUL are characterized by Raman and FTIR spectroscopies, X-ray diffraction, and differential scanning calorimetry. PMID:17567888

A Molecular docking study to predict enantioseparation of some chiral carboxylic acid derivatives by methyl-β-cyclodextrin

NASA Astrophysics Data System (ADS)

Nurhidayah, E. S.; Ivansyah, A. L.; Martoprawiro, M. A.; Zulfikar, M. A.

2018-05-01

A molecular docking study, using molecular mechanics calculations with Arguslab, was used to help predict the enantioseparation of some guest molecules of chiral carboxylic acid derivatives by heptakis-2,6-di-O-methyl-β-cyclodextrin (DIMEB) and heptakis-2,3,6-tri-O-methyl-β-cyclodextrin (TRIMEB) as host molecules. The small differences in the binding free energy values (ΔΔG) obtained from Arguslab did not indicate any significant enantioseparation. From the molecular docking simulation results, it is predicted that in the case of DIMEB as host molecule, R-enantiomer of Etodolac, Fenoprofen, Indoprofen, Ketorolac, and Naproxen will be eluted first than S-enantiomer; However, S-enantiomer of Carprofen, Flurbiprofen, Ketoprofen, Pirprofen, Proglumide, Sulindac, Surprofen, and Zaltoprofen will be eluted first than R-enantiomer by DIMEB as host molecule. When TRIMEB is used as a host molecule, R-enantiomer of Carprofen, Flurbiprofen, Indoprofen, Ketoprofen, Naproxen, Pirprofen, and Surprofen will be eluted first than S-enantiomer; However, S-enantiomer of Etodolac, Fenoprofen, Ketorolac, Proglumide, Sulindac and Zaltoprofen will be eluted first than R-enantiomer by TRIMEB as host molecule.

Nanostructured lipid carriers-based flurbiprofen gel after topical administration: acute skin irritation, pharmacodynamics, and percutaneous absorption mechanism.

PubMed

Song, Aihua; Su, Zhen; Li, Sanming; Han, Fei

2015-01-01

In order to assess the preliminary safety and effectiveness of nanostructured lipid carriers-based flurbiprofen gel (FP NLC-gel), the acute irritation test, in vivo pharmacodynamics evaluation and pharmacokinetic study were investigated after topical application. No dropsy and erythema were observed after continuous dosing 7 d of FP NLC-gel on the rabbit skin, and the xylene-induced ear drossy could be inhibited by FP NLC-gel at different dosages. The maximum concentration of FP in rats muscle was 2.03 μg/g and 1.55 μg/g after oral and topical administration, respectively. While the peak concentration in untreated muscle after topical administration was only 0.37 μg/mL. And at any time, following topical administration the mean muscle-plasma concentration ratio Cmuscle/CPlasma was obviously higher than that following oral administration. Results indicated that FP could directly penetrate into the subcutaneous muscle tissue from the administration site. Thus, the developed FP NLC-gel could be a safe and effective vehicle for topical delivery of FP.

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers.

PubMed

Volak, Laurie P; Hanley, Michael J; Masse, Gina; Hazarika, Suwagmani; Harmatz, Jerold S; Badmaev, Vladimir; Majeed, Muhammed; Greenblatt, David J; Court, Michael H

2013-02-01

Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 μM and 0.6 μM, respectively). The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery.

PubMed

Gonzalez-Mira, E; Egea, M A; Souto, E B; Calpena, A C; García, M L

2011-01-28

The purpose of this study was to design and optimize a new topical delivery system for ocular administration of flurbiprofen (FB), based on lipid nanoparticles. These particles, called nanostructured lipid carriers (NLC), were composed of a fatty acid (stearic acid (SA)) as the solid lipid and a mixture of Miglyol(®) 812 and castor oil (CO) as the liquid lipids, prepared by the hot high pressure homogenization method. After selecting the critical variables influencing the physicochemical characteristics of the NLC (the liquid lipid (i.e. oil) concentration with respect to the total lipid (cOil/L (wt%)), the surfactant and the flurbiprofen concentration, on particle size, polydispersity index and encapsulation efficiency), a three-factor five-level central rotatable composite design was employed to plan and perform the experiments. Morphological examination, crystallinity and stability studies were also performed to accomplish the optimization study. The results showed that increasing cOil/L (wt%) was followed by an enhanced tendency to produce smaller particles, but the liquid to solid lipid proportion should not exceed 30 wt% due to destabilization problems. Therefore, a 70:30 ratio of SA to oil (miglyol + CO) was selected to develop an optimal NLC formulation. The smaller particles obtained when increasing surfactant concentration led to the selection of 3.2 wt% of Tween(®) 80 (non-ionic surfactant). The positive effect of the increase in FB concentration on the encapsulation efficiency (EE) and its total solubilization in the lipid matrix led to the selection of 0.25 wt% of FB in the formulation. The optimal NLC showed an appropriate average size for ophthalmic administration (228.3 nm) with a narrow size distribution (0.156), negatively charged surface (-33.3 mV) and high EE (∼90%). The in vitro experiments proved that sustained release FB was achieved using NLC as drug carriers. Optimal NLC formulation did not show toxicity on ocular tissues.

Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery

NASA Astrophysics Data System (ADS)

Gonzalez-Mira, E.; Egea, M. A.; Souto, E. B.; Calpena, A. C.; García, M. L.

2011-01-01

The purpose of this study was to design and optimize a new topical delivery system for ocular administration of flurbiprofen (FB), based on lipid nanoparticles. These particles, called nanostructured lipid carriers (NLC), were composed of a fatty acid (stearic acid (SA)) as the solid lipid and a mixture of Miglyol® 812 and castor oil (CO) as the liquid lipids, prepared by the hot high pressure homogenization method. After selecting the critical variables influencing the physicochemical characteristics of the NLC (the liquid lipid (i.e. oil) concentration with respect to the total lipid (cOil/L (wt%)), the surfactant and the flurbiprofen concentration, on particle size, polydispersity index and encapsulation efficiency), a three-factor five-level central rotatable composite design was employed to plan and perform the experiments. Morphological examination, crystallinity and stability studies were also performed to accomplish the optimization study. The results showed that increasing cOil/L (wt%) was followed by an enhanced tendency to produce smaller particles, but the liquid to solid lipid proportion should not exceed 30 wt% due to destabilization problems. Therefore, a 70:30 ratio of SA to oil (miglyol + CO) was selected to develop an optimal NLC formulation. The smaller particles obtained when increasing surfactant concentration led to the selection of 3.2 wt% of Tween® 80 (non-ionic surfactant). The positive effect of the increase in FB concentration on the encapsulation efficiency (EE) and its total solubilization in the lipid matrix led to the selection of 0.25 wt% of FB in the formulation. The optimal NLC showed an appropriate average size for ophthalmic administration (228.3 nm) with a narrow size distribution (0.156), negatively charged surface (-33.3 mV) and high EE (~90%). The in vitro experiments proved that sustained release FB was achieved using NLC as drug carriers. Optimal NLC formulation did not show toxicity on ocular tissues.

Target-controlled infusion of remifentanil with or without flurbiprofen axetil in sedation for extracorporeal shock wave lithotripsy of pancreatic stones: a prospective, open-label, randomized controlled trial.

PubMed

Yang, Yu-Guang; Hu, Liang-Hao; Chen, Hui; Li, Bo; Fan, Xiao-Hua; Li, Jin-Bao; Wang, Jia-Feng; Deng, Xiao-Ming

2015-11-07

Extracorporeal shock wave lithotripsy (ESWL) is an effective therapeutic method used to treat patients with pancreatic stones. However, the anesthesia for this procedure has been underappreciated, with minimal reports of these procedures in certain case series with general or epidural anesthesia. A cohort of 60 patients who elected to undergo ESWL in order to treat pancreatic stones for the first time were randomly selected and divided into two groups. One group of patients received target controlled infusion (TCI) of remifentanil, while the other group of patients received TCI of remifentanil plus a bolus of flurbiprofen axetil (a cyclooxygenase inhibitor) (Rem group and Rem + Flu group, n = 30 for each group). The Dixon's up-and-down method was used to calculate the half maximum effective concentration (EC50) of remifentanil. Visual analogue scales of pain, Ramsay sedation scale, hemodynamic changes, and adverse events were also recorded. The EC50 of remifentanil was calculated to be 4.0 ng/ml (95 % confidential interval: 3.84 ng/ml, 4.16 ng/ml) and 2.76 ng/ml (95 % confidential interval: 2.63 ng/ml, 2.89 ng/ml) in the Rem group and Rem + Flu group respectively (p < 0.001). Pain score was comparable between the two groups, while the Ramsay sedation scale was higher in the Rem group. Hemodynamic data showed that patients in the Rem group experienced higher mean arterial pressures and higher heart rates across the procedures. Patients in Rem group demonstrated a lower respiratory rate (p < 0.001) and a lower SpO2 (p = 0.001). Less adverse events occurred in Rem + Flu group, including a reduced respiratory depression requiring wake-up as well as reduced postoperative nausea and vomiting. Remifentanil plus flurbiprofen axetil provided satisfactory analgesia and sedation for ESWL of pancreatic stones with less adverse events. (Clinicaltrial.gov: NCT01998217 ; registered on November 19, 2013).

New Approaches for Prostate Cancer Combination Therapy

DTIC Science & Technology

2007-04-01

in DU145 cells. Strong inducers of apoptosis included Sulindac sulfide, Finasteride , Diclofenac, Flufenamic acid, Flurbiprofen, Sulindac sulfone and... Finasteride , a selective 5-alpha-reductase inhibitor, is not known to inhibit COX-2, strongly induces MDA-7/IL-24 expression and apoptosis, whereas the...ibuprofen, aspirin, acet- aminophen, and naproxen were obtained from Sigma-Aldrich (St. Louis, MO). Meloxicam, celecoxib, diclofenac, finasteride , and

[[Chiral separation of five arylpropionic acid drugs and determination of their enantiomers in pharmaceutical preparations by reversed-phase high performance liquid chromatography with cellulose-tris-(4-methylbenzoate) stationary phase

PubMed

Luo, An; Wan, Qiang; Fan, Huajun; Chen, Zhi; Wu, Xuehao; Huang, Xiaowen; Zang, Linquan

2014-09-01

Chromatographic behaviors for enantiomeric separation of arylpropionic acid drugs were systematically developed by reversed phase-high performance liquid chromatography (RP-HPLC) using cellulose-tris-(4-methylbenzoate) (CTMB) as chiral stationary phase (CSP). The effects of the composition of the mobile phase, additives and temperature on chiral separation of flurbiprofen, pranoprofen, naproxen, ibuprofen and loxoprofen were further investigated. The enantiomers had been successfully separated on CSP of CTMB by the mobile phase of methanol-0.1% (v/v) formic acid except naproxen by acetonitrile-0.1% (v/v) formic acid at 25 °C. The mechanisms of the racemic resolution for the above mentioned five drugs are discussed thermodynamically and structurally. The resolutions between respective enantiomers for arylpropionic acid drugs on CTMB had significant differences due to their chromatographic behaviors. The order of resolutions ranked pranoprofen, loxoprofen, flurbiprofen, ibuprofen and naproxen. The method established has been successfully applied to the determination of the enantiomers of the five drugs in commercial preparations under the optimized conditions. It proved that the method is simple, reliable and accurate.

Flurbiprofen : A non-selective cyclooxygenase (COX) inhibitor for treatment of non-infectious, non-necrotising anterior scleritis

PubMed Central

Agrawal, Rupesh; Lee, Cecilia; Gonzalez-Lopez, Julio J.; Khan, Sharmina; Rodrigues, Valeria; Pavesio, Carlos

2016-01-01

Objective To analyse the safety and efficacy of a non-selective cyclo-oxygenase (COX) inhibitor in the management of non-infectious, non-necrotising anterior scleritis. Methods Retrospective chart review of 126 patients with non-necrotising anterior scleritis treated with oral flurbiprofen (Froben®(Abbott Healthcare)) with ( group B, n=61) or without topical steroids (group A, n=65) was performed and time to remission was plotted. Results The observed incidence rate was 1.07 (95% CI: 0.57–1.99) per 1000 person-years with failure rate of 0.68 (95% CI: 0.22–2.12) per 1000 person-years in group A and 1.41 (95% CI: 0.67–2.96) per 1000 person-years in group B. The failure rate was 3.97(1.89–9.34) per 1000 person-years with hazard ratio of 10.01 ( 95% CI: 2.52–39.65; p<0.001) for patients with associated systemic disease. Conclusion To our best knowledge, this is the first and largest case series on the safety and efficacy of a non-selective COX inhibitor in the management of anterior scleritis. PMID:26308394

Effect of liquid-to-solid lipid ratio on characterizations of flurbiprofen-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for transdermal administration.

PubMed

Song, Aihua; Zhang, Xiaoshu; Li, Yanting; Mao, Xinjuan; Han, Fei

2016-08-01

The aim of this study is to evaluate the effect of liquid-to-solid lipid ratio on properties of flurbiprofen-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), and to clarify the superiority of NLCs over SLNs for transdermal administration. Particle size, zeta potential, drug encapsulation efficiency, in vitro occlusion factor, differential scanning calorimetry, X-ray diffractometry, in vitro percutaneous permeation profile, and stability of SLNs and NLCs were compared. Particle size, zeta potential, drug encapsulation efficiency, in vitro occlusion factor, and in vitro percutaneous permeation amount of the developed NLCs were all <200 nm, < -20 mV, >78%, >35, and >240 μg/cm(2), respectively, however, for SLNs were 280 nm, -29.11 mV, 63.2%, 32.54, and 225.9 μg/cm(2), respectively. After 3 months storage at 4 °C and 25 °C, almost no significant differences between the evaluated parameters of NLCs were observed. However, for SLNs, particle size was increased to higher than 300 nm (4 °C and 25 °C), drug encapsulation efficiency was decreased to 51.2 (25 °C), in vitro occlusion factor was also decreased to lower than 25 (4 °C and 25 °C), and the cumulative amount was decreased to 148.9 μg/cm(2) (25 °C) and 184.4 μg/cm(2) (4 °C), respectively. And DSC and XRD studies indicated that not only the crystalline peaks of the encapsulated flurbiprofen disappeared but also obvious difference between samples and bulk Compritol® ATO 888 was seen. It could be concluded that liquid-to-solid lipid ratio has significant impact on the properties of SLNs and NLCs, and NLCs showed better stability than SLNs. Therefore, NLCs might be a better option than SLNs for transdermal administration.

The laser desorption/laser ionization mass spectra of some anti-inflammatory drugs

NASA Astrophysics Data System (ADS)

Milnes, John; Rogers, Kevin; Jones, Sian; Gormally, John

1994-03-01

The IR laser desorption/ultraviolet laser ionization time-of-flight mass spectra are reported for the anti-inflammatory drugs indomethacin, acemetacin, ibuprofen, flurbiprofen, diflunisal and mefenamic acid. It is found that the six compounds can be readily ionized by two photon absorption at a fixed wavelength of 266 nm. Mass spectra have been obtained under conditions of high ionizing irradiance and the observed fragmentation behaviour is discussed.

Polymeric nanoparticles - Influence of the glass transition temperature on drug release.

PubMed

Lappe, Svenja; Mulac, Dennis; Langer, Klaus

2017-01-30

The physico-chemical characterisation of nanoparticles is often lacking the determination of the glass transition temperature, a well-known parameter for the pure polymer carrier. In the present study the influence of water on the glass transition temperature of poly (DL-lactic-co-glycolic acid) nanoparticles was assessed. In addition, flurbiprofen and mTHPP as model drugs were incorporated in poly (DL-lactic-co-glycolic acid), poly (DL-lactic acid), and poly (L-lactic acid) nanoparticles. For flurbiprofen-loaded nanoparticles a decrease in the glass transition temperature was observed while mTHPP exerted no influence on this parameter. Based on this observation, the release behaviour of the drug-loaded nanoparticles was investigated at different temperatures. For all preparations an initial burst release was measured that could be attributed to the drug adsorbed to the large nanoparticle surface. At temperatures above the glass transition temperature an instant drug release of the nanoparticles was observed, while at lower temperatures less drug was released. It could be shown that the glass transition temperature of drug loaded nanoparticles in suspension more than the corresponding temperature of the pure polymer is the pivotal parameter when characterising a nanostructured drug delivery system. Copyright © 2016 Elsevier B.V. All rights reserved.

Studies on self-nanoemulsifying drug delivery system of flurbiprofen employing long, medium and short chain triglycerides.

PubMed

Daar, Junaid; Khan, Ahmad; Khan, Jallat; Khan, Amjad; Khan, Gul Majid

2017-03-01

The aim of the study was to successfully design, formulate and evaluate self-nanoemulsifying drug delivery system (SNEDDS) of poorly aqueous soluble drug viz. flurbiprofen using long (LCT), medium (MCT) and short chain triglycerides (SCT). The SNEDDS are thermodynamically stable lipid based drug delivery systems which consist of mixture of oil, surfactant and co-surfactant. Upon aqueous dilution, this mixture produces nano-emulsion spontaneously on slight agitation. The excipients intended to be used were screened for their potential to dissolve the drug and to form clear dispersion upon aqueous dilution. Labrafil M 1944 CS, capryol-90 and triacetin were selected as long, medium and short chain triglycerides, respectively, as lipids while tween-80 and polyethylene glycol-400 (PEG-400)/ethanol (3:1 ratio) were selected as surfactant and co-surfactant, respectively. The excipients were studied at every possible combination ratios using pseudo-ternary diagram. The LCT, MCT and SCT-SNEDDS were optimized using thermodynamic studies, percentage transmittance value, viscosity, refractive index (RI), electrical conductivity, globule size analysis and in-vitro drug release studies. The drug release profiles of optimized SNEDDS were then compared with market product at different pH mediums. The LCT-SNEDDS was considered to be superior for enhancement of the drug bioavailability when compared with other SNEDDS formulations and market product.

Inhibition of amyloidogenesis by non-steroidal anti-inflammatory drugs and their hybrid nitrates

PubMed Central

Schiefer, Isaac T.; Abdul-Hay, Samer; Wang, Huali; Vanni, Michael; Qin, Zhihui; Thatcher, Gregory R. J.

2011-01-01

Poor blood-brain barrier penetration of non-steroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer’s disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogs were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogs were obtained with enhanced anti-inflammatory and anti-amyloidogenic properties compared to 1, however, esterification led to elevated Aβ1–42 levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate, CHF5074. Although hybrid nitrates elevated Aβ1–42 at higher concentration, SALA activity was observed at low concentrations (≤ 1 µM): both Aβ1–42 and the ratio of Aβ1–42/Aβ1–40 were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach towards a clinically useful SALA. PMID:21405086

The nature of hydrogen-bonding interactions in nonsteroidal anti-inflammatory drugs revealed by polarized IR spectroscopy

NASA Astrophysics Data System (ADS)

Hachuła, Barbara

2018-01-01

The influence of hydrogen-bonding interactions in the solid phase on the IR spectroscopic pattern of the νOsbnd H band of nonsteroidal anti-inflammatory drugs (NSAIDs) was studied experimentally by IR spectroscopy with the use of polarized light at two temperatures (293 K and 77 K) and in isotopic dilution. The neat and deuterated crystals of (S)-naproxen ((S)-NPX), (R)-flurbiprofen ((R)-FBP), (RS)-flurbiprofen ((RS)-FBP) and (RS)-ketoprofen ((RS)-KTP) were obtained by melt crystallization between the two squeezed CaF2 plates. The vibrational spectra of selected α-aryl propionic acid derivatives (2APAs) reflected the characteristics of their hydrogen-bond networks, i.e., 2APAs were characterized by the chain ((S)-NPX, (R)-FBP) and by dimeric ((RS)-FBP, (RS)-KTP) arrangement of hydrogen bonds in the crystal lattice. Spectroscopic results showed that the interchain (through-space) exciton coupling, between two laterally-spaced hydrogen bonds, dominates in the crystals of four NSAIDs. The same exciton coupled hydrogen bonds were also responsible for the H/D isotopic recognition mechanism in the crystalline spectra of deuterated 2APAs. The presented spectral results may help to predict the hydrogen bond motifs in the crystalline NSAIDs, which structures are not yet known, based on their IR spectra of hydrogen bond in the crystals.

Effects of Flurbiprofen Axetil on Postoperative Analgesia and Cytokines in Peripheral Blood of Thoracotomy Patients.

PubMed

Zhou, Mi; Li, Beiping; Kong, Ming

2015-06-01

The objective is to study the effects of flurbiprofen axetil (FA) with fentanyl together in postoperative controlled intravenous analgesia (PCIA) on pain intensity, cytokine levels in peripheral blood and adverse reactions of thoracotomy patients. Fifty thoracotomy patients were divided into a FA and a control group, each with 25 cases. Postoperative analgesia was administered in the two groups using PCIA. The pressing times of analgesia pump, the visual analog scale (VAS) scores during resting and coughing at 2, 6, 24, 48, 72 h after surgery and the incidence of adverse drug reactions were recorded. Levels of IL-1β, IL-6, IL-8, IL-2, and TNF-α in peripheral blood were determined before the administration of FA (T0), and at 24 h (T1), 48 h (T2), 72 h (T3) after surgery. The analgesia pump pressing times in the FA group was less than that of the control group. The VAS scores during resting and coughing at 2, 6, 24, 48, 72 h after surgery, were statistically less than those of control group. The incidence rate of nausea and vomiting was insignificantly different between the two groups. Administration of FA together with PCIA in thoracotomy patients can improve postoperative analgesia.

Combining nitric oxide release with anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.

PubMed

L'Episcopo, Francesca; Tirolo, Cataldo; Caniglia, Salvatore; Testa, Nunzio; Serra, Pier A; Impagnatiello, Francesco; Morale, Maria C; Marchetti, Bianca

2010-11-23

Current evidence suggests a role of neuroinflammation in the pathogenesis of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of basal ganglia injury. Reportedly, nonsteroidal anti-inflammatory drugs (NSAIDs) mitigate DAergic neurotoxicity in rodent models of PD. Consistent with these findings, epidemiological analysis indicated that certain NSAIDs may prevent or delay the progression of PD. However, a serious impediment of chronic NSAID therapy, particularly in the elderly, is gastric, renal and cardiac toxicity. Nitric oxide (NO)-donating NSAIDs, have a safer profile while maintaining anti-inflammatory activity of parent compounds. We have investigated the oral activity of the NO-donating derivative of flurbiprofen, [2-fluoro-α-methyl (1,1'-biphenyl)-4-acetic-4-(nitrooxy)butyl ester], HCT1026 (30 mg kg(-1) daily in rodent chow) in mice exposed to the parkinsonian neurotoxin MPTP. Ageing mice were fed with a control, flurbiprofen, or HCT1026 diet starting ten days before MPTP administration and continuing for all the experimental period. Striatal high affinity synaptosomal dopamine up-take, motor coordination assessed with the rotarod, tyrosine hydroxylase (TH)- and dopamine transporter (DAT) fiber staining, stereological cell counts, immunoblotting and gene expression analyses were used to assess MPTP-induced nigrostriatal DAergic toxicity and glial activation 1-40 days post-MPTP. HCT1026 was well tolerated and did not cause any measurable toxic effect, whereas flurbiprofen fed mice showed severe gastrointestinal side-effects. HCT1026 efficiently counteracted motor impairment and reversed MPTP-induced decreased synaptosomal [3H]dopamine uptake, TH- and DAT-stained fibers in striatum and TH+ neuron loss in substantia nigra pars compacta (SNpc), as opposed to age-matched mice fed with a control diet. These effects were associated to a significant decrease in reactive macrophage antigen-1 (Mac-1)-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase (PHOX), and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons. Oral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic (DAergic) neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD.

Single Intravenous Dose of Novel Flurbiprofen-Loaded Proniosome Formulations Provides Prolonged Systemic Exposure and Anti-inflammatory Effect.

PubMed

Verma, Preeti; Prajapati, Sunil K; Yadav, Rajbharan; Senyschyn, Danielle; Shea, Peter R; Trevaskis, Natalie L

2016-11-07

Vesicular and colloidal delivery systems can be designed to control drug release spatially and temporally to improve drug efficacy and side effect profiles. Niosomes (vesicles prepared from nonionic surfactants in aqueous media) are gaining interest as an alternative vesicular delivery system as they offer advantages such as biocompatibility, chemical stability, low cost, high purity, and versatility. However, the physical stability of niosomes, like other vesicular systems, is limited by vesicle fusion, aggregation, and leakage. Proniosomes (dehydrated powder or gel formulations that spontaneously form niosomes on hydration with aqueous media) can overcome these physical stability problems and are more convenient for sterilization, storage, transport, distribution, and dosing. Proniosomes have mostly been explored for their potential to enhance transdermal and oral absorption. In this study we assess, for the first time, the potential for hydrated proniosomes to sustain systemic exposure and therapeutic effect after intravenous delivery. Proniosomes carrying the anti-inflammatory drug, flurbiprofen, were prepared by spraying different nonionic surfactants (span 20, span 40, and span 60 in varying ratios with span 80) and cholesterol onto a sorbitol carrier. The proniosome powders were characterized for surface morphology and flow properties. Niosome formation was assessed at three different hydration temperatures (25, 37, and 45 °C), and the niosomes were assessed for vesicle size, entrapment efficiency, and sterility. OLP proniosomes prepared with a high ratio of span 80 to span 20 were found to spontaneously form vesicles of small size and high drug loading on hydration with aqueous media. The OLP derived niosomes successfully sustained in vitro drug release, in vivo pharmacokinetics, and the anti-inflammatory effect of flurbiprofen in an acute (rat paw edema) model of inflammation when compared to a control solution formulation. The study demonstrates that hydrated proniosomes can prolong systemic drug exposure over 3 days and provide a sustained therapeutic effect. The developed proniosomes represent a novel approach to treat acute pain and inflammation with the potential to be administered as a single intravenous dose by a clinician at the time of injury or surgery that provides adequate relief for several days and reduces fluctuations in therapy. Similar systems loaded with different drugs have potential for broader application in anesthesia, anti-infective, antiemetic, and cancer therapy.

New Approaches for Prostate Cancer Combination Therapy

DTIC Science & Technology

2008-04-01

5 times whereas Finasteride , Diclofenac and Sulindac Sulfone 5 can be reduced 2 times when compared with the solvent controls, and still resulting...Flufenamic acid and Sulindac Sulfide; 20, 10, 5 and 2nM Flurbiprofen; 50, 25,10 and 5 µM Finasteride ; 200, 100,50 and 25 µM NS-398 and Sulindac...Diclofenac, Sulindac Sulfide, Finasteride and NS398 and NF-B inhibitors 6-Amino-4-(4-phenoxyphenylethylamino) quinazoline and IKK- 2 inhibitor SC-514

In vitro cytogenetic evaluation of the particular combination of flurbiprofen and roxithromycin.

PubMed

Timocin, Taygun; Husunet, Mehmet Tahir; Valipour, Ebrahim; Norizadeh Tazehkand, Mostafa; Celik, Rima; Topaktas, Mehmet; Ila, Hasan B

2017-07-01

Flurbiprofen (FLB) (anti-inflammatory and analgesic drug) and roxithromycin (RXM) (antibiotic) were widely used in world wide. This study deals with investigation of genotoxicity, cytotoxicity, and oxidative stress effects of a particular combination of these drugs in human cultured lymphocytes. Also, DNA damaging-protective effects of combination of these drugs were analyzed on plasmid DNA. Human lymphocytes were treated with different concentrations (FLB + RXM; 10 μg/mL + 25 μg/mL, 15 μg/mL + 50 μg/mL, and 20 μg/mL + 100 μg/mL) of the drugs following by study of their genotoxic and cytotoxic effects by analysis of cytokinesis-block micronucleus test and nuclear division index, respectively. The effect of the combination in aspect of anti-oxidative and DNA damaging activity was evaluated on Pet-22b plasmid. According to our results, the combination of FLB and RXM did not show a notable genotoxic effect on cells. Although each of the substances had been shown as a cytotoxic agent by previous researchers, in this research, the combination of these drugs did not exhibit any adverse effect on cell division. FLB had DNA protection effect against H 2 O 2 while in combination with RXM had not the same effect on the plasmid.

Core-shell alginate-ghatti gum modified montmorillonite composite matrices for stomach-specific flurbiprofen delivery.

PubMed

Bera, Hriday; Ippagunta, Sohitha Reddy; Kumar, Sanoj; Vangala, Pavani

2017-07-01

Novel alginate-arabic gum (AG) gel membrane coated alginate-ghatti gum (GG) modified montmorillonite (MMT) composite matrices were developed for intragastric flurbiprofen (FLU) delivery by combining floating and mucoadhesion mechanisms. The clay-biopolymer composite matrices containing FLU as core were accomplished by ionic-gelation technique. Effects of polymer-blend (alginate:GG) ratios and crosslinker (CaCl 2 ) concentrations on drug entrapment efficiency (DEE, %) and cumulative drug release after 8h (Q 8h , %) were studied to optimize the core matrices by a 3 2 factorial design. The optimized matrices (F-O) demonstrated DEE of 91.69±1.43% and Q 8h of 74.96±1.56% with minimum errors in prediction. The alginate-AG gel membrane enveloped optimized matrices (F-O, coated) exhibited superior buoyancy, better ex vivo mucoadhesion and slower drug release rate. The drug release profile of FLU-loaded uncoated and coated optimized matrices was best fitted in Korsmeyer-Peppas model with anomalous diffusion and case-II transport driven mechanism, respectively. The uncoated and coated matrices containing FLU were also characterized for drug-excipients compatibility, drug crystallinity, thermal behaviour and surface morphology. Thus, the newly developed alginate-AG gel membrane coated alginate-GG modified MMT composite matrices are appropriate for intragastric delivery of FLU over an extended period of time with improved therapeutic benefits. Copyright © 2017 Elsevier B.V. All rights reserved.

First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms.

PubMed

Borgegard, Tomas; Juréus, Anders; Olsson, Fredrik; Rosqvist, Susanne; Sabirsh, Alan; Rotticci, Didier; Paulsen, Kim; Klintenberg, Rebecka; Yan, Hongmei; Waldman, Magnus; Stromberg, Kia; Nord, Johan; Johansson, Jonas; Regner, Anna; Parpal, Santiago; Malinowsky, David; Radesater, Ann-Cathrin; Li, Tingsheng; Singh, Rajeshwar; Eriksson, Hakan; Lundkvist, Johan

2012-04-06

γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-β (Aβ) peptides. The Aβ42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aβ production by targeting the APP. Here, we describe novel GSMs that are selective for Aβ modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aβ both in cell and cell-free systems as well as lower amyloidogenic Aβ42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aβ modulation and have a different mechanism of action compared with the original class of GSMs described.

The nature of hydrogen-bonding interactions in nonsteroidal anti-inflammatory drugs revealed by polarized IR spectroscopy.

PubMed

Hachuła, Barbara

2018-01-05

The influence of hydrogen-bonding interactions in the solid phase on the IR spectroscopic pattern of the ν OH band of nonsteroidal anti-inflammatory drugs (NSAIDs) was studied experimentally by IR spectroscopy with the use of polarized light at two temperatures (293K and 77K) and in isotopic dilution. The neat and deuterated crystals of (S)-naproxen ((S)-NPX), (R)-flurbiprofen ((R)-FBP), (RS)-flurbiprofen ((RS)-FBP) and (RS)-ketoprofen ((RS)-KTP) were obtained by melt crystallization between the two squeezed CaF 2 plates. The vibrational spectra of selected α-aryl propionic acid derivatives (2APAs) reflected the characteristics of their hydrogen-bond networks, i.e., 2APAs were characterized by the chain ((S)-NPX, (R)-FBP) and by dimeric ((RS)-FBP, (RS)-KTP) arrangement of hydrogen bonds in the crystal lattice. Spectroscopic results showed that the interchain (through-space) exciton coupling, between two laterally-spaced hydrogen bonds, dominates in the crystals of four NSAIDs. The same exciton coupled hydrogen bonds were also responsible for the H/D isotopic recognition mechanism in the crystalline spectra of deuterated 2APAs. The presented spectral results may help to predict the hydrogen bond motifs in the crystalline NSAIDs, which structures are not yet known, based on their IR spectra of hydrogen bond in the crystals. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer’s Disease

PubMed Central

Cacciatore, Ivana; Marinelli, Lisa; Fornasari, Erika; Cerasa, Laura S.; Eusepi, Piera; Türkez, Hasan; Pomilio, Cristina; Reale, Marcella; D’Angelo, Chiara; Costantini, Erica; Di Stefano, Antonio

2016-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL4–9) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)-α-lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and Aβ(25–35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1β and TNF-α in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD. PMID:27376271

Preparation and characterization of fast dissolving flurbiprofen and esomeprazole solid dispersion using spray drying technique.

PubMed

Pradhan, Roshan; Tran, Tuan Hiep; Kim, Sung Yub; Woo, Kyu Bong; Choi, Yong Joo; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

2016-04-11

We aimed to develop an immediate-release flurbiprofen (FLU) and esomeprazole (ESO) combination formulation with enhanced gastric aqueous solubility and dissolution rate. Aqueous solubility can be enhanced by formulating solid dispersions (SDs) with a polyvinylpyrrolidone (PVP)-K30 hydrophilic carrier, using spray-drying technique. Aqueous and gastric pH dissolution can be achieved by macro-environmental pH modulation using sodium bicarbonate (NaHCO3) and magnesium hydroxide (Mg(OH)2) as the alkaline buffer. FLU/ESO-loaded SDs (FLU/ESO-SDs) significantly improved aqueous solubility of both drugs, compared to each drug powder. Dissolution studies in gastric pH and water were compared with the microenvironmental pH modulated formulations. The optimized FLU/ESO-SD powder formulation consisted of FLU/ESO/PVP-K30/sodium carbonate (Na2CO3) in a weight ratio 1:0.22:1.5:0.3, filled in the inner capsule. The outer capsule consisted of NaHCO3 and Mg(OH)2, which created the macro-environmental pH modulation. Increased aqueous and gastric pH dissolution of FLU and ESO from the SD was attributed to the alkaline buffer effects and most importantly, to drug transformation from crystalline to amorphous SD powder, clearly revealed by scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction studies. Thus, the combined FLU and ESO SD powder can be effectively delivered as an immediate-release formulation using the macro-environmental pH modulation concept. Copyright © 2016. Published by Elsevier B.V.

Filamentous fungal biofilm for production of human drug metabolites.

PubMed

Amadio, Jessica; Casey, Eoin; Murphy, Cormac D

2013-07-01

In drug development, access to drug metabolites is essential for assessment of toxicity and pharmacokinetic studies. Metabolites are usually acquired via chemical synthesis, although biological production is potentially more efficient with fewer waste management issues. A significant problem with the biological approach is the effective half-life of the biocatalyst, which can be resolved by immobilisation. The fungus Cunninghamella elegans is well established as a model of mammalian metabolism, although it has not yet been used to produce metabolites on a large scale. Here, we describe immobilisation of C. elegans as a biofilm, which can transform drugs to important human metabolites. The biofilm was cultivated on hydrophilic microtiter plates and in shake flasks containing a steel spring in contact with the glass. Fluorescence and confocal scanning laser microscopy revealed that the biofilm was composed of a dense network of hyphae, and biochemical analysis demonstrated that the matrix was predominantly polysaccharide. The medium composition was crucial for both biofilm formation and biotransformation of flurbiprofen. In shake flasks, the biofilm transformed 86% of the flurbiprofen added to hydroxylated metabolites within 24 h, which was slightly more than planktonic cultures (76%). The biofilm had a longer effective lifetime than the planktonic cells, which underwent lysis after 2×72 h cycles, and diluting the Sabouraud dextrose broth enabled the thickness of the biofilm to be controlled while retaining transformation efficiency. Thus, C. elegans biofilm has the potential to be applied as a robust biocatalyst for the production of human drug metabolites required for drug development.

An insight into the molecular mechanism of the temporary enhancement effect of isopulegol decanoate on the skin.

PubMed

Liu, Xiaochang; Liu, Meiying; Liu, Chao; Quan, Peng; Zhao, Yongshan; Fang, Liang

2017-08-30

Chemical enhancers are widely used to facilitate drug permeation in transdermal drug delivery system (TDDS) and the effect of chemical enhancers is desired to be temporary. Though temporary enhancement effect of chemical enhancers has been widely discussed, there is still a lack of knowledge about the molecular mechanism of temporary enhancement effect. Using the skin permeation of flurbiprofen as a probe, the temporary enhancement effect of isopulegol decanoate (ISO-10) was evaluated with in vitro permeation experiment and confocal laser scanning microscopy (CLSM). In addition, molecular mechanism of skin recovery was explored with skin retention of ISO-10, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), molecular dynamic (MD) simulation and transepidermal water loss (TEWL). Temporary enhancement effect of ISO-10 was observed by the permeation of flurbiprofen after the treatment of 180min. Furthermore, temporary enhancement effect of ISO-10 on the diffusion of intercellular lipid in the stratum cornuem (SC) was observed by ATR-FTIR, molecular dynamic (MD) simulation. The SC barrier function recovered with the existence of ISO-10 in the lipid bilayer as indicated by the retention study and TEWL. In conclusion, the lipid bilayer accepted the enhancer as a new component to form a new stable arrangement, resulted the recovery of the skin barrier function. This work processed a novel mechanism of the recovery of skin barrier function after the addition of chemical enhancers. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of a Silicone Membrane as an Alternative to Human Skin for Determining Skin Permeation Parameters of Chemical Compounds.

PubMed

Uchida, Takashi; Yakumaru, Masafumi; Nishioka, Keisuke; Higashi, Yoshihiro; Sano, Tomohiko; Todo, Hiroaki; Sugibayashi, Kenji

2016-01-01

We evaluated the effectiveness of a silicone membrane as an alternative to human skin using the skin permeation parameters of chemical compounds. An in vitro permeation study using 15 model compounds was conducted, and permeation parameters comprising permeability coefficient (P), diffusion parameter (DL(-2)), and partition parameter (KL) were calculated from each permeation profile. Significant correlations were obtained in log P, log DL(-2), and log KL values between the silicone membrane and human skin. DL(-2) values of model compounds, except flurbiprofen, in the silicone membrane were independent of the lipophilicity of the model compounds and were 100-fold higher than those in human skin. For antipyrine and caffeine, which are hydrophilic, KL values in the silicone membrane were 100-fold lower than those in human skin, and P values, calculated as the product of a DL(-2) and KL, were similar. For lipophilic compounds, such as n-butyl paraben and flurbiprofen, KL values for silicone were similar to or 10-fold higher than those in human skin, and P values for silicone were 100-fold higher than those in human skin. Furthermore, for amphiphilic compounds with log Ko/w values from 0.5 to 3.5, KL values in the silicone membrane were 10-fold lower than those in human skin, and P values for silicone were 10-fold higher than those in human skin. The silicone membrane was useful as a human skin alternative in an in vitro skin permeation study. However, depending on the lipophilicity of the model compounds, some parameters may be over- or underestimated.

Automated system for on-line desorption of dried blood spots applied to LC/MS/MS pharmacokinetic study of flurbiprofen and its metabolite.

PubMed

Déglon, Julien; Thomas, Aurélien; Daali, Youssef; Lauer, Estelle; Samer, Caroline; Desmeules, Jules; Dayer, Pierre; Mangin, Patrice; Staub, Christian

2011-01-25

This paper illustrates the development of an automated system for the on-line bioanalysis of dried blood spots (on-line DBS). In this way, a prototype was designed for integration into a conventional LC/MS/MS, allowing the successive extraction of 30 DBS toward the analytical system without any sample pretreatment. The developed method was assessed for the DBS analysis of flurbiprofen (FLB) and its metabolite 4-hydroxyflurbiprofen (OH-FLB) in human whole blood (i.e. 5 μL). The automated procedure was fully validated based on international criteria and showed good precision, trueness, and linearity over the expected concentration range (from 10 to 1000 ng/mL and 100 to 10,000 ng/mL for OH-FLB and FLB respectively). Furthermore, the prototype showed good results in terms of recovery and carry-over. Stability of both analytes on filter paper was also investigated and the results suggested that DBS could be stored at ambient temperature for over 1 month. The on-line DBS automated system was then successfully applied to a pharmacokinetic study performed on healthy male volunteers after oral administration of a single 50-mg dose of FLB. Additionally, a comparison between finger capillary DBS and classic venous plasma concentrations was investigated. A good correlation was observed, demonstrating the complementarity of both sampling forms. The automated system described in this article represents an efficient tool for the LC/MS/MS analysis of DBS samples in many bioanalytical applications. Copyright © 2010 Elsevier B.V. All rights reserved.

Antinociceptive Effect of Racemic Flurbiprofen and Caffeine Co-Administration in an Arthritic Gout-Type Pain in Rats.

PubMed

Liévano-Reyes, Ricardo; Pérez-Méndez, Hermínia Ines; Solís-Oba, Aida; Jaramillo-Morales, Osmar Antonio; Espinosa-Juárez, Josué Vidal; López-Muñoz, Francisco Javier

2016-06-01

Preclinical Research Drug combinations are routinely used in the treatment of pain. In drug associations, adjuvants such as caffeine, are employed with different non-steroidal anti-inflammatories drugs (NSAIDs), however, at present does not exist studies showing the effect of the combination of racemic flurbiprofen (rac-Flur) in association with caffeine. The objective of this work was to evaluate the combination of rac-Flur + caffeine oral in arthritic gout-type pain in rats. The antinociceptive effects of the rac-Flur alone and in combination with caffeine were analyzed on a pain-induced functional impairment model in rat. rac-Flur induced a dose-dependent antinociceptive effect and caffeine did not present any effect. The combination of rac-Flur and caffeine achieve a higher percentage of antinociceptive effect compared with the individual administration of rac-Flur. The dose-response curve (DRCs) shows that the combination of rac-Flur (31.6 mg/kg) + caffeine (17.8 mg/kg) exhibited the maximal antinociceptive efficacy (294.0 ± 21.2 area units), while rac-Flur alone (31.6 mg/kg) showed 207.2 ± 35.2 au, thus indicating an increase in efficacy (potentiation). Furthermore, the DRCs of the combinations presented a displacement to the left, indicating a change in the potency. Caffeine is able to increase the effect of rac-Flur in the arthritic gout-type pain in rats. Drug Dev Res 77 : 192-198, 2016.   © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The Long-Term Safety of S-Flurbiprofen Plaster for Osteoarthritis Patients: An Open-Label, 52-Week Study.

PubMed

Yataba, Ikuko; Otsuka, Noboru; Matsushita, Isao; Matsumoto, Hideo; Hoshino, Yuichi

2016-08-01

The newly developed S-flurbiprofen plaster (SFPP) is a tape-type patch that shows innovative percutaneous absorption. This study was designed to evaluate the safety of a long-term 52-week SFPP application to osteoarthritis (OA) patients. This was a multi-center, open-label, uncontrolled prospective study that included 201 OA patients. SFPP at 40 mg/day was applied to the site of pain in 101 patients and at 80 mg/day (2 patches) in 100 patients at a total of 301 sites for 52 weeks. The affected sites assessed included the knee (192), lumbar spine (66), cervical spine (26), and others (17). Drug safety was evaluated by medical examination, laboratory tests, and examination of vital signs. Efficacy was evaluated by the patient's and clinician's global assessments and clinical symptoms. Most patients (80.1 %) completed the 52-week SFPP application. The majority of drug-related adverse events (AEs) included mild dermatitis at the application sites and occurred in 46.8 % of the sites. No photosensitive dermatitis was observed. Systemic AEs occurred in 9.0 % of the patients; a serious AE (gastric ulcer hemorrhage) occurred in one patient. No clinically significant changes in the laboratory tests and vital signs were observed. The efficacy evaluation showed an improvement from 2 weeks after the SFPP application, which continued during the 52 weeks' treatment. No apparent safety concerns were observed, even during the long-term SFPP application. Therefore, SFPP could be an additional pharmacotherapy in OA treatment.

Combined use of l-alanine tert butyl ester lactate and trimethyl-β-cyclodextrin for the enantiomeric separations of 2-arylpropionic acids nonsteroidal anti-inflammatory drugs.

PubMed

Mavroudi, Maria C; Kapnissi-Christodoulou, Constantina P

2015-10-01

In this study, a new CE method, employing a binary system of trimethyl-β-CD (TM-β-CD) and a chiral amino acid ester-based ionic liquid (AAIL), was developed for the chiral separation of seven 2-arylpropionic acid nonsteroidal anti-inflammatory drugs (NSAIDs). In particular, the enantioseparation of ibuprofen, ketoprofen, carprofen, indoprofen, flurbiprofen, naproxen, and fenoprofen was improved significantly by supporting the BGE with the chiral AAIL l-alanine tert butyl ester lactate (l-AlaC4 Lac). Parameters, such as concentrations of TM-β-CD and l-AlaC4 Lac, and buffer pH, were systematically examined in order to optimize the chiral separation of each NSAID. It was observed that the addition of the AAIL into the BGE improved both resolution and efficiency significantly. After optimization of separation conditions, baseline separation (Rs >1.5) of five of the analytes was achieved in less than 11 min, while the resolution of ibuprofen and flurbiprofen was approximately 1.2. The optimized enantioseparation conditions for all analytes involve a BGE of 5 mM sodium acetate/acetic acid (pH 5.0), an applied voltage of 30 kV, and a temperature of 20°C. In addition, the results obtained by computing the %-RSD values of the EOF and the two enantiomer peaks, demonstrated excellent run-to-run, batch-to-batch, and day-to-day reproducibilities. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Perioperative analgesia with a buprenorphine transdermal patch for hallux valgus surgery: a prospective, randomized, controlled study

PubMed Central

Xu, Can; Li, Mingqing; Wang, Chenggong; Li, Hui; Liu, Hua

2018-01-01

Purpose Hallux valgus surgery often results in significant postoperative pain. Adequate control of pain is essential for patient satisfaction and improves the outcome of the procedure. This study aimed to investigate the perioperative analgesic effect of a buprenorphine transdermal patch in patients who underwent hallux valgus surgery. Patients and methods A total of 90 patients were randomly divided into the following three groups based on the perioperative analgesic method: flurbiprofen axetil intravenous injection (Group F), oral celecoxib (Group C), and buprenorphine transdermal delivery system (BTDS) (Group BTDS). The pain status, degree of satisfaction, adverse effects, and administration of tramadol hydrochloride for uncontrolled pain were recorded on the night before surgery, postoperative day 1, postoperative day 2, and postoperative day 3. Results The BTDS could effectively control perioperative pain for patients undergoing hallux valgus surgery. The analgesic effect of the BTDS was better than that of oral celecoxib. In addition, statistically significant differences were not observed in the visual analog scale (VAS) scores, adverse effects, and rescue analgesia between the patients who received the BTDS and the patients who received the flurbiprofen axetil intravenous injection. However, the degree of patient satisfaction of the BTDS group was significantly higher (P<0.05) than that of the other two groups. Conclusion The BTDS (a preemptive analgesia regimen) could exert an analgesic effect during the perioperative period for patients who had received hallux valgus surgery, and this effect is beneficial for sustaining postoperative physiological and psychological states and promoting functional rehabilitation. PMID:29731664

Flurbiprofen axetil increases arterial oxygen partial pressure by decreasing intrapulmonary shunt in patients undergoing one-lung ventilation.

PubMed

Chai, Xiao-Qing; Ma, Jun; Xie, Yan-Hu; Wang, Di; Chen, Kun-Zhou

2015-12-01

In the present study, we investigated whether flurbiprofen axetil (FA) alleviates hypoxemia during one-lung ventilation (OLV) by reducing the pulmonary shunt/total perfusion (Q s/Q t) ratio, and examined the relationship between the Q s/Q t ratio and the thromboxane B2 (TXB2)/6-keto-prostaglandin F1α (6-K-PGF1α) ratio. Sixty patients undergoing esophageal resection for carcinoma were randomly assigned to groups F and C (n = 30 for each group). FA and placebo were administered i.v. 15 min before skin incision in groups F and C, respectively. The partial pressure of arterial oxygen (PaO2) was measured and the Q s/Q t ratio was calculated. Serum TXB2, 6-K-PGF1α, and endothelin (ET) were measured by radioimmunoassay. The relationship between TXB2/6-K-PGF1α and Q s/Q t was investigated. Compared with group C, PaO2 was higher and the Q s/Q t ratio was lower during OLV in group F (P < 0.05). After treatment with FA, both serum TXB2 and 6-K-PGF1α decreased significantly (P < 0.05) but the TXB2/6-K-PGF1α ratio increased significantly (P < 0.01). Increases in the TXB2/6-K-PGF1α ratio were correlated with reductions in the Q s/Q t ratio during OLV in group F (r = -0.766, P < 0.01). There was no significant difference in serum ET between groups F and C. Treatment with FA reduced the Q s/Q t ratio and further increased the PaO2 level during OLV, possibly due to upregulation of the vasoactive agent TXB2/6-K-PGF1α ratio.

Metal organic frameworks as a drug delivery system for flurbiprofen.

PubMed

Al Haydar, Muder; Abid, Hussein Rasool; Sunderland, Bruce; Wang, Shaobin

2017-01-01

Metal organic frameworks (MOFs) have attracted more attention in the last decade because of a suitable pore size, large surface area, and high pore volume. Developing biocompatible MOFs such as the MIL family as a drug delivery system is possible. Flurbiprofen (FBP), a nonsteroidal anti-inflammatory agent, is practically insoluble in aqueous solution, and, therefore, needs suitable drug delivery systems. Different biocompatible MOFs such as Ca-MOF and Fe-MILs (53, 100, and 101) were synthesized and employed for FBP delivery. A sample of 50 mg of each MOF was mixed and stirred for 24 h with 10 mL of 5 mg FBP in acetonitrile (40%) in a sealed container. The supernatant of the mixture after centrifuging was analyzed by high-performance liquid chromatography to determine the loaded quantity of FBP on the MOF. The overnight-dried solid material after centrifuging the mixture was analyzed for loading percent using X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy, nuclear magnetic resonance, and FBP release profile. The loading values of FBP were achieved at 10.0%±1%, 20%±0.8%, 37%±2.3%, and 46%±3.1% on Ca-MOF, Fe-MIL-53, Fe-MIL-101, and Fe-MIL-100, respectively. The FBP release profiles were investigated in a phosphate buffer solution at pH 7.4. The total release of the FBP after 2 days was obtained at 72.9, 75.2, 78.3, and 90.3% for Ca-MOF, Fe-MIL-100, Fe-MIL-53, and Fe-MIL-101, respectively. The MOFs are shown to be a promising drug delivery option for FBP with a significant loading percent and relatively prolonged drug release.

Preoperative But Not Postoperative Flurbiprofen Axetil Alleviates Remifentanil-induced Hyperalgesia After Laparoscopic Gynecological Surgery: A Prospective, Randomized, Double-blinded, Trial.

PubMed

Zhang, Linlin; Shu, Ruichen; Zhao, Qi; Li, Yize; Wang, Chunyan; Wang, Haiyun; Yu, Yonghao; Wang, Guolin

2017-05-01

Acute remifentanil exposure during intraoperative analgesia might enhance sensitivity to noxious stimuli and nociceptive responses to innocuous irritation. Cyclooxygenase inhibition was demonstrated to attenuate experimental remifentanil-induced hyperalgesia (RIH) in rodents and human volunteers. The study aimed to compare the effects of preoperative and postoperative flurbiprofen axetil (FA) on RIH after surgery. Ninety patients undergoing elective laparoscopic gynecologic surgery were randomly assigned to receive either intravenous placebo before anesthesia induction (Group C); or intravenous FA (1.0 mg/kg) before anesthesia induction (Group F1) or before skin closure (Group F2). Anesthesia consisted off sevoflurane and remifentanil (0.30 μg/kg/min). Postoperative pain was managed by sufentanil titration in the postanesthetic care unit, followed by sufentanil infusion via patient-controlled analgesia. Mechanical pain threshold (primary outcome), pain scores, sufentanil consumption, and side-effects were documented for 24 hours postoperatively. Postoperative pain score in Group F1 was lower than Group C. Time of first postoperative sufentanil titration was prolonged in Group F1 than Group C (P=0.021). Cumulative sufentanil consumption in Group F1 was lower than Group C (P<0.001), with a mean difference of 8.75 (95% confidence interval, 5.21-12.29) μg. Mechanical pain threshold on the dominant inner forearm was more elevated in Group F1 than Group C (P=0.005), with a mean difference of 17.7 (95% confidence interval, 5.4-30.0) g. Normalized hyperalgesia area was decreased in Group F1 compared to Group C (P=0.007). No statistically significant difference was observed between Group F2 and Group C. Preoperative FA reduces postoperative RIH in patients undergoing laparoscopic gynecologic surgery under sevoflurane-remifentanil anesthesia.

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation.

PubMed

Li, Shujuan; Wang, Xiaoyu; Wang, Yingying; Zhao, Qianqian; Zhang, Lina; Yang, Xinggang; Liu, Dandan; Pan, Weisan

2015-01-01

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na2CO3 at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12 h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.

Sustained release of intravitreal flurbiprofen from a novel drug-in-liposome-in-hydrogel formulation.

PubMed

Pachis, K; Blazaki, S; Tzatzarakis, M; Klepetsanis, P; Naoumidi, E; Tsilimbaris, M; Antimisiaris, S G

2017-11-15

A novel Flurbiprofen (FLB)-in-liposome-in-hydrogel formulation was developed, as a method to sustain the release and increase the ocular bioavailability of FLB following intravitreal injection. For this, FLB loading into liposomes was optimized and liposomes were entrapped in thermosensitive hydrogels consisted of Pluronic F-127 (P). FLB solution, liposomes, and FLB dissolved in hydrogel were also used as control formulations. Actively loaded liposomes were found to be optimal for high FLB loading and small size, while in vitro studies revealed that P concentration of 18% (w/v) was best to retain the integrity of the hydrogel-dispersed liposome, compared to a 20% concentration. The in vitro release of FLB was significantly sustained when FLB-liposomes were dispersed in the hydrogel compared to hydrogel dissolved FLB, as well as the other control formulations. In vivo studies were carried out in pigmented rabbits which were injected through a 27G needle with 1mg/mL FLB in the different formulation-types. Ophthalmic examinations after intravitreal injection of all FLB formulations, revealed no evidence of inflammation, hemorrhage, uveitis or endophthalmitis. Pharmacokinetic analysis results confirm that the hybrid drug delivery system increases the bioavailability (by 1.9 times compared to solution), and extends the presence of the drug in the vitreous cavity, while liposome and hydrogel formulations demonstrate intermediate performance. Furthermore the hybrid system increases MRT of FLB in aqueous humor and retina/choroid tissues, compared to all the control formulations. Currently the potential therapeutic advances of FLB sustained release formulations for IVT administration are being evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

Combined flurbiprofen and cyclosporin-A does not attenuate bone loss and exaggerates renal impairment.

PubMed

Sass, D A; Rucinski, B; Bryer, H P; Mann, G N; Yuan, Z; Ma, Y; Jee, W S; Epstein, S

1996-10-01

Cyclosporine (CsA) is a potent immunosuppressant that has revolutionized the success of organ transplantation. Flurbiprofen (FB), a propionic acid derivative NSAID, has been demonstrated in vivo to reduce osteoclast numbers in normal rats. The aim of this experiment was to determine whether addition of FB to CsA-treated rats could prevent the bone changes associated with CsA therapy. Forty-eight 10-12-week-old male Sprague-Dawley rats were randomized to receive, daily for 28 days: (1) CsA vehicle p.o. plus FB vehicle sc; (2) CsA (15 mg/kg) p.o. plus FB vehicle sc, (3) CsA vehicle p.o. plus FB (1.5 mg/kg) sc; and (4) CsA (15 mg/kg) p.o. plus FB (1.5 mg/kg) sc. Rats were weighed and venous blood sampled at baseline, 14 days, and 28 days for determination of glucose, Ca+2, BUN, creatinine, PTH, osteocalcin, and 1,25(OH)2 vitamin D. Tibiae were removed following killing, after double labeling for histomorphometry. Body mass was significantly lower than control in all rats receiving CsA on days 14 and 28 while blood glucose was only elevated in the CsA alone group. Day 28 BUN and creatinine were significantly elevated in the CsA group and the combination of CsA and FB revealed an exacerbation of this trend. Vitamin D and osteocalcin were consistently increased in the CsA and CsA/FB groups. Bone histomorphometry showed evidence of trabecular osteopenia in CsA and CsA/FB groups. CsA alone resulted in elevated bone turnover. FB was unable to prevent the trabecular bone loss induced by CsA therapy. This experiment indicates no role for FB as a therapeutic option in CsA-induced bone disease at the given doses and duration of treatment by virtue of its lack of bone sparing ability and adverse renal effects when the two drugs are administered concurrently.

Simultaneous determination of flurbiprofen and its hydroxy metabolite in human plasma by liquid chromatography-tandem mass spectrometry for clinical application.

PubMed

Lee, Hye-In; Choi, Chang-Ik; Byeon, Ji-Yeong; Lee, Jung-Eun; Park, So-Young; Kim, Young-Hoon; Kim, Se-Hyung; Lee, Yun-Jeong; Jang, Choon-Gon; Lee, Seok-Yong

2014-11-15

Flurbiprofen (FLB) is one of the phenylalkanoic acid derivatives of non-steroidal anti-inflammatory drugs used for the management of pain and inflammation in patients with arthritis. We developed and validated a rapid and sensitive high-performance liquid chromatography analytical method utilizing tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of FLB and its major metabolite, 4'-hydroxyflurbiprofen (4'-OH-FLB), in human plasma. Probenecid was used as an internal standard (IS). After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of the two analytes was achieved using a reversed-phase Luna C18 column (2.0mm×50mm, 5μm particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.5)-methanol (15:85, v/v) and quantified by MS/MS detection in ESI negative ion mode. The flow rate of the mobile phase was 250μl/min and the retention times of FLB, 4'-OH-FLB, and IS were 1.1, 0.8, and 0.9min, respectively. The calibration curves were linear over a range of 0.01-10μg/ml for FLB and 0.01-1μg/ml for 4'-OH-FLB. The lower limit of quantifications using 100μl of human plasma was 0.01μg/ml for both analytes. The mean accuracy and precision for intra- and inter-run validation of FLB and 4'-OH-FLB were all within acceptable limits. The present HPLC-MS/MS method showed improved sensitivity for quantification of the FLB and its major metabolite in human plasma compared with previously described analytical methods. The validated method was successfully applied to a pharmacokinetic study in humans. Copyright © 2014 Elsevier B.V. All rights reserved.

Freeze drying optimization of polymeric nanoparticles for ocular flurbiprofen delivery: effect of protectant agents and critical process parameters on long-term stability.

PubMed

Ramos Yacasi, Gladys Rosario; Calpena Campmany, Ana Cristina; Egea Gras, María Antonia; Espina García, Marta; García López, María Luisa

2017-04-01

The stabilization of flurbiprofen loaded poly-ɛ-caprolactone nanoparticles (FB-PɛCL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development. Optimization of the FD to improve long-term stability of ocular administration's FB-PɛCL-NPs. FB-PɛCL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components. Optimized FB-PɛCL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10 °C for 1 h, freezing at -50 °C for 4 h, PD at +5 °C and 0.140 mbar for 24 h and a SD at +45 °C during 10 h. These conditions showed 188.4 ± 1.3 nm, 0.087 ± 0.014, 85.5 ± 1.4%, 0.61 ± 0.12%, -16.4 ± 0.1 mV and 325 ± 7 mOsm/kg of average size, polydispersity index, entrapment efficiency, residual moisture, surface charge and osmolality, respectively. It performed a long-term stability >12 months. DSC and XRD spectra confirmed adequate chemical interaction between formulation components and showed a semi-crystalline state after FD. An optimal freeze dried ocular formulation was achieved. Evidently, the successful design of this promising colloidal system resulted from rational cooperation between a good formulation and the right conditions in the FD process.

Inhibition of inducible nitric oxide synthase expression by novel nonsteroidal anti-inflammatory derivatives with gastrointestinal-sparing properties.

PubMed Central

Cirino, G.; Wheeler-Jones, C. P.; Wallace, J. L.; Del Soldato, P.; Baydoun, A. R.

1996-01-01

1. The effects of novel nitric oxide-releasing nonsteroidal anti-inflammatory compounds (NO-NSAIDs) on induction of nitric oxide (NO) synthase by bacterial lipopolysaccharide (LPS) were examined in a murine cultured macrophage cell line, J774. 2. LPS-induced nitrite production was markedly attenuated by the nitroxybutylester derivatives of flurbiprofen (FNBE), aspirin, ketoprofen, naproxen, diclofenac and ketorolac, with each compound reducing accumulated nitrite levels by > 40% at the maximum concentrations (100 micrograms ml-1) used. 3. Further examination revealed that nitrite production was inhibited in a concentration-dependent (1-100 micrograms ml-1) manner by FNBE which at 100 micrograms ml-1 decreased LPS-stimulated levels by 63.3 +/- 8.6% (n = 7). The parent compound flurbiprofen was relatively ineffective over the same concentration-range, inhibiting nitrite accumulation by 24 +/- 0.9% (n = 3) at the maximum concentration used (100 micrograms ml-1). 4. FNBE reduced LPS-induced nitrite production when added to cells up to 4 h after LPS. Thereafter, FNBE caused very little or no reduction in nitrite levels. Furthermore NO-NSAIDs (100 micrograms ml-1) did not inhibit the metabolism of L-[3H]-arginine to citrulline by NO synthase isolated from LPS-activated macrophages. 5. Western blot analysis demonstrated that NO synthase expression was markedly attenuated following co-incubation of J774 cell with LPS (1 microgram ml-1; 24 h) and FNBE (100 micrograms ml-1; 24 h). Thus taken together, these findings indicate that NO-NSAIDs inhibit induction of NO synthase without directly affecting enzyme activity. 6. In conclusion our results indicate that NO-NSAIDs can inhibit the inducible L-arginine-NO pathway, and are capable of suppressing NO synthesis by inhibiting expression of NO synthase. The clinical implications of these findings remain to be established. Images Figure 4 PMID:8730734

Cyclodextrins as a chiral mobile phase additive in nano-liquid chromatography: comparison of reversed-phase silica monolithic and particulate capillary columns.

PubMed

Rocco, Anna; Maruška, Audrius; Fanali, Salvatore

2012-03-01

Enantioseparations of racemic nonsteroidal anti-inflammatory drugs (naproxen, ibuprofen, ketoprofen, flurbiprofen, suprofen, indoprofen, cicloprofen, and carprofen) were performed by nano-liquid chromatography, employing achiral capillary columns and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD) or hydroxylpropyl-β-cyclodextrin (HP-β-CD) as a chiral mobile phase additive (CMPA). Working under the same experimental conditions (in terms of mobile phase and linear velocity), the performance of a RP-C18 monolithic column was compared with that of a RP-C18 packed column of the same dimensions (100 μm i.d. × 10 cm). Utilizing a mobile phase composed of 30% ACN (v/v) buffered with 50 mM sodium acetate at pH 3, and containing 30 mM TM-β-CD, the monolithic column provided faster analysis but lower resolution than the packed column. This behavior was ascribed to the high permeability of the monolithic column, as well as to its minor selectivity. HP-β-CD was chosen as an alternative to TM-β-CD. Employing the monolithic column, the effects of different parameters such as HP-β-CD concentration, mobile phase composition, and pH on the retention factor and the chiral resolution of the analytes were studied. For the most of the analytes, enantioresolution (which ranged from R(s) = 1.80 for naproxen to R(s) = 0.86 for flurbiprofen) was obtained with a mobile phase consisting of sodium acetate buffer (25 mM, pH 3), 10% MeOH, and 15 mM HP-β-CD. When the same experimental conditions were used with the packed column, no compound eluted within 1 h. Upon increasing the percentage of organic modifier to favor analyte elution, only suprofen eluted within 30 min, with an R(s) value of 1.14 (20% MeOH). Replacing MeOH with ACN resulted in a loss of enantioresolution, except for naproxen (R(s) = 0.89).

Green hydrophilic interaction chromatography using ethanol-water-carbon dioxide mixtures.

PubMed

Pereira, Alberto dos Santos; Girón, Ana Jiménez; Admasu, Engdawork; Sandra, Pat

2010-03-01

In hydrophilic interaction chromatography (HILIC), best results are obtained with high concentrations of acetonitrile. In the framework of green chromatography, different concentrations of carbon dioxide were added to the mobile phases acetonitrile-water and ethanol-water and the impact on retention and separation in HILIC using bare silica as stationary phase was explored. The features of HILIC using enhanced-fluidity mobile phases are illustrated with the analysis of the nucleobases and a mixture containing the nucleobases and cortisol, flurbiprofen, theophylline and caffeine. For both organic constituents, the elution window is widened in function of the carbon dioxide concentration and selectivity changes. At high concentrations of carbon dioxide in ethanol, separations were similar to those obtained with acetonitrile without carbon dioxide addition.

Drug/protein interactions studied by time-resolved fluorescence spectroscopy

NASA Astrophysics Data System (ADS)

Gustavsson, Thomas; Markovitsi, Dimitra; Vayá, Ignacio; Bonancía, Paula; Jiménez, M. C.; Miranda, Miguel A.

2014-09-01

We report here on a recent time-resolved fluorescence study [1] of the interaction between flurbiprofen (FBP), a chiral non-steroidal anti-inflammatory drug, and human serum albumin (HSA), the main transport protein in the human body. We compare the results obtained for the drug-protein complex with those of various covalently linked flurbiprofentryptophan dyads having well-defined geometries. In all cases stereoselective dynamic fluorescence quenching is observed, varying greatly from one system to another. In addition, the fluorescence anisotropy decays also display a clear stereoselectivity. For the drug-protein complexes, this can be interpreted in terms of the protein microenvironment playing a significant role in the conformational relaxation of FBP, which is more restricted in the case of the (R)- enantiomer.

Condensed bridgehead nitrogen heterocyclic system: synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxy acetic acid.

PubMed

Amir, Mohd; Kumar, Harish; Javed, S A

2008-10-01

Several 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles (3a,b) with various substituted aromatic acids and aryl/alkyl isothiocyanates through a one-pot reaction. These compounds were investigated for their anti-inflammatory, analgesic, ulcerogenic, lipid peroxidation, antibacterial and antifungal activities. Some of the synthesized compounds showed potent anti-inflammatory activity along with minimal ulcerogenic effect and lipid peroxidation, compared to those of ibuprofen and flurbiprofen. Some of the tested compounds also showed moderate antimicrobial activity against tested bacterial and fungal strains.

Cross-reactions in patch testing and photopatch testing with ketoprofen, thiaprophenic acid, and cinnamic aldehyde.

PubMed

Pigatto, P; Bigardi, A; Legori, A; Valsecchi, R; Picardo, M

1996-12-01

In the last 7 years, we have studied 123 patients with allergic reactions to topical arylpropionic anti-inflammatory drugs. We have investigated the rate of sensitization and the irritant potential of one of them, ketoprofen, and its cross-reactivity with such other derivatives as ibuproxam, ibuprofen, naproxen, fenoprofen, flurbiprofen, and thiaprofenic acid. Sensitization was single in most cases, and ketoprofen was the drug most often involved. The combination most frequently found was ketoprofen plus ibuproxam. The most frequent cross-reactions were to fragrance mix, especially cinnamic aldehyde and balsam of Peru, both contact and photocontact sensitizers. Because there is a ketonic group in the molecule of ketoprofen and cinnamic aldehyde and after conversion of thiaprofenic acid, this could be the trigger for this particular allergy and cross-reactivity.

Design and ocular tolerance of flurbiprofen loaded ultrasound-engineered NLC.

PubMed

Gonzalez-Mira, E; Egea, M A; Garcia, M L; Souto, E B

2010-12-01

Packaging small drug molecules, such as non-steroidal anti-inflammatory drugs (NSAIDs) into nanoparticulate systems has been reported as a promising approach to improve the drug's bioavailability, biocompatibility and safety profiles. In the last 20 years, lipid nanoparticles (lipid dispersions) entered the nanoparticulate library as novel carrier systems due to their great potential as an alternative to other systems such as polymeric nanoparticles and liposomes for several administration routes. For ocular instillation nanoparticulate carriers are required to have a low mean particle size, with the lowest polydispersity as possible. The purpose of this work was to study the combined influence of 2-level, 4-factor variables on the formulation of flurbiprofen (FB), a lipophilic NSAID, in lipid carriers currently named as nanostructured lipid carriers (NLC). NLC were produced with stearic acid (SA) and castor oil (CO) stabilized by Tween® 80 (non-ionic surfactant) in aqueous dispersion. A 2(4) full factorial design based on 4 independent variables was used to plan the experiments, namely, the percentage of SA with regard to the total lipid, the FB concentration, the stabilizer concentration, and the storage conditions (i.e., storage temperature). The effects of these parameters on the mean particle size, polydispersity index (PI) and zeta potential (ZP) were investigated as dependent variables. The optimization process was achieved and the best formulation corresponded to the NLC formulation composed of 0.05 (wt%) FB, 1.6 (wt%) Tween® 80 and a 50:50 ratio of SA to CO, with an average diameter of 288 nm, PI 0.245 of and ZP of -29 mV. This factorial design study has proven to be a useful tool in optimizing FB-loaded NLC formulations. Stability of the optimized NLC was predicted using a TurbiScanLab® and the ocular tolerance was assessed in vitro and in vivo by the Eytex® and Draize test, respectively. The developed systems were shown physico-chemically stable with high tolerance for eye instillation. Copyright © 2010 Elsevier B.V. All rights reserved.

The effects of the topical administration of non-steroidal anti-inflammatory drugs on corneal epithelium and corneal sensitivity in normal subjects.

PubMed

Aragona, P; Tripodi, G; Spinella, R; Laganà, E; Ferreri, G

2000-04-01

To study the changes in the corneal epithelium and corneal sensitivity of healthy subjects after the topical administration of non-steroidal anti-inflammatory drugs (NSAIDs; diclofenac, indomethacin, flurbiprofen and ketorolac) frequently used in ocular therapy. A double-masked parallel clinical study was undertaken on 90 subjects (45 men, 45 women; Caucasian; age 21-46 years, mean +/- SD 27.1 +/- 5 years). The subjects were divided into six groups: group 1 was treated with placebo, group 2 with 0.1% diclofenac, group 3 with 0.1% indomethacin, group 4 with 0.03% flurbiprofen, group 5 with 0.5% ketorolac and group 6 with 0.4% oxybuprocaine. One eye was randomly treated with the study drug and the fellow eye was treated with placebo. The medications were instilled four times, at 5 min intervals. Assessment of the corneal epithelium was carried out by vital fluorescein stain before instillation and 5, 15, 30 and 60 min after instillation of the last drop. Subjective burning sensation was assessed by asking participants to rate burning on a scale from 0 (none) to 3 (severe). After 1 week, assessment of corneal sensitivity was carried out by the Cochet-Bonnet method, repeating the above scheme of instillation and measurement times. None of the study drugs, with the exception of oxybuprocaine, produced evident epithelial damage. All the drugs caused a mean burning sensation greater than the placebo. The diclofenac-treated group showed a statistically significant decrease in corneal sensitivity (p < 0.001) at the measurement carried out 15 min after instillation of the last drop and lasting up to the end of the study, when the corneal anaesthesia was similar to that induced by the topical anaesthetic treatment. No significant changes were demonstrated for the other NSAIDs when compared either with the placebo-treated eyes or with the fellow eyes. Despite a similar mechanism of action and analgesic activity to the other NSAIDs tested, diclofenac was able to induce a reduction in corneal sensitivity. More studies are needed to determine the mechanism of action responsible for this effect.

pH-metric solubility. 2: correlation between the acid-base titration and the saturation shake-flask solubility-pH methods.

PubMed

Avdeef, A; Berger, C M; Brownell, C

2000-01-01

The objective of this study was to compare the results of a normal saturation shake-flask method to a new potentiometric acid-base titration method for determining the intrinsic solubility and the solubility-pH profiles of ionizable molecules, and to report the solubility constants determined by the latter technique. The solubility-pH profiles of twelve generic drugs (atenolol, diclofenac.Na, famotidine, flurbiprofen, furosemide, hydrochlorothiazide, ibuprofen, ketoprofen, labetolol.HCl, naproxen, phenytoin, and propranolol.HCl), with solubilities spanning over six orders of magnitude, were determined both by the new pH-metric method and by a traditional approach (24 hr shaking of saturated solutions, followed by filtration, then HPLC assaying with UV detection). The 212 separate saturation shake-flask solubility measurements and those derived from 65 potentiometric titrations agreed well. The analysis produced the correlation equation: log(1/S)titration = -0.063(+/- 0.032) + 1.025(+/- 0.011) log(1/S)shake-flask, s = 0.20, r2 = 0.978. The potentiometrically-derived intrinsic solubilities of the drugs were: atenolol 13.5 mg/mL, diclofenac.Na 0.82 microg/mL, famotidine 1.1 mg/ mL, flurbiprofen 10.6 microg/mL, furosemide 5.9 microg/mL, hydrochlorothiazide 0.70 mg/mL, ibuprofen 49 microg/mL, ketoprofen 118 microg/mL, labetolol.HCl 128 microg/mL, naproxen 14 microg/mL, phenytoin 19 microg/mL, and propranolol.HCl 70 microg/mL. The new potentiometric method was shown to be reliable for determining the solubility-pH profiles of uncharged ionizable drug substances. Its speed compared to conventional equilibrium measurements, its sound theoretical basis, its ability to generate the full solubility-pH profile from a single titration, and its dynamic range (currently estimated to be seven orders of magnitude) make the new pH-metric method an attractive addition to traditional approaches used by preformulation and development scientists. It may be useful even to discovery scientists in critical decision situations (such as calibrating computational prediction methods).

Up-regulation of cyclooxygenase-2 by product-prostaglandin E2

NASA Technical Reports Server (NTRS)

Tjandrawinata, R. R.; Hughes-Fulford, M.

1997-01-01

The development of prostate cancer has been linked to high level of dietary fat intake. Our laboratory investigates the connection between cancer cell growth and fatty acid products. Studying human prostatic carcinoma PC-3 cells, we found that prostaglandin E2 (PGE2) increased cell growth and up-regulated the gene expression of its own synthesizing enzyme, cyclooxygenase-2 (COX-2). PGE2 increased COX-2 mRNA expression dose-dependently with the highest levels of stimulation seen at the 3-hour period following PGE2 addition. The NSAID flurbiprofen (5 microM), in the presence of exogenous PGE2, inhibited the up-regulation of COX-2 mRNA and cell growth. These data suggest that the levels of local intracellular PGE2 play a major role in the growth of prostate cancer cells through an activation of COX-2 gene expression.

Development and characterization of activated hydrochars from orange peels as potential adsorbents for emerging organic contaminants.

PubMed

Fernandez, M E; Ledesma, B; Román, S; Bonelli, P R; Cukierman, A L

2015-05-01

Activated hydrochars obtained from the hydrothermal carbonization of orange peels (Citrus sinensis) followed by various thermochemical processing were assessed as adsorbents for emerging contaminants in water. Thermal activation under flows of CO2 or air as well as chemical activation with phosphoric acid were applied to the hydrochars. Their characteristics were analyzed and related to their ability to uptake three pharmaceuticals (diclofenac sodium, salicylic acid and flurbiprofen) considered as emerging contaminants. The hydrothermal carbonization and subsequent activations promoted substantial chemical transformations which affected the surface properties of the activated hydrochars; they exhibited specific surface areas ranging from 300 to ∼620 m(2)/g. Morphological characterization showed the development of coral-like microspheres dominating the surface of most hydrochars. Their ability to adsorb the three pharmaceuticals selected was found largely dependent on whether the molecules were ionized or in their neutral form and on the porosity developed by the new adsorbents. Copyright © 2015 Elsevier Ltd. All rights reserved.

Separation-oriented derivatization of native fluorescent compounds through fluorous labeling followed by liquid chromatography with fluorous-phase.

PubMed

Sakaguchi, Yohei; Yoshida, Hideyuki; Todoroki, Kenichiro; Nohta, Hitoshi; Yamaguchi, Masatoshi

2009-06-15

We have developed a new and simple method based on "fluorous derivatization" for LC of native fluorescent compounds. This method involves the use of a column with a fluorous stationary phase. Native fluorescent analytes with target functional groups are precolumn derivatized with a nonfluorescent fluorous tag, and the fluorous-labeled analytes are retained in the column, whereas underivatized substances are not. Only the retained fluorescent analytes are detected fluorometrically at appropriate retention times, and retained substrates without fluorophores are not detected. In this study, biologically important carboxylic acids (homovanillic acid, vanillylmandelic acid, and 5-hydroxyindoleacetic acid) and drugs (naproxen, felbinac, flurbiprofen, and etodolac) were used as model native fluorescent compounds. Experimental results indicate that the fluorous-phase column can selectively retain fluorous compounds including fluorous-labeled analytes on the basis of fluorous separation. We believe that separation-oriented derivatization presented here is the first step toward the introduction of fluorous derivatization in quantitative LC analysis.

Calculation of Cyclodextrin Binding Affinities: Energy, Entropy, and Implications for Drug Design

PubMed Central

Chen, Wei; Chang, Chia-En; Gilson, Michael K.

2004-01-01

The second generation Mining Minima method yields binding affinities accurate to within 0.8 kcal/mol for the associations of α-, β-, and γ-cyclodextrin with benzene, resorcinol, flurbiprofen, naproxen, and nabumetone. These calculations require hours to a day on a commodity computer. The calculations also indicate that the changes in configurational entropy upon binding oppose association by as much as 24 kcal/mol and result primarily from a narrowing of energy wells in the bound versus the free state, rather than from a drop in the number of distinct low-energy conformations on binding. Also, the configurational entropy is found to vary substantially among the bound conformations of a given cyclodextrin-guest complex. This result suggests that the configurational entropy must be accounted for to reliably rank docked conformations in both host-guest and ligand-protein complexes. In close analogy with the common experimental observation of entropy-enthalpy compensation, the computed entropy changes show a near-linear relationship with the changes in mean potential plus solvation energy. PMID:15339804

Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs.

PubMed

Sanz-Blasco, Sara; Valero, Ruth A; Rodríguez-Crespo, Ignacio; Villalobos, Carlos; Núñez, Lucía

2008-07-23

Dysregulation of intracellular Ca(2+) homeostasis may underlie amyloid beta peptide (Abeta) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Abeta(1-42) oligomers, the assembly state correlating best with cognitive decline in AD, but not Abeta fibrils, induce a massive entry of Ca(2+) in neurons and promote mitochondrial Ca(2+) overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Abeta oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca(2+) overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca(2+) overload, cytochrome c release and cell death induced by Abeta oligomers. Our results indicate that i) mitochondrial Ca(2+) overload underlies the neurotoxicity induced by Abeta oligomers and ii) inhibition of mitochondrial Ca(2+) overload provides a novel mechanism of neuroprotection by NSAIDs against Abeta oligomers and AD.

Engineering substrate promiscuity in halophilic alcohol dehydrogenase (HvADH2) by in silico design.

PubMed

Cassidy, Jennifer; Bruen, Larah; Rosini, Elena; Molla, Gianluca; Pollegioni, Loredano; Paradisi, Francesca

2017-01-01

An alcohol dehydrogenase from the halophilic archaeon Haloferax volcanii (HvADH2) has been engineered by rational design to broaden its substrate scope towards the conversion of a range of aromatic substrates, including flurbiprofenol, that is an intermediate of the non-steroidal anti-inflammatory drug, flurbiprofen. Wild-type HvADH2 showed minimal activity with flurbiprofenol (11.1 mU/mg). A homology model of HvADH2 was built and docking experiments with this substrate revealed that the biphenyl rings of flurbiprofenol formed strong interactions with residues F85 and F108, preventing its optimal binding in the active site. Mutations at position 85 however did not increase activity. Site directed mutagenesis at position F108 allowed the identification of three variants showing a significant (up to 2.3-fold) enhancement of activity towards flurbiprofenol, when compared to wild-type HvADH2. Interestingly, F108G variant did not show the classic inhibition in the presence of (R)-enantiomer when tested with rac-1-phenylethanol, underling its potential in racemic resolution of secondary alcohols.

Effect of polymer viscosity on physicochemical properties and ocular tolerance of FB-loaded PLGA nanospheres.

PubMed

Araújo, J; Vega, E; Lopes, C; Egea, M A; Garcia, M L; Souto, E B

2009-08-01

Poly(lactide-co-glycolide) acid (PLGA) nanospheres incorporating flurbiprofen (FB) were produced by the solvent displacement technique, for ocular applications aiming to avoid/minimize inflammation induced by surgical trauma. In this work, a PLGA of low viscosity has been tested and the results obtained were compared with those previously reported by Vega et al. The physicochemical properties of the developed formulations were evaluated by measuring particle size, zeta potential and FB entrapment efficiency, showing no significant differences. Release studies demonstrated that the formulation produced with PLGA of higher viscosity revealed a slower drug release rate. Stability analysis, for a period of 75 days, was performed using three complementary methods: (i) turbidity experiments using a Turbiscan optical analyzer, (ii) particle size measurements, and (iii) zeta potential analysis. The results revealed long-term physicochemical stability suitability for ophthalmic use, being independent from the polymer viscosity. The ocular tolerance was assessed by an alternative in vitro method to animal experimentation, the HET-CAM. For all developed formulations no ocular irritancy has been detected.

Cubosomes as targeted drug delivery systems - a biopharmaceutical approach.

PubMed

Lakshmi, Naga M; Yalavarthi, Prasanna R; Vadlamudi, Harini C; Thanniru, Jyotsna; Yaga, Gowri; K, Haritha

2014-01-01

Cubosomes are reversed bicontinuous cubic phases and possess unique physicochemical properties. These special systems are receiving much attention for the delivery of various hydrophilic, hydrophobic and amphiphilic drugs with enhanced bioavailability and high loading capacity. A wide variety of drugs are applicable for cubosome formulation for various routes of delivery. The lipids used in cubosome formulation are more stable and offer stability to the formulation during shelf-life. The article reviews about the back ground, techniques of cubosome preparation such as high pressure homogenization, probe ultrasonication and automated cubosome preparation; and also methods of cubosomes preparation such as top down, bottom up and other methods with pictorial presentation. This article emphasizes the phase transition and also targeted approaches of cubosomes. The characterization studies for cubosomes such as cryo transmission electron microscopy, differential scanning calorimetry and scanning electron microscopy followed by in-vitro and in-vivo evaluation studies of cubosomes were explained with appropriate examples. Recent applications of cubosomes were explained with reference to flurbiprofen, odorranalectin, diazepam and dexamethasone. The advantages, disadvantages and limitations of cubosomal technology were emphasized.

Peripheral analgesic sites of action of anti-inflammatory drugs.

PubMed

Ferreira, S H

2002-07-01

Inflammatory signs and symptoms of redness, swelling, heat and pain are due to the effects of inflammatory mediators released during the inflammatory response. Depending on the type of injurious stimuli and the tissue involved, the array of mediators may differ but eicosanoids are involved in the genesis of inflammatory pain. They are responsible for the hypersensitisation of the nociceptors (allodynialhyperalgesia). The basic mechanism of analgesic action of nonsteroidal anti-inflammatory drugs results from the inhibition of prostaglandin synthesis (prostacyclin or PGE2), thus preventing nociceptor threshold lowering. Because there is a temporal hierarchy in the release of inflammatory mediators, there are several targets for the action of peripheral acting analgesics before and after the inhibition of prostaglandin synthesis. Blockade of the release and inhibition of inducible cyclooxygenase explain the analgesic action of glucocorticoids. Nimesulide also has an inhibitory action on the cascade of hypersensitising cytokines. Some analgesics, such as dipyrone, flurbiprofen or diclofenac, act directly upon ongoing inflammatory hypersensitisation. Those analgesics restore the nociceptor by stimulating the arginine/NO/cGMP/K(ATP) channel pathway.

[Perioperative thyroid storm in a patient with undiscovered hyperthyroidism].

PubMed

Nakamura, Shinji; Nishmyama, Tomoki; Hanaoka, Kazuo

2005-04-01

Thyroid storm can develop in patients with longstanding untreated hyperthyroidism. It is more often precipitated by an acute event such as surgery, trauma, or infection. We experienced a case in whom thyroid storm occurred during surgery, while he had no preoperative diagnosis of thyroid disease. A 30-year-old man was scheduled for left tympanoplasty. Anesthesia was induced and maintained with sevoflurane and nitrous oxide in oxygen. Heart rate and rectal temperature went up to 140 beats x min(-1) and 39 degrees C, respectively, in 3 hours during surgery. Cooling blanket, cold fluid infusion, flurbiprofen, diltiazem, and verapamil were used to decrease body temperature and heart rate. Surgery was completed and after emergence he was in agitation for 4 hours along with hyperpyrexia and tachycardia. He was diagnosed as hyperthyroidism by postoperative physical and laboratory examination. Thiamazole and propranorol were administered. In one week, symptom has declined with body temperature and heart rate of around 36 degrees C and 90 beats x min(-1), respectively. We should be more careful about evaluation of preoperative patients.

Exploring the Electrical Conductivity of Cytochrome P450 by Nano-Electrode and Conductive Atomic Force Microscopy

NASA Astrophysics Data System (ADS)

Li, Debin; Gu, Jianhua; Chye, Yewhee; Lederman, David; Kabulski, Jarod; Gannett, Peter; Tracy, Timothy

2006-03-01

There is a growing interest in measuring the conductivity of electron-transfer proteins. The cytochrome P450 (CP450) enzymes represent an important class of heme-containing enzymes. Immobilizing CP450 enzymes on a surface can be used for studying a single enzyme with respect to electron transfer. The spin state of the heme iron can change upon binding of a substrate. In our experiment, CP450 (diameter ˜ 5 nm) has been bonded to a metal surface. Nano-electrodes (gap < 10 nm) were fabricated by defining a bridge via e-beam lithography and then breaking the junction by electromigration at low temperatures. We have examined the electronic properties of CP450 by itself and after binding CP450 with flurbiprofen. The room temperature I-V conductivity is reminiscent to cyclic voltammetry measurements, indicating the presence of strong ionic transfer. At lower temperatures (100 K) the I-V characteristics indicate electronic transport dominated by tunneling processes. The conductive AFM is an additional method used to examine the enzyme's electronic properties. The results from two methods will be discussed..

Development and in vitro evaluation of potential electromodulated transdermal drug delivery systems based on carbon nanotube buckypapers.

PubMed

Schwengber, Alex; Prado, Héctor J; Bonelli, Pablo R; Cukierman, Ana L

2017-07-01

Buckypapers based on different types of carbon nanotubes with and without the addition of four model drugs, two of basic nature (clonidine hydrochloride, selegiline hydrochloride) and the others of acidic character (flurbiprofen, ketorolac tromethamine) were prepared and characterized. The influence of the conditions employed in the preparation of the buckypapers (dispersion time and solvents used in the preparation, as well as the type of carbon nanotubes used and the characteristics of the drug involved) on their conductivity was especially examined. The in vitro performance of the drug loaded buckypapers as passive and active transdermal drug release systems, the latter being modulated by means of the application of electric voltages, was studied. Passive drug loaded buckypapers presented characteristic release profiles, also depending on the drug used, which indicate differences in the drug-carbon nanotubes non-covalent interactions. Application of electrical biases of appropriate polarities enabled the modulation of the drug release profiles in any desired direction. Different mathematical models were fitted to passive and electromodulated experimental release data for the four model drugs. Among these models, the most appropriate for data description was a two-compartment pseudo-second-order one. Copyright © 2017 Elsevier B.V. All rights reserved.

Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots.

PubMed

Bosilkovska, M; Samer, C F; Déglon, J; Rebsamen, M; Staub, C; Dayer, P; Walder, B; Desmeules, J A; Daali, Y

2014-09-01

The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography-tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session.

Geneva Cocktail for Cytochrome P450 and P-Glycoprotein Activity Assessment Using Dried Blood Spots

PubMed Central

Bosilkovska, M; Samer, C F; Déglon, J; Rebsamen, M; Staub, C; Dayer, P; Walder, B; Desmeules, J A; Daali, Y

2014-01-01

The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P-gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7-day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography–tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P-gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one- and three-point (at 2, 3, and 6 h) DBS-sampling methods were found to reliably reflect CYP and P-gp activities at each session. PMID:24722393

Prediction of selectivity for enantiomeric separations of uncharged compounds by capillary electrophoresis involving dual cyclodextrin systems.

PubMed

Abushoffa, Adel M; Fillet, Marianne; Hubert, Phillipe; Crommen, Jacques

2002-03-01

The single-isomer polyanionic cyclodextrin (CD) derivative heptakis-6-sulfato-beta-cyclodextrin (HSbetaCD) has been tested as chiral additive for the enantioseparation of non-steroidal anti-inflammatory drugs, such as fenoprofen, flurbiprofen, ibuprofen and ketoprofen, in capillary electrophoresis, using a pH 2.5 phosphoric acid-triethanolamine buffer in the reversed polarity mode. In most cases, the enantiomers of these acidic compounds, present in uncharged form at that pH, were only poorly resolved with HSbetaCD alone. However, the use of HSbetaCD in combination with the neutral CD derivative, heptakis-(2,3,6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD), which has a particularly high enantioselectivity towards these compounds, has led to complete enantioresolution in reasonably low migration times in most cases. Affinity constants for the enantiomers with the two cyclodextrins were determined, using linear regression in a two-step approach. Affinity constants with the charged HSbetaCD were first calculated in single systems while those with the neutral TMbetaCD were determined in dual systems. Selectivity for the enantiomeric separation of these compounds in dual CD systems could be predicted using recently developed mathematical models.

[Drug-induced oral ulcerations].

PubMed

Madinier, I; Berry, N; Chichmanian, R M

2000-06-01

Different side effects of drugs have been described in the oral cavity, including oral ulcerations. Direct contact between drugs and oral mucosa may induce chemical burn or local hypersensitivity. Less frequently, these drug-induced oral ulcerations are part of a complex reaction with cutaneous or systemic manifestations. Sometimes, one or more oral ulcerations appear as the main side-effect of a drug, or exceptionally as solitary lesions. Solitary oral ulcerations usually appear after few weeks of treatment. In most of cases, these lesions resist to conventional treatments, with a rapid healing following the suppression of the responsible drug. This diagnosis is usually difficult, particularly with patients receiving multiple drug therapy. Besides, special attention must be paid to new drugs. Oral ulcerations following symptoms of burning mouth, metallic taste, dysgueusia or agueusia are strongly suggestive of a pharmacological origin. Most of the molecules able to induce solitary oral ulcerations are commonly prescribed in a) rheumatology: NSAI (diclofenac, flurbiprofen, indomethacin, naproxen), long-term rheumatoid arthritis therapy (azathioprine, methotrexate, penicillamine, gold compounds, tiopronin); b) cardiology: angiotensin-converting-enzyme inhibitors (captopril, enalapril), angiotensin 2-receptor antagonist (losartan), anti-angorous (nicorandil), c) psychiatry: antidepressants (fluoxetine, lithium), d) AIDS therapy (foscarnet, zalcitabine).

Computational fluid dynamics study of viscous fingering in supercritical fluid chromatography.

PubMed

Subraveti, Sai Gokul; Nikrityuk, Petr; Rajendran, Arvind

2018-01-26

Axi-symmetric numerical simulations are carried out to study the dynamics of a plug introduced through a mixed-stream injection in supercritical fluid chromatographic columns. The computational fluid dynamics model developed in this work takes into account both the hydrodynamics and adsorption equilibria to describe the phenomena of viscous fingering and plug effect that contribute to peak distortions in mixed-stream injections. The model was implemented into commercial computational fluid dynamics software using user-defined functions. The simulations describe the propagation of both the solute and modifier highlighting the interplay between the hydrodynamics and plug effect. The simulated peaks showed good agreement with experimental data published in the literature involving different injection volumes (5 μL, 50 μL, 1 mL and 2 mL) of flurbiprofen on Chiralpak AD-H column using a mobile phase of CO 2 and methanol. The study demonstrates that while viscous fingering is the main source of peak distortions for large-volume injections (1 mL and 2 mL) it has negligible impact on small-volume injections (5 μL and 50 μL). Band broadening in small-volume injections arise mainly due to the plug effect. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Novel surface-modified nanostructured lipid carriers with partially deacetylated water-soluble chitosan for efficient ocular delivery.

PubMed

Tian, Baocheng; Luo, Qiuhua; Song, Shuangshuang; Liu, Dandan; Pan, Hao; Zhang, Wenji; He, Ling; Ma, Shilin; Yang, Xinggang; Pan, Weisan

2012-03-01

The objective of this study was to propose novel surface-modified nanostructured lipid carriers with partially deacetylated water-soluble chitosan (NLC-PDSC) as an efficient ocular delivery system to improve its transcorneal penetration and precorneal retention. PDSC with a deacetylation degree of around 50% was synthesized using an improved method. NLC loaded with flurbiprofen (FB) were prepared by melt emulsification method. They presented spherical morphology under both transmission electron microscope and scanning electron microscope. After coating with 0.15% (w/v) PDSC solution, the NLC showed a core-shell structure and a reversed zeta potential. The enhanced transcorneal penetration of the coated NLC was evaluated using isolated rabbit corneas, with significantly increased apparent permeability coefficient being 1.40- and 1.75-fold of the NLC and FB phosphate solution (FB-sol; p < 0.05), respectively. Precorneal retention assessed by gamma scintigraphy in vivo showed that the area under the remaining activity-time curve of the PDSC-coated formulation was 1.3-fold of the NLC and 2.4-fold of FB-sol. Moreover, in vivo ocular tolerance study indicated that there was no difference in irritation between the coated and noncoated NLC. In conclusion, novel NLC demonstrate high potential for ocular drug delivery. Copyright © 2011 Wiley Periodicals, Inc.

In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs.

PubMed

Tahara, Kohei; Nishikawa, Masahiro; Matsui, Ko; Hisazumi, Koji; Onodera, Risako; Tozuka, Yuichi; Takeuchi, Hirofumi

2016-09-01

The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano™ continuous crystallizer (PCC). Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent-antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo. The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size. PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.

[Postoperative pain management by intravenous patient-controlled analgesia in patients undergoing upper abdominal gastrointestinal surgery].

PubMed

Kajiyama, Seiji; Niihata, Tomoko; Sugimoto, Yuki; Kawamoto, Masashi

2012-10-01

We conducted a retrospective study to evaluate the effectiveness of intravenous patient-controlled analgesia (IVPCA) in the early postoperative period after upper abdominal gastrointestinal surgery. We also evaluated the postoperative effects of intraoperative analgesic dosage in patients after this surgery. A total of 59 adult patients classified as ASA 1-3 were allocated to one of two groups: Group A, 23 patients who requested IVPCA more than 50 times, and Group B, 36 patients with fewer than 50 requests. IVPCA was induced using morphine 1 mg x ml(-1) without a base dose. The bolus dose was 1 ml and the lock-out time was 5 min. There was no significant difference between the two groups in the total intraoperative remifentanil dosage/body weight/surgical duration, predicted effect-site concentration of fentanyl during extubation, and utilization of flurbiprofen. The doses of morphine were significantly higher, and the visual analogue scale scores for pain at rest and during movement tended to be lower in group A than in group B. The results of this study suggest that the effects of intraoperative analgesics may not be significant. Patients who had received the above mentioned anesthetic regimen intraoperatively also required full postoperative analgesia as well.

Comparative Study of Three Methods for Affinity Measurements: Capillary Electrophoresis Coupled with UV Detection and Mass Spectrometry, and Direct Infusion Mass Spectrometry

NASA Astrophysics Data System (ADS)

Mironov, Gleb G.; Logie, Jennifer; Okhonin, Victor; Renaud, Justin B.; Mayer, Paul M.; Berezovski, Maxim V.

2012-07-01

We present affinity capillary electrophoresis and mass spectrometry (ACE-MS) as a comprehensive separation technique for label-free solution-based affinity analysis. The application of ACE-MS for measuring affinity constants between eight small molecule drugs [ibuprofen, s-flurbiprofen, diclofenac, phenylbutazone, naproxen, folic acid, resveratrol, and 4,4'-(propane-1,3-diyl) dibenzoic acid] and β-cyclodextrin is described. We couple on-line ACE with MS to combine the separation and kinetic capability of ACE together with the molecular weight and structural elucidation of MS in one system. To understand the full potential of ACE-MS, we compare it with two other methods: Direct infusion mass spectrometry (DIMS) and ACE with UV detection (ACE-UV). After the evaluation, DIMS provides less reliable equilibrium dissociation constants than separation-based ACE-UV and ACE-MS, and cannot be used solely for the study of noncovalent interactions. ACE-MS determines apparent dissociation constants for all reacting small molecules in a mixture, even in cases when drugs overlap with each other during separation. The ability of ACE-MS to interact, separate, and rapidly scan through m/z can facilitate the simultaneous affinity analysis of multiple interacting pairs, potentially leading to the high-throughput screening of drug candidates.

[In-vitro evaluation of cinnarizine as a competing agent to beta-cyclodextrin inclusion complexes: effect of cinnarizine on the membrane permeation rate of progesterone from its beta-cyclodextrin inclusion complex].

PubMed

Muraoka, Atsushi; Tokumura, Tadakazu; Machida, Yoshiharu

2008-01-01

The use of competing agents is considered a powerful tool for the development of a drug-delivery system with drug/cyclodextrin inclusion complexes. However, there are very few studies examining this issue. To explain this phenomenon, it was thought that a competing agent with a sufficiently high stability constant had not yet been reported. In this study, cinnarizine (CN), which has a high stability constant with beta-cyclodextrin (beta-CD) and unique solubility characteristics, was selected, and its ability as a competing agent was examined in a membrane permeability study. The permeability study showed that the permeation rates of the drugs flurbiprofen, progesterone, and spironolactone decreased with their stability constants with the addition of beta-CD. In one of the drugs, progesterone (Pro), the decrease was restored by the addition of CN. The amount of CN added was a 1:1 molar ratio to the amount of Pro. However, no similar action was induced with the addition of DL-phenylalanine (Phe) in the permeation study at the 1:5 (Pro:Phe) molar ratio. These finding indicate that CN acts as a competing agent, and its action is much stronger than that of Phe.

The influence of arachidonic acid metabolites on cell division in the intestinal epithelium and in colonic tumors.

PubMed

Petry, F M; Tutton, P J; Barkla, D H

1984-09-01

Various metabolites of arachidonic acid are now known to influence cell division. In this paper the effects on cell proliferation of arachidonic acid, some inhibitors of arachidonic acid metabolism and some analogs of arachidonic acid metabolites is described. The epithelial cell proliferation rate in the jejunum, in the descending colon and in dimethylhydrazine-induced tumors of rat colon was measured using a stathmokinetic technique. Administration of arachidonic acid resulted in retardation of cell proliferation in each of the tissues examined. A cyclooxygenase inhibitor (Flurbiprofen) prevented this effect of arachidonic acid in the jejunal crypts and in colonic tumors, but not in colonic crypts. In contrast, inhibitors of both cyclooxygenase and lipoxygenase (Benoxaprofen and BW755c) prevented the effect of arachidonic acid in the colonic crypts and reduced its effect on colonic tumours but did not alter its effect on the jejunum. An inhibitor of thromoboxane A2 synthetase (U51,605) was also able to prevent the inhibitory effect of arachidonic acid on colonic tumors. Treatment with 16,16-dimethyl PGE2 inhibited cell proliferation in jejunal crypts and in colonic tumors, as did a thromboxane A2 mimicking agent, U46619. Nafazatrom, an agent that stimulates prostacyclin synthesis and inhibits lypoxygenase, promoted cell proliferation in the jejunal crypts and colonic crypts, but inhibited cell proliferation in colonic tumours.

Structural evaluation of crystalline ternary γ-cyclodextrin complex.

PubMed

Higashi, Kenjirou; Ideura, Saori; Waraya, Haruka; Moribe, Kunikazu; Yamamoto, Keiji

2011-01-01

The structure of a crystalline γ-cyclodextrin (γ-CD) ternary complex containing salicylic acid (SA) and flurbiprofen (FBP) prepared by sealed heating was investigated. FBP/γ-CD inclusion complex was prepared by coprecipitation; its molar ratio was determined as 1/1. Powder X-ray diffraction measurements showed that the molecular packing of γ-CD changed from hexagonal to monoclinic columnar form by sealed heating of SA with dried FBP/γ-CD inclusion complex, indicating ternary complex formation. The stoichiometry of SA/FBP/γ-CD was estimated as 2/1/1. Solid-state transformation of γ-CD molecular packing upon water vapor adsorption and desorption was irreversible for this ternary complex, in contrast to the reversible transition for the FBP/γ-CD inclusion complex. The ternary complex contained one FBP molecule in the cavity of γ-CD and two SA molecules in the intermolecular space between neighboring γ-CD column stacks. Infrared and (13) C solid-state NMR spectroscopies revealed that the molecular states of SA and FBP changed upon ternary complex formation. In the complex, dimer FBP molecules were sandwiched between two γ-CD molecules whereas each monomer SA molecule was present in the intermolecular space of γ-CD. Ternary complex formation was also observed for other drug-guest systems using naproxen and ketoprofen. Thus, the complex can be used to formulate variety of drugs. Copyright © 2010 Wiley-Liss, Inc. and the American Pharmacists Association

Ion mobility spectrometry as a simple and rapid method to measure the plasma propofol concentrations for intravenous anaesthesia monitoring

NASA Astrophysics Data System (ADS)

Wang, Xin; Zhou, Qinghua; Jiang, Dandan; Gong, Yulei; Li, Enyou; Li, Haiyang

2016-11-01

The plasma propofol concentration is important information for anaesthetists to monitor and adjust the anaesthesia depth for patients during a surgery operation. In this paper, a stand-alone ion mobility spectrometer (IMS) was constructed for the rapid measurement of the plasma propofol concentrations. Without any sample pre-treatment, the plasma samples were dropped on a piece of glass microfiber paper and then introduced into the IMS cell by the thermal desorption directly. Each individual measurement could be accomplished within 1 min. For the plasma propofol concentrations from 1 to 12 μg mL-1, the IMS response was linear with a correlation coefficient R2 of 0.998, while the limit of detection was evaluated to be 0.1 μg mL-1. These measurement results did meet the clinical application requirements. Furthermore, other clinically-often-used drugs, including remifentanil, flurbiprofen and atracurium, were found no significant interference with the qualitative and quantitative analysis of the plasma propofol. The plasma propofol concentrations measured by IMS were correlated well with those measured by the high performance liquid chromatography (HPLC). The results confirmed an excellent agreement between these two methods. Finally, this method was applied to monitor the plasma propofol concentrations for a patient undergoing surgery, demonstrating its capability of anaesthesia monitoring in real clinical environments.

Mechanically induced c-fos expression is mediated by cAMP in MC3T3-E1 osteoblasts

NASA Technical Reports Server (NTRS)

Fitzgerald, J.; Hughes-Fulford, M.

1999-01-01

In serum-deprived MC3T3-E1 osteoblasts, mechanical stimulation caused by mild (287 x g) centrifugation induced a 10-fold increase in mRNA levels of the proto-oncogene, c-fos. Induction of c-fos was abolished by the cAMP-dependent protein kinase inhibitor H-89, suggesting that the transient c-fos mRNA increase is mediated by cAMP. Down-regulation of protein kinase C (PKC) activity by chronic TPA treatment failed to significantly reduce c-fos induction, suggesting that TPA-sensitive isoforms of PKC are not responsible for c-fos up-regulation. In addition, 287 x g centrifugation increased intracellular prostaglandin E2 (PGE2) levels 2.8-fold (P<0. 005). Since we have previously shown that prostaglandin E2 (PGE2) can induce c-fos expression via a cAMP-mediated mechanism, we asked whether the increase in c-fos mRNA was due to centrifugation-induced PGE2 release. Pretreatment with the cyclooxygenase inhibitors indomethacin and flurbiprofen did not hinder the early induction of c-fos by mechanical stimulation. We conclude that c-fos expression induced by mild mechanical loading is dependent primarily on cAMP, not PKC, and initial induction of c-fos is not necessarily dependent on the action of newly synthesized PGE2.

Effective virtual screening protocol for CYP2C9 ligands using a screening site constructed from flurbiprofen and S-warfarin pockets

NASA Astrophysics Data System (ADS)

Polgár, Tímea; Menyhárd, Dóra K.; Keserű, György M.

2007-09-01

An effective virtual screening protocol was developed against an extended active site of CYP2C9, which was derived from X-ray structures complexed with flubiprofen and S-warfarin. Virtual screening has been effectively supported by our structure-based pharmacophore model. Importance of hot residues identified by mutation data and structural analysis was first estimated in an enrichment study. Key role of Arg108 and Phe114 in ligand binding was also underlined. Our screening protocol successfully identified 76% of known CYP2C9 ligands in the top 1% of the ranked database resulting 76-fold enrichment relative to random situation. Relevance of the protocol was further confirmed in selectivity studies, when 89% of CYP2C9 ligands were retrieved from a mixture of CYP2C9 and CYP2C8 ligands, while only 22% of CYP2C8 ligands were found applying the structure-based pharmacophore constraints. Moderate discrimination of CYP2C9 ligands from CYP2C18 and CYP2C19 ligands could also be achieved extending the application domain of our virtual screening protocol for the entire CYP2C family. Our findings further demonstrate the existence of an active site comprising of at least two binding pockets and strengthens the need of involvement of protein flexibility in virtual screening.

Investigation of pH Influence on Skin Permeation Behavior of Weak Acids Using Nonsteroidal Anti-Inflammatory Drugs.

PubMed

Chantasart, Doungdaw; Chootanasoontorn, Siriwan; Suksiriworapong, Jiraphong; Li, S Kevin

2015-10-01

As a continuing effort to understand the skin permeation behavior of weak acids and bases, the objectives of the present study were to evaluate skin permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) under the influence of pH, investigate the mechanism of pH effect, and examine a previous hypothesis that the effective skin pH for drug permeation is different from donor solution pH. In vitro permeability experiments were performed in side-by-side diffusion cells with diclofenac, ibuprofen, flurbiprofen, ketoprofen, and naproxen and human skin. The donor solution pH significantly affected skin permeation of NSAIDs, whereas no effect of the receiver pH was observed. Similar to previous observations, the apparent permeability coefficient versus donor solution pH relationships deviated from the predictions (fractions of unionized NSAIDs) according to the acid/base theory. The influences of the viable epidermis barrier, polar pathway transport, ion permeation across skin, and effective skin pH were investigated. The effective pH values for skin permeation determined using the NSAIDs (weak acids) in this study were different from those obtained previously with a weak base at the same donor solution pH conditions, suggesting that the observed permeability-pH relationships could not be explained solely by possible pH differences between skin and donor solution. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

The potential use of novel chitosan-coated deformable liposomes in an ocular drug delivery system.

PubMed

Chen, Hongdan; Pan, Hao; Li, Panpan; Wang, Hui; Wang, Xin; Pan, Weisan; Yuan, Yue

2016-07-01

In this study, novel chitosan-coated deformable liposomes (DL-CS) were proposed as an ocular drug delivery system to prolong pre-corneal retention, and improve transcorneal penetration and absorption. Flurbiprofen-loaded deformable liposomes (FP-DL) were prepared by a modified ethanol injection method and then coated with chitosan. Both DL and DL-CS exhibited a homogeneous particle size distribution, high encapsulation efficiency and good stability. After coating with 0.1% CS, the zeta potential was shifted from negative to positive. The apparent permeability coefficient of FP-DL-0.1% CS evaluated using isolated rabbit corneas was 1.29-, 1.95- and 4.59- fold greater than that of uncoated FP-DL, conventional liposomes and FP solution (P<0.01), respectively. The in vivo pre-corneal retention time and elimination dynamics were assessed using gamma scintigraphy technology. The area under the remaining activity-time of FP-DL-0.1% CS was prolonged 2.84- and 1.53-fold compared with that of the FP solution and FP-DL groups, respectively. Moreover, the ocular irritation test in vivo revealed that DL-0.1% CS produced no ocular damage or abnormal clinical signs. These results indicate that DL-CS appears to be a novel ophthalmic drug delivery strategy with the potential to overcome the limitations of conventional eye drops. Copyright © 2016 Elsevier B.V. All rights reserved.

Simultaneous chiral discrimination of multiple profens by cyclodextrin-modified capillary electrophoresis in normal and reversed polarity modes.

PubMed

La, Sookie; Kim, Jiyung; Kim, Jung-Han; Goto, Junichi; Kim, Kyoung-Rae

2003-08-01

Simultaneous enantioseparations of nine profens for their accurate chiral discrimination were achieved by capillary electrophoresis (CE) in the normal polarity (NP) mode with a single cyclodextrin (CD) system and in the reversed polarity (RP) mode with a dual CD system. The single CD system in the NP mode employed heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD) added at 75 mM-100 mM 2-(N-morpholino)ethanesulfonic acid buffer (pH 6.0) as the optimum run buffer. The dual CD system operated in the RP mode used 30 mM TMbetaCD and 1.0% anionic carboxymethyl-beta-cyclodextrin dissolved in pH 3.0, 100 mM phosphoric acid-triethanolamine buffer containing 0.01% hexadimethrine bromide added to reverse the electroosmotic flow. Fairly good enantiomeric resolutions and the opposite enantiomer migration orders were achieved in the two modes. Relative migration times to internal standard under respective optimum conditions were characteristic of each enantiomer with good precision (< 2% relative standard deviation, RSD), thereby enabling to crosscheck the chemical identification of profens and also their accurate chiralities. The method linearity in the two modes was found to be adequate (r > or = 0.9991) for the chiral assay of the profens investigated. Simultaneous enantiomeric purity test of ibuprofen, ketoprofen and flurbiprofen in a mixture was feasible in a single analysis by the present method.

Kondogogu gum-Zn+2-pectinate emulgel matrices reinforced with mesoporous silica for intragastric furbiprofen delivery.

PubMed

Bera, Hriday; Nadimpalli, Jhansirani; Kumar, Sanoj; Vengala, Pavani

2017-11-01

Flurbiprofen (FLU), a non-steroidal anti-inflammatory drug, exhibits limited clinical response due to its poor physicochemical properties. This study aimed at developing reliable drug carriers for intrgastric FLU delivery with a view to improve biopharmaceutical characteristics of drug and modulate its release in a controlled manner. In this context, FLU-loaded kondogogu gum (KG)-Zn +2 -low methoxyl (LM) pectinate emulgel matrices reinforced with calcium silicate (CS) were accomplished by ionotropic gelation technique employing zinc acetate as cross-linker and characterized for their in vitro performances. All the formulations demonstrated excellent drug encapsulation efficiency (DEE, 46-87%) and sustained drug release behavior (Q 7h , 70-91%). These quality attributes were remarkably influenced by polymer-blend (LM pectin:KG) ratios, low-density oil types and CS inclusion. The drug release profile of the FLU-loaded optimized matrices (F-7) was best fitted in Korsmeyer-Peppas model with Fickian diffusion driven mechanism. It also conferred excellent in vitro gastroretention capabilities. Moreover, the drug-excipient compatibility, alteration of crystallinity and thermal behavior of drug and surface morphology of matrices were evidenced with the results of FTIR, XRD, DSC and SEM analyses, respectively. Thus, the newly developed matrices are appropriate for sustained intragastric FLU delivery and simultaneous zinc supplementation for effective inflammation and arthritis management. Copyright © 2017 Elsevier B.V. All rights reserved.

Enantioselective simultaneous analysis of selected pharmaceuticals in environmental samples by ultrahigh performance supercritical fluid based chromatography tandem mass spectrometry.

PubMed

Camacho-Muñoz, Dolores; Kasprzyk-Hordern, Barbara; Thomas, Kevin V

2016-08-31

In order to assess the true impact of each single enantiomer of pharmacologically active compounds (PACs) in the environment, highly efficient, fast and sensitive analytical methods are needed. For the first time this paper focuses on the use of ultrahigh performance supercritical fluid based chromatography coupled to a triple quadrupole mass spectrometer to develop multi-residue enantioselective methods for chiral PACs in environmental matrices. This technique exploits the advantages of supercritical fluid chromatography, ultrahigh performance liquid chromatography and mass spectrometry. Two coated modified 2.5 μm-polysaccharide-based chiral stationary phases were investigated: an amylose tris-3,5-dimethylphenylcarbamate column and a cellulose tris-3-chloro-4-methylphenylcarbamate column. The effect of different chromatographic variables on chiral recognition is highlighted. This novel approach resulted in the baseline resolution of 13 enantiomers PACs (aminorex, carprofen, chloramphenicol, 3-N-dechloroethylifosfamide, flurbiprofen, 2-hydroxyibuprofen, ifosfamide, imazalil, naproxen, ofloxacin, omeprazole, praziquantel and tetramisole) and partial resolution of 2 enantiomers PACs (ibuprofen and indoprofen) under fast-gradient conditions (<10 min analysis time). The overall performance of the methods was satisfactory. The applicability of the methods was tested on influent and effluent wastewater samples. To the best of our knowledge, this is the first feasibility study on the simultaneous separation of chemically diverse chiral PACs in environmental matrices using ultrahigh performance supercritical fluid based chromatography coupled with tandem mass spectrometry. Copyright © 2016 Elsevier B.V. All rights reserved.

Using Chemoinformatics, Bioinformatics, and Bioassay to Predict and Explain the Antibacterial Activity of Nonantibiotic Food and Drug Administration Drugs.

PubMed

Kahlous, Nour Aldin; Bawarish, Muhammad Al Mohdi; Sarhan, Muhammad Arabi; Küpper, Manfred; Hasaba, Ali; Rajab, Mazen

2017-04-01

Discovering of new and effective antibiotics is a major issue facing scientists today. Luckily, the development of computer science offers new methods to overcome this issue. In this study, a set of computer software was used to predict the antibacterial activity of nonantibiotic Food and Drug Administration (FDA)-approved drugs, and to explain their action by possible binding to well-known bacterial protein targets, along with testing their antibacterial activity against Gram-positive and Gram-negative bacteria. A three-dimensional virtual screening method that relies on chemical and shape similarity was applied using rapid overlay of chemical structures (ROCS) software to select candidate compounds from the FDA-approved drugs database that share similarity with 17 known antibiotics. Then, to check their antibacterial activity, disk diffusion test was applied on Staphylococcus aureus and Escherichia coli. Finally, a protein docking method was applied using HYBRID software to predict the binding of the active candidate to the target receptor of its similar antibiotic. Of the 1,991 drugs that were screened, 34 had been selected and among them 10 drugs showed antibacterial activity, whereby drotaverine and metoclopramide activities were without precedent reports. Furthermore, the docking process predicted that diclofenac, drotaverine, (S)-flurbiprofen, (S)-ibuprofen, and indomethacin could bind to the protein target of their similar antibiotics. Nevertheless, their antibacterial activities are weak compared with those of their similar antibiotics, which can be potentiated further by performing chemical modifications on their structure.

Enhancement of the conductivity detection signal in capillary electrophoresis systems using neutral cyclodextrins as sweeping agents.

PubMed

Boublík, Milan; Riesová, Martina; Dubský, Pavel; Gaš, Bohuslav

2018-06-01

Conductivity detection is a universal detection technique often encountered in electrophoretic separation systems, especially in modern chip-electrophoresis based devices. On the other hand, it is sparsely combined with another contemporary trend of enhancing limits of detection by means of various preconcentration strategies. This can be attributed to the fact that a preconcentration experimental setup usually brings about disturbances in a conductivity baseline. Sweeping with a neutral sweeping agent seems a good candidate for overcoming this problem. A neutral sweeping agent does not hinder the conductivity detection while a charged analyte may preconcentrate on its boundary due to a decrease in its effective mobility. This study investigates such sweeping systems theoretically, by means of computer simulations, and experimentally. A formula is provided for the reliable estimation of the preconcentration factor. Additionally, it is demonstrated that the conductivity signal can significantly benefit from slowing down the analyte and thus the overall signal enhancement can easily overweight amplification caused solely by the sweeping process. The overall enhancement factor can be deduced a priori from the linearized theory of electrophoresis implemented in the PeakMaster freeware. Sweeping by neutral cyclodextrin is demonstrated on an amplification of a conductivity signal of flurbiprofen in a real drug sample. Finally, a possible formation of unexpected system peaks in systems with a neutral sweeping agent is revealed by the computer simulation and confirmed experimentally. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[A case of gastric cancer accompanied by disseminated carcinomatosis of bone marrow wherein long-term chemotherapy was enabled by early supportive palliative care].

PubMed

Yamagiwa, Tetsuya; Amakawa, Ryuichi; Takeda, Yasuhiro; Fukuda, Akiko; Ito, Satoko; Nakayama, Shinya; Shiotani, Tomohiro; Watanabe, Go; Kita, Kenkichi; Yamaoka, Yoshio

2014-02-01

Here we report gastric cancer accompanied by bone marrow carcinomatosis in a patient for whom long-term chemotherapy was enabled by early pain-relief therapy. A 45-year-old man was admitted to our hospital because of back pain associated with multiple spinal tumors in June 2011. Blood tests showed a trend toward disseminated intravascular coagulation(DIC) and gastric cancer was suspected as the primary lesion. Because pain was severe, emergency pain relief was provided by flurbiprofen axetil and a continuous subcutaneous infusion of fentanyl citrate. After bone marrow examination gave a diagnosis of poorly differentiated adenocarcinoma, we performed sequential methotrexate(MTX)and 5-fluorouracil(5-FU)therapy. The therapy successfully decreased tumor marker levels, and alkaline phosphatase and lactate dehydrogenase levels normalized. Finally, gastric cancer accompanied by bone marrow carcinomatosis was diagnosed. Because the patient had anxiety and spiritual pain from the time of admission, psychiatric care was also required. In November 2011, the tumor recurred, and we switched therapy to a combination of S-1 and cisplatin. The patient's pain was controlled by combined treatment with a fentanyl patch and etodolac, and he was discharged in December 2011. However, severe pain recurred and pain therapy was continued. DIC developed in February 2012 and transiently resolved after resuming combination therapy with MTX and 5-FU; however, it subsequently recurred, leading to the patient's death in May 2012.

Prostaglandin E2 and the protein kinase A pathway mediate arachidonic acid induction of c-fos in human prostate cancer cells

NASA Technical Reports Server (NTRS)

Chen, Y.; Hughes-Fulford, M.

2000-01-01

Arachidonic acid (AA) is the precursor for prostaglandin E2 (PGE2) synthesis and increases growth of prostate cancer cells. To further elucidate the mechanisms involved in AA-induced prostate cell growth, induction of c-fos expression by AA was investigated in a human prostate cancer cell line, PC-3. c-fos mRNA was induced shortly after addition of AA, along with a remarkable increase in PGE2 production. c-fos expression and PGE2 production induced by AA was blocked by a cyclo-oxygenase inhibitor, flurbiprofen, suggesting that PGE2 mediated c-fos induction. Protein kinase A (PKA) inhibitor H-89 abolished induction of c-fos expression by AA, and partially inhibited PGE2 production. Protein kinase C (PKC) inhibitor GF109203X had no significant effect on c-fos expression or PGE2 production. Expression of prostaglandin (EP) receptors, which mediate signal transduction from PGE2 to the cells, was examined by reverse transcription polymerase chain reaction in several human prostate cell lines. EP4 and EP2, which are coupled to the PKA signalling pathway, were expressed in all cells tested. Expression of EP1, which activates the PKC pathway, was not detected. The current study showed that induction of the immediate early gene c-fos by AA is mediated by PGE2, which activates the PKA pathway via the EP2/4 receptor in the PC-3 cells.

Mixed Micelle System Produced by Interaction Between Transglycosylated Stevia and an Ionic Surfactant Improves Dissolution Profile of Mefenamic Acid.

PubMed

Fujimori, Miki; Kadota, Kazunori; Tozuka, Yuichi

2017-04-01

Transglycosylated stevia (stevia-G) can effectively improve the dissolution and bioavailability of poorly water-soluble drugs. Furthermore, addition of an ionic surfactant to stevia-G solution has been shown to enhance the dissolution effect of stevia-G on flurbiprofen. Herein, 4 surfactants, namely sodium dodecyl sulfate, sodium N-dodecanoylsarcosinate, sodium monododecyl phosphate, and lauryltrimethylammonium chloride (LTAC) were screened to investigate their synergistic effect with stevia-G in enhancing the solubility of mefenamic acid (MFA). The ternary formulation containing LTAC produced the highest increase in solubility, whereas the binary MFA/LTAC formulation did not increase the solubility of MFA. Surface tension was evaluated to analyze the interaction between stevia-G and each ionic surfactant, wherein the Rubingh model was applied to predict mixed micelle formation between stevia-G and LTAC. Interaction parameters calculated by the Rubingh model reflected mixed micelle formation between stevia-G and LTAC relative to the self-interactions of the 2 individual surfactants. All interaction parameters in this system showed negative values, indicating a favorable interaction (e.g., hydrogen bond or electrostatic and dipole) between binary components in the mixed micelles. Spray-dried particles of ternary formulations (MFA/stevia-G/LTAC) were prepared to evaluate the dissolution profile and physicochemical properties. Dissolution profiling showed that the concentration of MFA released from spray-dried particles was significantly higher than untreated MFA. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Propofol depresses cisplatin cytotoxicity via the inhibition of gap junctions.

PubMed

Zhang, Yuan; Wang, Xiyan; Wang, Qin; Ge, Hui; Tao, Liang

2016-06-01

The general anesthetic, propofol, affects chemotherapeutic activity, however, the mechanism underlying its effects remains to be fully elucidated. Our previous study showed that tramadol and flurbiprofen depressed the cytotoxicity of cisplatin via the inhibition of gap junction (GJ) intercellular communication (GJIC) in connexin (Cx)32 HeLa cells. The present study investigated whether the effects of propofol on the cytotoxicity of cisplatin were mediated by GJ in U87 glioma cells and Cx26‑transfected HeLa cells. Standard colony formation assay was used to determine the cytotoxicity of cisplatin. Parachute dye coupling assay was used to measure GJ function, and western blot analysis was used to determine the expression levels of Cx32. The results revealed that exposure of the U87 glioma cells and the Cx26-transfected HeLa cells to cisplatin for 1 h reduced clonogenic survival in low density cultures (without GJs) and high density cultures (with GJs). However, the toxic effect was higher in the high density culture. In addition, pretreatment of the cells with propofol significantly reduced cisplatin‑induced cytotoxicity, but only in the presence of functional GJs. Furthermore, propofol significantly inhibited dye coupling through junctional channels, and a long duration of exposure of the cells to propofol downregulated the expression levels of Cx43 and Cx26. These results demonstrated that the inhibition of GJIC by propofol affected the therapeutic efficacy of chemotherapeutic drugs. The present study provides evidence of a novel mechanism underlying the effects of analgesics in counteracting chemotherapeutic efficiency.

Impact of the counterion on the solubility and physicochemical properties of salts of carboxylic acid drugs.

PubMed

David, S E; Timmins, P; Conway, B R

2012-01-01

Salt formation is a widely used approach to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. In order to better understand the relationships between the active drug, the selected counterion and the resultant salt form, crystalline salts were formed using four different carboxylic acid drugs and a closely related series of amine counterions. Thirty-six related crystalline salts were prepared, characterized and the relationship between solubility and dissolution behaviour and other properties of the salt and the counterion studied. Salts of four model acid drugs, gemfibrozil, flurbiprofen, ibuprofen and etodolac were prepared using the counterions butylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol and tris(hydroxymethyl)aminomethane. Salt formation was confirmed, the salts were characterized and their corresponding solubilities determined and rationalized with respect to the counterions' properties. The properties of the salt highly dependent on the nature of the counterion and, although there is considerable variation, some general conclusion can be drawn. For the alkyl amines series, increasing chain length leads to a reduction in solubility across all the acidic drugs studied and a reduction in melting point, thus contradicting simplistic relationships between solubility and melting point. Small, compact counterions consistently produce crystalline salts with high melting point accompanied with a modest improvement in solubility and the nature of hydrogen bonding between the ions has a major impact on the solubility.

Drug-in-cyclodextrin-in-liposomes: A novel drug delivery system for flurbiprofen.

PubMed

Zhang, Lina; Zhang, Qi; Wang, Xin; Zhang, Wenji; Lin, Congcong; Chen, Fen; Yang, Xinggang; Pan, Weisan

2015-08-15

A novel delivery system based on drug-cyclodextrin (CD) complexation and liposomes has been developed to improve therapeutic effect. Three different means, i.e., co-evaporation (COE), co-ground (GR) and co-lyophilization (COL) and three different CDs (β-CD, HP-β-CD and SBE-β-CD) were contrasted to investigate the characteristics of the end products. FP/FP-CD loaded liposomes were obtained by thin layer evaporation technique. Size, zeta potential and encapsulation efficiency were investigated by light scattering analysis and minicolumn centrifugation. Differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) showed the amorphous form of complexes and spherical morphology of FP-HP-β-CD COE loaded liposomes. The pH 7.4 phosphate buffer solution (PBS) was selected as the medium for the in vitro release. Wistar rats were put into use to study the pharmacokinetic behavior in vivo. FP-HP-β-CD COE loaded liposomes showed the better physicochemical characters that followed the average particle size, polydispersity index, zeta potential and mean encapsulation efficiency 158±10 nm, 0.19±0.1, -12.4±0.1 mW and 56.1±0.5%, separately. The relative bioavailability of FP-HP-β-CD COE loaded liposomes was 420%, 201% and 402% compared with FP solution, FP-HP-β-CD and FP-liposomes, respectively. In conclusion, the novel delivery system improved the relative bioavailability of FP significantly and provided a perspective way for delivery of insoluble drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Prediction of poly(ethylene) glycol-drug eutectic compositions using an index based on the van't Hoff equation.

PubMed

Law, Devalina; Wang, Weili; Schmitt, Eric A; Long, Michelle A

2002-03-01

To define an index based on the van't Hoff equation that can be used as a screening tool for predicting poly(ethylene) glycol (PEG)-drug eutectic composition. Phase diagrams of PEG with ritonavir, ibuprofen, fenofibrate. naproxen, and griseofulvin were constructed using differential scanning calorimetry, hot stage microscopy and powder X-ray diftractometry. Previously reported phase diagrams were also used to test the predictive capability of the index. This work shows that a modified van't Hoff equation can be used to model the drug liquidus line of these phase diagrams. The slope of the liquidus line depends on the melting point (T(f)d) and heat of fusion (deltaH(f)d) of the drug and describes the initial rate at which the eutectic or monotectic point is approached. Based on this finding, a dimensionless index Ic was defined. The index can be calculated from the melting points of the pure components and heat of fusion of the drug. In addition to the compounds listed above, the index was found to predict the eutectic composition for flurbiprofen, temazepam and indomethacin. These compounds range over 150 degrees C in T(f)d, and from 25-65 kJ/mole in deltaH(f)d. Using Ic the approximate eutectic composition for eight different compounds was predicted. The index provides a useful screening tool for assessing the maximum drug loading in a drug-polymer eutectic/monotectic formulation.

Chiral separation of terbutaline and non-steroidal anti-inflammatory drugs by using a new lysine-bridged hemispherodextrin in capillary electrophoresis.

PubMed

Cucinotta, V; Messina, M; Contino, A; Maccarrone, G; Orlandini, S; Giuffrida, A

2017-10-25

A method for the separation of a mixture of terbutaline and non-steroidal anti-inflammatory drugs was developed using capillary electrophoresis with a new hemispherodextrin, ad hoc designed, the lysine - bridged hemispherodextrin (THLYSH). The use of lysine residues to bridge the trehalose capping unit moiety to the cyclodextrin cavity gives rise to a receptor with two long chains with amine nitrogen atoms, whose charge can be easily tuned as a function of the solution pH. The new hemispherodextrin was accurately characterised by ESI-MS and NMR spectroscopy, also highlighting its protonation behaviour. Circular dichroism and ESR spectroscopy measurements were also carried out to test its inclusion ability towards anthraquinone-3-sulfonate and its metal coordination ability towards copper(II) ion, respectively. Analogously to the other hemispherodextrins, the main skill of this new derivative lies in its chiral selector properties, as shown by the separation of the enantiomeric pairs of terbutaline and ibuprofen, flurbiprofen, suprofen and tiaprofenic acid by capillary electrophoresis. The focused use of the solution equilibria involved in the separations made it possible to understand the phenomena occurring in solution, and to finely tune the charge status of the receptor. In this way the chiral separation of the racemic mixture was successfully obtained, even if the receptor was individually used, differently by the other hemispherodextrins previously studied whose chiral separation capabilities are present only if used as binary mixtures. Copyright © 2017 Elsevier B.V. All rights reserved.

Penetration enhancing effects of selected natural oils utilized in topical dosage forms.

PubMed

Viljoen, Joe M; Cowley, Amé; du Preez, Jan; Gerber, Minja; du Plessis, Jeanetta

2015-01-01

Various natural products, including oils, have been utilized as penetration enhancers due to their "safety profiles". These oils contain fatty acids promoting skin permeability through lipid fluidization within the stratum corneum; and might therefore be able to effectively enhance transdermal drug delivery. We investigated possible penetration enhancing properties of selected oils, utilizing flurbiprofen as marker compound in emulgel formulations. The formulations were compared to a liquid paraffin emulgel and a hydrogel to establish any significant penetration enhancing effects. Gas chromatographic analysis of the natural oils was performed at ambient temperature to determine the fatty acid composition in each selected natural oils. Franz cell diffusion studies and tape stripping methods were employed to study delivery of the marker into, and through the skin. The following rank order for the emulgel flux-values was obtained: Hydrogel > olive oil > liquid paraffin > coconut oil > grape seed oil > Avocado oil ≥ Crocodile oil > Emu oil. Results suggested that oils containing predominantly mono-unsaturated oleic acid, on average increased the flux of the marker to a larger extent than oils containing an almost even mixture of both mono- and poly-unsaturated fatty acids. Oils comprising saturated fatty acids (SFAs) with alkyl chains between C12 and C14, increased the marker flux to a higher extent than oils containing C16-C18 SFAs. Effects observed for branched fatty acids, however, did not vary significantly from effects for unbranched fatty acids with the same carbon chain length. Natural oils possess penetration enhancing effects.

Conjugation of cell-penetrating peptides with poly(lactic-co-glycolic acid)-polyethylene glycol nanoparticles improves ocular drug delivery

PubMed Central

Vasconcelos, Aimee; Vega, Estefania; Pérez, Yolanda; Gómara, María J; García, María Luisa; Haro, Isabel

2015-01-01

In this work, a peptide for ocular delivery (POD) and human immunodeficiency virus transactivator were conjugated with biodegradable poly(lactic-co-glycolic acid) (PGLA)–polyethylene glycol (PEG)-nanoparticles (NPs) in an attempt to improve ocular drug bioavailability. The NPs were prepared by the solvent displacement method following two different pathways. One involved preparation of PLGA NPs followed by PEG and peptide conjugation (PLGA-NPs-PEG-peptide); the other involved self-assembly of PLGA-PEG and the PLGA-PEG-peptide copolymer followed by NP formulation. The conjugation of the PEG and the peptide was confirmed by a colorimetric test and proton nuclear magnetic resonance spectroscopy. Flurbiprofen was used as an example of an anti-inflammatory drug. The physicochemical properties of the resulting NPs (morphology, in vitro release, cell viability, and ocular tolerance) were studied. In vivo anti-inflammatory efficacy was assessed in rabbit eyes after topical instillation of sodium arachidonate. Of the formulations developed, the PLGA-PEG-POD NPs were the smaller particles and exhibited greater entrapment efficiency and more sustained release. The positive charge on the surface of these NPs, due to the conjugation with the positively charged peptide, facilitated penetration into the corneal epithelium, resulting in more effective prevention of ocular inflammation. The in vitro toxicity of the NPs developed was very low; no ocular irritation in vitro (hen’s egg test–chorioallantoic membrane assay) or in vivo (Draize test) was detected. Taken together, these data demonstrate that PLGA-PEG-POD NPs are promising vehicles for ocular drug delivery. PMID:25670897

Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production.

PubMed

Wanngren, Johanna; Ottervald, Jan; Parpal, Santiago; Portelius, Erik; Strömberg, Kia; Borgegård, Tomas; Klintenberg, Rebecka; Juréus, Anders; Blomqvist, Jenny; Blennow, Kaj; Zetterberg, Henrik; Lundkvist, Johan; Rosqvist, Susanne; Karlström, Helena

2012-09-21

The γ-secretase complex is an appealing drug target when the therapeutic strategy is to alter amyloid-β peptide (Aβ) aggregation in Alzheimer disease. γ-Secretase is directly involved in Aβ formation and determines the pathogenic potential of Aβ by generating the aggregation-prone Aβ42 peptide. Because γ-secretase mediates cleavage of many substrates involved in cell signaling, such as the Notch receptor, it is crucial to sustain these pathways while altering the Aβ secretion. A way of avoiding interference with the physiological function of γ-secretase is to use γ-secretase modulators (GSMs) instead of inhibitors of the enzyme. GSMs modify the Aβ formation from producing the amyloid-prone Aβ42 variant to shorter and less amyloidogenic Aβ species. The modes of action of GSMs are not fully understood, and even though the pharmacology of GSMs has been thoroughly studied regarding Aβ generation, knowledge is lacking about their effects on other substrates, such as Notch. Here, using immunoprecipitation followed by MALDI-TOF MS analysis, we found that two novel, second generation GSMs modulate both Notch β and Aβ production. Moreover, by correlating S3-specific Val-1744 cleavage of Notch intracellular domain (Notch intracellular domain) to total Notch intracellular domain levels using immunocytochemistry, we also demonstrated that Notch intracellular domain is not modulated by the compounds. Interestingly, two well characterized, nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drug), R-flurbiprofen and sulindac sulfide, affect only Aβ and not Notch β formation, indicating that second generation GSMs and nonsteroidal anti-inflammatory drug-based GSMs have different modes of action regarding Notch processing.

Nanocomposite formation between alpha-glucosyl stevia and surfactant improves the dissolution profile of poorly water-soluble drug.

PubMed

Uchiyama, Hiromasa; Tozuka, Yuichi; Nishikawa, Masahiro; Takeuchi, Hirofumi

2012-05-30

The formation of a hybrid-nanocomposite using α-glucosyl stevia (Stevia-G) and surfactant was explored to improve the dissolution of flurbiprofen (FP). As reported previously, the dissolution amount of FP was enhanced in the presence of Stevia-G, induced by the formation of an FP and Stevia-G-associated nanostructure. When a small amount of sodium dodecyl sulfate (SDS) was present with Stevia-G, the amount of dissolved FP was extremely enhanced. This dissolution-enhancement effect was also observed with the cationic surfactant of dodecyl trimethyl ammonium bromide, but not with the non-ionic surfactant of n-octyl-β-D-maltopyranoside. To investigate the dissolution-enhancement effect of Stevia-G/SDS mixture, the pyrene I(1)/I(3) ratio was plotted versus the Stevia-G concentration. The pyrene I(1)/I(3) ratio of Stevia-G/SDS mixture had a sigmoidal curve at lower Stevia-G concentrations compared to the Stevia-G solution alone. These results indicate that the Stevia-G/SDS mixture provides a hydrophobic core around pyrene molecules at lower Stevia-G concentrations, leading to nanocomposite formation between Stevia-G and SDS. The nanocomposite of Stevia-G/SDS showed no cytotoxicity to Caco-2 cells at a mixture of 0.1% SDS and 1% Stevia-G solution, whereas 0.1% SDS solution showed high toxicity. These results suggest that the nanocomposite formation of Stevia-G/SDS may be useful way to enhance the dissolution of poorly water-soluble drugs without special treatment. Copyright © 2012 Elsevier B.V. All rights reserved.

Comparing the Efficacy of Ophthalmic NSAIDs in Common Indications: A Literature Review to Support Cost-effective Prescribing.

PubMed

Wilson, Daniel J; Schutte, Scott M; Abel, Steven R

2015-06-01

To review the commercially available ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs), identify opportunities for therapeutic substitutions within and outside of their Food and Drug Administration (FDA)-approved indications, and identify clinically superior drugs within the class for specific indications. A PubMed search (1992 through January 2014) was performed on the terms diclofenac, ketorolac, flurbiprofen, bromfenac, and nepafenac. Clinical trials, meta-analyses, and review articles were evaluated if they were written in English and pertained to human subjects. Studies were excluded if they were in vitro studies, solely evaluated pharmacokinetic or pharmacodynamic properties, did not relate to the topical ophthalmic route, did not evaluate the FDA-approved indications of any available ophthalmic NSAID, or compared a reviewed drug with a nonreviewed drug (without placebo comparison). A total of 67 articles met the criteria for evaluation. Article quality, study design, and dosing of the medications were assessed to determine the clinical applicability of the results. The quality of the article was determined using the Oxford Centre for Evidence-based Medicine Levels of Evidence 1. Many formulations of the 5 reviewed NSAIDs have been studied across the 4 primary indications. These indications are (1) pain and inflammation associated with cataract surgery, (2) pain associated with corneal refractive surgery, (3) inhibition of intraoperative miosis, and (4) seasonal allergic conjunctivitis. Several studies have directly compared drugs within this class and have identified instances in which certain selections are therapeutically superior or equivalent to another. This information provides practitioners with guidance in selecting an optimal medication. © The Author(s) 2015.

Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells

NASA Technical Reports Server (NTRS)

Tjandrawinata, R. R.; Dahiya, R.; Hughes-Fulford, M.

1997-01-01

Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E2 (dmPGE2) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE2 to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE2 concentration. DmPGE2 also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE2 concentration, with maximum stimulation seen at 5 microg ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen (5 microM), in the presence of exogenous dmPGE2, inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE2 has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE2, perhaps resulting from changes in local cellular PGE2 concentrations.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2006-01-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs:(R)-Flurbiprofen, 90Yttrium-DOTA-huJ591; ABT-510, ACP-103, Ad5-FGF4, adalimumab, ademetionine, AG-7352, alemtuzumab, Amb a 1 ISS-DNA, anakinra, apaziquone, aprepitant, aripiprazole, atazanavir sulfate; BAL-8557, bevacizumab, BMS-188797, bortezomib, bosentan, brivudine; Calcipotriol/betamethasone dipropionate, cannabidiol, caspofungin acetate, catumaxomab, CERE-120, cetuximab, ciclesonide, cilomilast, cizolirtine citrate, Cypher, cystemustine; Dalbavancin, darifenacin hydrobromide, dasatinib, deferasirox, denosumab, desmoteplase, dihydrexidine, dimethyl fumarate, dutasteride, DW-166HC; Eculizumab, enfuvirtide, entecavir, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, eszopiclone, etoricoxib, everolimus; Fallypride, febuxostat, fenretinide, fesoterodine, fingolimod hydrochloride; Gabapentin enacarbil, gefitinib; hMaxi-K, human papillomavirus vaccine, HYAL-CT1101; Imatinib mesylate, indiplon, inolimomab, ISAtx-247; J591; Lacosamide, landiolol, lasofoxifene tartrate, lestaurtinib, lidocaine/prilocaine, linezolid, lixivaptan, lonafarnib, lopinavir, lopinavir/ritonavir, lumiracoxib; Natalizumab, nesiritide; OC-108, omalizumab, onercept, OSC; Palifermin, palonosetron hydrochloride, parathyroid hormone (human recombinant), parecoxib sodium, PD-MAGE-3 vaccine, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pelitinib, pitavastatin calcium, plerixafor hydrochloride, posaconazole, prasterone sulfate, pregabalin; Ramelteon, ranelic acid distrontium salt, rasburicase, rosuvastatin calcium, rotigotine, RSD-1235, rufinamide, rupatadine fumarate; Sarizotan hydrochloride, SHL-749, sirolimus-eluting stent, solifenacin succinate, sunitinib malate; Tadalafil, talampanel, tasidotin hydrochloride, Taxus, tegaserod maleate, telavancin hydrochloride, tenofovir disoproxil fumarate, tiotropium bromide, tocilizumab, tositumomab, treprostinil sodium, tridolgosir hydrochloride, TTS-CD3; Ularitide; Valdecoxib, Val-Tyr sardine peptidase, vardenafil hydrochloride hydrate, voriconazole; Yttrium (90Y) edotreotide, Yttrium 90 (90Y) ibritumomab tiuxetan; Zileuton, zucapsaicin.

Increasing procaspase 8 expression using repurposed drugs to induce HIV infected cell death in ex vivo patient cells

PubMed Central

Sampath, Rahul; Cummins, Nathan W.; Natesampillai, Sekar; Bren, Gary D.; Chung, Thomas D.; Baker, Jason; Henry, Keith; Pagliuzza, Amélie; Badley, Andrew D.

2017-01-01

HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell-associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8. However, cell death is prevented, possibly due to low procaspase 8 expression. Here, we tested whether increasing procaspase 8 levels in CD4 T cells will produce more Casp8p41 following HIV reactivation, causing more reactivated cells to die. Screening 1277 FDA approved drugs identified 168 that increased procaspase 8 expression by at least 1.7-fold. Of these 30 were tested for anti-HIV effects in an acute HIVIIIb infection model, and 9 drugs at physiologic relevant levels significantly reduced cell-associated HIV DNA. Primary CD4 T cells from ART suppressed HIV patients were treated with one of these 9 drugs and reactivated with αCD3/αCD28. Four drugs significantly increased Casp8p41 levels following HIV reactivation, and decreased total cell associated HIV DNA levels (flurbiprofen: p = 0.014; doxycycline: p = 0.044; indomethacin: p = 0.025; bezafibrate: P = 0.018) without effecting the viability of uninfected cells. Thus procaspase 8 levels can be increased pharmacologically and, in the context of HIV reactivation, increase Casp8p41 causing death of reactivating cells and decreased HIV DNA levels. Future studies will be required to define the clinical utility of this or similar approaches. PMID:28628632

Polymer brush hexadecyltrimethylammonium bromide (CTAB) modified poly (propylene-g-styrene sulphonic acid) fiber (ZB-1): CTAB/ZB-1 as a promising strategy for improving the dissolution and physical stability of poorly water-soluble drugs.

PubMed

Cao, Jinxu; Yang, Baixue; Wang, Yumei; Wei, Chen; Wang, Hongyu; Li, Sanming

2017-11-01

The feasibility of polymer brush as drug delivery vehicle was demonstrated with the goal of improving the dissolution and physical stability of poorly water-soluble drugs. Polymer brush CTAB/ZB-1 was synthesized by electrostatic interaction using a physical modification method with anionic poly (propylene-g-styrene sulphonic acid) fiber (ZB-1) as the substrate and cationic hexadecyltrimethylammonium bromide (CTAB) as the modifier. The polymer brush structure of CTAB/ZB-1 was validated by atomic force microscopy (AFM) and the channels of brush provided the drug loading sites. Flurbiprofen (FP), a BCS class II representative drug, was selected as the model poorly water-soluble drug to be loaded into this polymer brush. Then the drug loading and release were systematically investigated. Besides, the transformation from crystalline FP to amorphous state was observed by differential scanning calorimeter (DSC). In vitro dissolution in pure water and pH1.2 HCl media with/without 0.1% sodium dodecyl sulfate (SDS) was tested. Moreover, the optimal formulations (namely carrier/drug ratios) were determined. The results demonstrated prominent improvement of dissolution when FP was released from CTAB/ZB-1. After a long time storage, FP remained amorphous in CTAB/ZB-1 according to DSC determinations and performed an approximately equivalent dissolution compared with fresh samples, suggesting the advantage of CTAB/ZB-1 as carrier in enhancing the physical stability of drugs. The study introduced the versatile easily formulated polymer brush CTAB/ZB-1 and demonstrated the potential of polymer brush as an alternative approach for improving the dissolution and physical stability of poorly water-soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Generalized model of electromigration with 1:1 (analyte:selector) complexation stoichiometry: part II. Application to dual systems and experimental verification.

PubMed

Müllerová, Ludmila; Dubský, Pavel; Gaš, Bohuslav

2015-03-06

Interactions among analyte forms that undergo simultaneous dissociation/protonation and complexation with multiple selectors take the shape of a highly interconnected multi-equilibrium scheme. This makes it difficult to express the effective mobility of the analyte in these systems, which are often encountered in electrophoretical separations, unless a generalized model is introduced. In the first part of this series, we presented the theory of electromigration of a multivalent weakly acidic/basic/amphoteric analyte undergoing complexation with a mixture of an arbitrary number of selectors. In this work we demonstrate the validity of this concept experimentally. The theory leads to three useful perspectives, each of which is closely related to the one originally formulated for simpler systems. If pH, IS and the selector mixture composition are all kept constant, the system is treated as if only a single analyte form interacted with a single selector. If the pH changes at constant IS and mixture composition, the already well-established models of a weakly acidic/basic analyte interacting with a single selector can be employed. Varying the mixture composition at constant IS and pH leads to a situation where virtually a single analyte form interacts with a mixture of selectors. We show how to switch between the three perspectives in practice and confirm that they can be employed interchangeably according to the specific needs by measurements performed in single- and dual-selector systems at a pH where the analyte is fully dissociated, partly dissociated or fully protonated. Weak monoprotic analyte (R-flurbiprofen) and two selectors (native β-cyclodextrin and monovalent positively charged 6-monodeoxy-6-monoamino-β-cyclodextrin) serve as a model system. Copyright © 2015 Elsevier B.V. All rights reserved.

Aggravation by paroxetine, a selective serotonin reuptake inhibitor, of antral lesions generated by nonsteroidal anti-inflammatory drugs in rats.

PubMed

Takeuchi, Koji; Tanaka, Akiko; Nukui, Kazuo; Kojo, Azusa; Gyenge, Melinda; Amagase, Kikuko

2011-09-01

Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.

Carprofen Induction of p75NTR Dependent Apoptosis via the p38 MAPK Pathway in Prostate Cancer Cells

PubMed Central

Khwaja, Fatima S.; Quann, Emily J.; Pattabiraman, Nagarajan; Wynne, Shehla; Djakiew, Daniel

2008-01-01

The p75NTR functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we demonstrated that treatment with R-flurbiprofen or ibuprofen induced p75NTR expression in several prostate cancer cell lines leading to p75NTR mediated decreased survival. Utilizing the 2-phenyl propionic acid moiety of these profens as a pharmacophore, we screened an in silico data base of 30 million compounds and identified carprofen as having an order of magnitude greater activity for induction of p75NTR levels and inhibition of cell survival. Prostate (PC-3, DU-145) and bladder (T24) cancer cells were more sensitive to carprofen induction of p75NTR associated loss of survival than breast (MCF7) and fibroblast (3T3) cells. Transfection of prostate cell lines with a dominant negative form of p75NTR prior to carprofen treatment partially rescued cell survival demonstrating a cause and effect relationship between carprofen induction of p75NTR levels and inhibition of survival. Carprofen induced apoptotic nuclear fragmentation in prostate but not in MCF7 and 3T3 cells. Furthermore, siRNA knockdown of the p38 MAPK protein prevented induction of p75NTR by carprofen in both prostate cell lines. Carprofen treatment induced phosphorylation of p38 MAPK as early as within 1 minute. Expression of a dominant negative form of MK2, the kinase downstream of p38 MAPK frequently associated with signaling cascades leading to apoptosis, prevented carprofen induction of the p75NTR protein. Collectively, we identify carprofen as a highly potent profen capable of inducing p75NTR dependent apoptosis via the p38 MAPK pathway in prostate cancer cells. PMID:18974393

CYP2C9 Amino Acid Residues Influencing Phenytoin Turnover and Metabolite Regio- and Stereochemistry

PubMed Central

Mosher, Carrie M.; Tai, Guoying; Rettie, Allan E.

2009-01-01

Phenytoin has been an effective anticonvulsant agent for over 60 years, although its clinical use is complicated by nonlinear pharmacokinetics, a narrow therapeutic index, and metabolically based drug-drug interactions. Although it is well established that CYP2C9 is the major cytochrome P450 enzyme controlling metabolic elimination of phenytoin through its oxidative conversion to (S)-5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), nothing is known about the amino acid binding determinants within the CYP2C9 active site that promote metabolism and maintain the tight stereocontrol of hydroxy metabolite formation. This knowledge gap was addressed here through the construction of nine active site mutants at amino acid positions Phe100, Arg108, Phe114, Leu208, and Phe476 and in vitro analysis of the steady-state kinetics and stereochemistry of p-HPPH formation. The F100L and F114W mutants exhibited 4- to 5-fold increases in catalytic efficiency, whereas the F100W, F114L, F476L, and F476W mutants lost >90% of their phenytoin hydroxylation capacity. This pattern of effects differs substantially from that found previously for (S)-warfarin and (S)-flurbiprofen metabolism, suggesting that these three ligands bind within discrete locations in the CYP2C9 active site. Only the F114L, F476L, and L208V mutants altered phenytoin's orientation during catalytic turnover. The L208V mutant also uniquely demonstrated enhanced 6-hydroxylation of (S)-warfarin. These latter data provide the first experimental evidence for a role of the F-G loop region in dictating the catalytic orientation of substrates within the CYP2C9 active site. PMID:19258521

Prediction of Rate Constant for Supramolecular Systems with Multiconfigurations.

PubMed

Guo, Tao; Li, Haiyan; Wu, Li; Guo, Zhen; Yin, Xianzhen; Wang, Caifen; Sun, Lixin; Shao, Qun; Gu, Jingkai; York, Peter; Zhang, Jiwen

2016-02-25

The control of supramolecular systems requires a thorough understanding of their dynamics, especially on a molecular level. It is extremely difficult to determine the thermokinetic parameters of supramolecular systems, such as drug-cyclodextrin complexes with fast association/dissociation processes by experimental techniques. In this paper, molecular modeling combined with novel mathematical relationships integrating the thermodynamic/thermokinetic parameters of a series of isomeric multiconfigurations to predict the overall parameters in a range of pH values have been employed to study supramolecular dynamics at the molecular level. A suitable form of Eyring's equation was derived and a two-stage model was introduced. The new approach enabled accurate prediction of the apparent dissociation/association (k(off)/k(on)) and unbinding/binding (k-r/kr) rate constants of the ubiquitous multiconfiguration complexes of the supramolecular system. The pyronine Y (PY) was used as a model system for the validation of the presented method. Interestingly, the predicted k(off) value ((40 ± 1) × 10(5) s(-1), 298 K) of PY is largely in agreement with that previously determined by fluorescence correlation spectroscopy ((5 ± 3) × 10(5) s(-1), 298 K). Moreover, the k(off)/k(on) and k-r/kr for flurbiprofen-β-cylcodextrin and ibuprofen-β-cyclodextrin systems were also predicted and suggested that the association processes are diffusion-controlled. The methodology is considered to be especially useful in the design and selection of excipients for a supramolecular system with preferred association and dissociation rate constants and understanding their mechanisms. It is believed that this new approach could be applicable to a wide range of ligand-receptor supramolecular systems and will surely help in understanding their complex mechanism.

Management of postoperative inflammation after cataract and complex ocular surgeries: a systematic review and Delphi survey.

PubMed

Aptel, Florent; Colin, Cyrille; Kaderli, Sema; Deloche, Catherine; Bron, Alain M; Stewart, Michael W; Chiquet, Christophe

2017-11-01

Prevention and management of postoperative ocular inflammation with corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) have been evaluated in several randomised controlled trials (RCTs). However, neither consensus regarding the efficacies of different regimens nor established guidelines are currently available. This has resulted in different practice patterns throughout the world. A systematic literature review found that for the management of postcataract inflammation nepafenac produced a positive outcome in three of three RCTs (3/3), as did ketorolac (1/1), bromfenac (7/7), loteprednol (3/3) and difluprednate (6/6), but not flurbiprofen (0/1). A single study found that betamethasone produced inconclusive results after retinal detachment (RD) surgery; ketorolac was effective (1/1) after vitrectomy, but triamcinolone was ineffective (0/1) after trabeculectomy. A two-round Delphi survey asked 28 international experts to rate both the inflammatory potential of different eye surgeries and their agreement with different treatment protocols. They rated trabeculectomy, RD surgery and combined phacovitrectomy as more inflammatory than cataract surgery. Vitrectomies for macular hole or epiretinal membrane were not deemed more inflammatory than cataract surgery. For trabeculectomy, they preferred to treat longer than for cataract surgery (NSAID + corticosteroid three times a day for 2 months vs 1 month). For vitrectomy alone, RD surgery and combined phacovitrectomy, the panel preferred the same treatment as for cataract surgery (NSAID + corticosteroid three times a day for 1 month). The discrepancy between preferred treatment and perception of the eye's inflammatory status by the experts for RD and combined vitreoretinal surgeries highlights the need for RCTs to establish treatment guidelines. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Non-steroidal anti-inflammatory drugs and gastroprotection with proton pump inhibitors: a focus on ketoprofen/omeprazole.

PubMed

Gigante, Antonio; Tagarro, Ignacio

2012-04-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed agents for rheumatic disorders such as osteoarthritis (OA), rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Despite the known association between NSAID use and gastropathy, however, only around one-third of patients at risk of NSAID-induced gastrointestinal toxicity receive adequate gastroprotection, and as many as 44% of these patients are non-adherent. We review the co-prescription of proton pump inhibitors (PPIs) for the prevention of NSAID-induced gastropathy, with a particular focus on the first fixed-dose NSAID/PPI formulation: ketoprofen/omeprazole modified-release capsules. The ketoprofen/omeprazole fixed-dose combination is available in doses of 100 mg/20 mg, 150 mg/20 mg or 200 mg/20 mg as a single capsule for once-daily administration. Ketoprofen monotherapy has been shown to be generally equivalent to other NSAIDs when used in the treatment of OA. In RA, ketoprofen has demonstrated equivalent efficacy to diclofenac, indometacin, piroxicam, aceclofenac, phenylbutazone, naproxen and flurbiprofen. Studies comparing ketoprofen with ibuprofen and sulindac in patients with RA have, in general, favoured ketoprofen. Studies in AS have generally reported similar efficacy between ketoprofen and phenylbutazone and pirprofen. Prophylaxis with omeprazole is effective for the prevention of gastroduodenal ulcers, maintenance of remission and alleviation of dyspeptic symptoms in NSAID recipients. Omeprazole is well tolerated, and adverse events are generally gastrointestinal in nature. The fixed-dose combination of ketoprofen and omeprazole has demonstrated bioequivalence to the respective monotherapies. The incidence of digestive symptoms and the need for dose reduction was reported to be lower with the combination than with its components. Ketoprofen/omeprazole modified-release capsules are the first fixed-dose NSAID/PPI formulation to be approved. This formulation ensures compliance with the gastroprotective prophylaxis, as whenever the NSAID is taken, the PPI is co-administered. Additionally, the once-daily formulation has the potential to improve adherence to anti-inflammatory therapy. © 2012 Adis Data Information BV. All rights reserved.

In Vivo and In Vitro Toxicodynamic Analyses of New Quinolone-and Nonsteroidal Anti-Inflammatory Drug-Induced Effects on the Central Nervous System

PubMed Central

Kita, Hideki; Matsuo, Hirotami; Takanaga, Hitomi; Kawakami, Junichi; Yamamoto, Koujirou; Iga, Tatsuji; Naito, Mikihiko; Tsuruo, Takashi; Asanuma, Atsushi; Yanagisawa, Keiji; Sawada, Yasufumi

1999-01-01

We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the γ-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 μM) > FRP (0.3 μM) > FLB (0.2 μM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model. PMID:10223919

Oxidative stress mediates through apoptosis the anticancer effect of phospho-nonsteroidal anti-inflammatory drugs: implications for the role of oxidative stress in the action of anticancer agents.

PubMed

Sun, Yu; Huang, Liqun; Mackenzie, Gerardo G; Rigas, Basil

2011-09-01

We assessed the relationship between oxidative stress, cytokinetic parameters, and tumor growth in response to novel phospho-nonsteroidal anti-inflammatory drugs (NSAIDs), agents with significant anticancer effects in preclinical models. Compared with controls, in SW480 colon and MCF-7 breast cancer cells, phospho-sulindac, phospho-aspirin, phospho-flurbiprofen, and phospho-ibuprofen (P-I) increased the levels of reactive oxygen and nitrogen species (RONS) and decreased GSH levels and thioredoxin reductase activity, whereas the conventional chemotherapeutic drugs (CCDs), 5-fluorouracil (5-FU), irinotecan, oxaliplatin, chlorambucil, paclitaxel, and vincristine, did not. In both cell lines, phospho-NSAIDs induced apoptosis and inhibited cell proliferation much more potently than CCDs. We then treated nude mice bearing SW480 xenografts with P-I or 5-FU that had an opposite effect on RONS in vitro. Compared with controls, P-I markedly suppressed xenograft growth, induced apoptosis in the xenografts (8.9 ± 2.7 versus 19.5 ± 3.0), inhibited cell proliferation (52.6 ± 5.58 versus 25.8 ± 7.71), and increased urinary F2-isoprostane levels (10.7 ± 3.3 versus 17.9 ± 2.2 ng/mg creatinine, a marker of oxidative stress); all differences were statistically significant. 5-FU's effects on tumor growth, apoptosis, proliferation, and F2-isoprostane were not statistically significant. F2-isoprostane levels correlated with the induction of apoptosis and the inhibition of cell growth. P-I induced oxidative stress only in the tumors, and its apoptotic effect was restricted to xenografts. Our data show that phospho-NSAIDs act against cancer through a mechanism distinct from that of various CCDs, underscore the critical role of oxidative stress in their effect, and indicate that pathways leading to oxidative stress may be useful targets for anticancer strategies.

Carprofen induction of p75NTR-dependent apoptosis via the p38 mitogen-activated protein kinase pathway in prostate cancer cells.

PubMed

Khwaja, Fatima S; Quann, Emily J; Pattabiraman, Nagarajan; Wynne, Shehla; Djakiew, Daniel

2008-11-01

The p75 neurotrophin receptor (p75(NTR)) functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75(NTR) expression in several prostate cancer cell lines leading to p75(NTR)-mediated decreased survival. Using the 2-phenyl propionic acid moiety of these profens as a pharmacophore, we screened an in silico database of 30 million compounds and identified carprofen as having an order of magnitude greater activity for induction of p75(NTR) levels and inhibition of cell survival. Prostate (PC-3 and DU-145) and bladder (T24) cancer cells were more sensitive to carprofen induction of p75(NTR)-associated loss of survival than breast (MCF-7) and fibroblast (3T3) cells. Transfection of prostate cell lines with a dominant-negative form of p75(NTR) before carprofen treatment partially rescued cell survival, showing a cause-and-effect relationship between carprofen induction of p75(NTR) levels and inhibition of survival. Carprofen induced apoptotic nuclear fragmentation in prostate but not in MCF-7 and 3T3 cells. Furthermore, small interfering RNA knockdown of the p38 mitogen-activated protein kinase (MAPK) protein prevented induction of p75(NTR) by carprofen in both prostate cell lines. Carprofen treatment induced phosphorylation of p38 MAPK as early as within 1 min. Expression of a dominant-negative form of MK2, the kinase downstream of p38 MAPK frequently associated with signaling cascades leading to apoptosis, prevented carprofen induction of the p75(NTR) protein. Collectively, we identify carprofen as a highly potent profen capable of inducing p75(NTR)-dependent apoptosis via the p38 MAPK pathway in prostate cancer cells.

Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation.

PubMed

Hosoi, Yoshio; Uno, Yasuhiro; Murayama, Norie; Fujino, Hideki; Shukuya, Mitsunori; Iwasaki, Kazuhide; Shimizu, Makiko; Utoh, Masahiro; Yamazaki, Hiroshi

2012-12-15

Cynomolgus monkeys are widely used as primate models in preclinical studies. However, some differences are occasionally seen between monkeys and humans in the activities of cytochrome P450 enzymes. R- and S-warfarin are model substrates for stereoselective oxidation in humans. In this current research, the activities of monkey liver microsomes and 14 recombinantly expressed monkey cytochrome P450 enzymes were analyzed with respect to R- and S-warfarin 6- and 7-hydroxylation. Monkey liver microsomes efficiently mediated both R- and S-warfarin 7-hydroxylation, in contrast to human liver microsomes, which preferentially catalyzed S-warfarin 7-hydroxylation. R-Warfarin 7-hydroxylation activities in monkey liver microsomes were not inhibited by α-naphthoflavone or ketoconazole, and were roughly correlated with P450 2C19 levels and flurbiprofen 4-hydroxylation activities in microsomes from 20 monkey livers. In contrast, S-warfarin 7-hydroxylation activities were not correlated with the four marker drug oxidation activities used. Among the 14 recombinantly expressed monkey P450 enzymes tested, P450 2C19 had the highest activities for R- and S-warfarin 7-hydroxylations. Monkey P450 3A4 and 3A5 slowly mediated R- and S-warfarin 6-hydroxylations. Kinetic analysis revealed that monkey P450 2C19 had high V(max) and low K(m) values for R-warfarin 7-hydroxylation, comparable to those for monkey liver microsomes. Monkey P450 2C19 also mediated S-warfarin 7-hydroxylation with V(max) and V(max)/K(m) values comparable to those for recombinant human P450 2C9. R-warfarin could dock favorably into monkey P450 2C19 modeled. These results collectively suggest high activities for monkey liver P450 2C19 toward R- and S-warfarin 6- and 7-hydroxylation in contrast to the saturation kinetics of human P450 2C9-mediated S-warfarin 7-hydroxylation. Copyright © 2012 Elsevier Inc. All rights reserved.

In vitro Inhibitory Effect of Gymnema sylvestre Extracts and Total Gymnemic Acids Fraction on Select Cytochrome P450 Activities in Rat Liver Microsomes.

PubMed

Vaghela, Madhuri; Iyer, Krishna; Pandita, Nancy

2018-04-01

Gymnema sylvestre R. Br. is a well-known Indian medicinal herb. Gymnemic acids are pentacyclic triterpenes saponins and active phytoconstituents of Gymnema sylvestre. The study aimed at evaluation of the in vitro rat liver cytochrome P450 (CYP) inhibition potential of extracts and total gymnemic acid (TA)-enriched fractions from G. sylvestre. Standardization of G. sylvestre [ethanolic (EL), hydroethanolic (HE), total acid of ethanolic (TAE), total acid of hydroethanolic (TAHE) and total acid of aqueous (TAAQ) extract] was done with respect to deacyl gymnemic acid (DAGA), using reverse phase-high performance liquid chromatography (RP-HPLC). Total triterpenoid content was determined by vanillin perchloric acid assay. Total triterpene content was found to be the highest in TAAQ (59.86 ± 0.005% w/w) and TAE (49.77 ± 0.009% w/w). TAAQ showed IC 50  ≤ 50 µg/ml for all selected CYP activities. Testosterone 6β-hydroxylation was strongly inhibited by TAE (IC 50 : 15.48 ± 2.13 µg/ml) and was moderately by TAAQ and EL with IC 50  ≥ 50 µg/ml. Flurbiprofen 4'-hydroxylation was subject to strong, weak and moderate inhibition by TAAQ (IC 50 : 34.67 ± 1.38 µg/ml), TAE (IC 50 : ≥ 50 µg/ml) and EL (IC 50 : > 50 µg/ml), respectively. Dextromethorphan O-demethylation was inhibited by TAHE and TAAQ. In vitro inhibition studies suggested that TA strongly inhibits activity of selected CYP. This inhibition may possibly be due to triterpenoids and gymnemic acids that have been reported to be present in it. Data also suggest a potential for possible in vivo herb-drug interactions involving G. sylvestre and other medications that are metabolized by the same CYP.

Coordination Polymers Derived from Non-Steroidal Anti-Inflammatory Drugs for Cell Imaging and Drug Delivery.

PubMed

Paul, Mithun; Dastidar, Parthasarathi

2016-01-18

A new series of Mn(II) coordination polymers, namely, [{Mn(L)(H2 O)2 }⋅2 Nap]∞ (CP1), [{Mn(L)(Ibu)2 (H2 O)2 }]∞ (CP2), [{Mn(L)(Flr)2 (H2 O)2 }]∞ (CP3), [{Mn(L)(Ind)2 (H2 O)2 }⋅H2 O]∞ (CP4), [{Mn2 (L)2 (μ-Flu)4 (H2 O)}⋅L]∞ (CP5), [{Mn2 (L)2 (μ-Tol)4 (H2 O)2 }]∞ (CP6) and [{Mn2 (L)2 (μ-Mef)4 (H2 O)2 }]∞ (CP7) (Nap=naproxen, Ibu=ibuprofen, Flr=flurbiprofen, Ind=indometacin, Flu=flufenamic acid, Tol=tolfenamic acid and Mef=mefenamic acid) derived from various non-steroidal anti-inflammatory drugs (NSAIDs) and the organic linker 1,2-bis(4-pyridyl)ethylene (L) have been synthesized with the aim of being used for cell imaging and drug delivery. Single-crystal X-ray diffraction (SXRD) studies revealed that the NSAID molecules were part of the coordination polymeric network either through coordination to the metal center (in the majority of the cases) or through hydrogen bonding. Remarkably, all the Mn(II) coordination polymers were found to be soluble in DMSO, thereby making them particularly suitable for the desired biological applications. Two of the coordination polymers (namely, CP1 and CP3) reported herein, were found to be photoluminescent both in the solid as well as in the solution state. Subsequent experiments (namely, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and PGE2 (prostaglandin E2 ) assays) established their biocompatibility and anti-inflammatory response. In vitro studies by using a macrophage cell line (i.e., RAW 264.7) revealed that both CP1 and CP3 were excellent cell imaging agents. Finally, biodegradability studies under simulated physiological conditions in phosphate-buffered saline (PBS) at pH 7.6 showed that slow and sustained release of the corresponding NSAID was indeed possible from both CP1 and CP3. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells.

PubMed

Uchida, Yasuo; Ito, Katsuaki; Ohtsuki, Sumio; Kubo, Yoshiyuki; Suzuki, Takashi; Terasaki, Tetsuya

2015-07-01

The purpose of this study was to clarify the expression of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) and its contribution to the supply of biotin and pantothenic acid to the human brain via the blood-brain barrier. DNA microarray and immunohistochemical analyses confirmed that SLC5A6 is expressed in microvessels of human brain. The absolute expression levels of SLC5A6 protein in isolated human and monkey brain microvessels were 1.19 and 0.597 fmol/μg protein, respectively, as determined by a quantitative targeted absolute proteomics technique. Using an antibody-free method established by Kubo et al. (2015), we found that SLC5A6 was preferentially localized at the luminal membrane of brain capillary endothelium. Knock-down analysis using SLC5A6 siRNA showed that SLC5A6 accounts for 88.7% and 98.6% of total [(3) H]biotin and [(3) H]pantothenic acid uptakes, respectively, by human cerebral microvascular endothelial cell line hCMEC/D3. SLC5A6-mediated transport in hCMEC/D3 was markedly inhibited not only by biotin and pantothenic acid, but also by prostaglandin E2, lipoic acid, docosahexaenoic acid, indomethacin, ketoprofen, diclofenac, ibuprofen, phenylbutazone, and flurbiprofen. This study is the first to confirm expression of SLC5A6 in human brain microvessels and to provide evidence that SLC5A6 is a major contributor to luminal uptake of biotin and pantothenic acid at the human blood-brain barrier. In humans, it was unclear (not concluded) about what transport system at the blood-brain barrier (BBB) is responsible for the brain uptakes of two vitamins, biotin and pantothenic acid, which are necessary for brain proper function. This study clarified for the first time that the solute carrier 5A6/Na(+) -dependent multivitamin transporter SLC5A6/SMVT is responsible for the supplies of biotin and pantothenic acid into brain across the BBB in humans. DHA, docosahexaenoic acid; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2. © 2015 International Society for Neurochemistry.

Risk of new acute myocardial infarction hospitalization associated with use of oral and parenteral non-steroidal anti-inflammation drugs (NSAIDs): a case-crossover study of Taiwan's National Health Insurance claims database and review of current evidence.

PubMed

Shau, Wen-Yi; Chen, Hsi-Chieh; Chen, Shu-Ting; Chou, Hsu-Wen; Chang, Chia-Hsuin; Kuo, Chuei-Wen; Lai, Mei-Shu

2012-02-02

Previous studies have documented the increased cardiovascular risk associated with the use of some nonsteroidal anti-inflammatory drugs (NSAIDs). Despite this, many old NSAIDs are still prescribed worldwide. Most of the studies to date have been focused on specific oral drugs or limited by the number of cases examined. We studied the risk of new acute myocardial infarction (AMI) hospitalization with current use of a variety of oral and parenteral NSAIDs in a nationwide population, and compared our results with existing evidence. We conducted a case-crossover study using the Taiwan's National Health Insurance claim database, identifying patients with new AMI hospitalized in 2006. The 1-30 days and 91-120 days prior to the admission were defined as case and matched control period for each patient, respectively. Uses of NSAIDs during the respective periods were compared using conditional logistic regression and adjusted for use of co-medications. 8354 new AMI hospitalization patients fulfilled the study criteria. 14 oral and 3 parenteral NSAIDs were selected based on drug utilization profile among 13.7 million NSAID users. The adjusted odds ratio, aOR (95% confidence interval), for risk of AMI and use of oral and parenteral non-selective NSAIDs were 1.42 (1.29, 1.56) and 3.35 (2.50, 4.47), respectively, and significantly greater for parenteral than oral drugs (p for interaction<0.01). Ketorolac was associated with the highest AMI risk among both of oral and parenteral NSAIDs studied, the aORs were 2.02 (1.00, 4.09) and 4.27 (2.90, 6.29) respectively. Use of oral flurbiprofen, ibuprofen, sulindac, diclofenac, and parenteral ketoprofen were also significantly associated with increased AMI risk. The results of the present study were consistent with the majority of evidence from previous studies. The collective evidence revealed the tendency of increased AMI risk with current use of some NSAIDs. A higher AMI risk associated with use of parenteral NSAIDs was observed in the present study. Ketorolac had the highest associated risk in both oral and parenteral NSAIDs studied. Though further investigation to confirm the association is warranted, prescribing physicians and the general public should be cautious about the potential risk of AMI when using NSAIDs.

Single dose dipyrone for acute postoperative pain

PubMed Central

Derry, Sheena; Faura, Clara; Edwards, Jayne; McQuay, Henry J; Moore, R Andrew

2014-01-01

Background Dipyrone (metamizole) is a non-steroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in others because of an association with life-threatening blood agranulocytosis. This review updates a 2001 Cochrane review, and no relevant new studies were identified, but additional outcomes were sought. Objectives To assess the efficacy and adverse events of single dose dipyrone in acute postoperative pain. Search methods The earlier review searched CENTRAL, MEDLINE, EMBASE, LILACS and the Oxford Pain Relief Database to December 1999. For the update we searched CENTRAL, MEDLINE,EMBASE and LILACS to February 2010. Selection criteria Single dose, randomised, double-blind, placebo or active controlled trials of dipyrone for relief of established moderate to severe postoperative pain in adults. We included oral, rectal, intramuscular or intravenous administration of study drugs. Data collection and analysis Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR) was used to calculate the number of participants achieving at least 50% pain relief. Derived results were used to calculate, with 95% confidence intervals, relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Use and time to use of rescue medication were additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g intravenous dipyrone (101), 2.5 g intramuscular dipyrone (99); fewer than 60 participants received any other dose. All studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, pethidine, tramadol, suprofen); eight used placebo controls. Over 70% of participants experienced at least 50% pain relief over 4 to 6 hours with oral dipyrone 500 mg compared to 30% with placebo in five studies (288 participants; NNT 2.4 (1.9 to 3.2)). Fewer participants needed rescue medication with dipyrone (7%) than with placebo (34%; four studies, 248 participants). There was no difference in participants experiencing at least 50% pain relief with 2.5 g intravenous dipyrone and 100 mg intravenous tramadol (70% vs 65%; two studies, 200 participants). No serious adverse events were reported. Authors’ conclusions Based on very limited information, single dose dipyrone 500 mg provides good pain relief to 70% of patients. For every five individuals given dipyrone 500 mg, two would experience this level of pain relief who would not have done with placebo, and fewer would need rescue medication, over 4 to 6 hours. PMID:20824835

Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions.

PubMed

Wakai, Abel; Lawrenson, John G; Lawrenson, Annali L; Wang, Yongjun; Brown, Michael D; Quirke, Michael; Ghandour, Omar; McCormick, Ryan; Walsh, Cathal D; Amayem, Ahmed; Lang, Eddy; Harrison, Nick

2017-05-18

Traumatic corneal abrasions are relatively common and there is a lack of consensus about analgesia in their management. It is therefore important to document the clinical efficacy and safety profile of topical ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs) in the management of traumatic corneal abrasions. To identify and evaluate all randomised controlled trials (RCTs) comparing the use of topical NSAIDs with placebo or any alternative analgesic interventions in adults with traumatic corneal abrasions (including corneal abrasions arising from foreign body removal), to reduce pain, and its effects on healing time. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 2), MEDLINE Ovid (1946 to 30 March 2017), Embase Ovid (1947 to 30 March 2017), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 30 March 2017), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/); searched 30 March 2017, ZETOC (1993 to 30 March 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 30 March 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 30 March 2017 and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 30 March 2017. We did not use any date or language restrictions in the electronic searches for trials.We checked the reference lists of identified trials to search for further potentially relevant studies. RCTs comparing topical NSAIDs to placebo or any alternative analgesic interventions in adults with traumatic corneal abrasions. Two review authors independently performed data extraction and assessed risks of bias in the included studies. We rated the certainty of the evidence using GRADE. We included nine studies that met the inclusion criteria, reporting data on 637 participants.The studies took place in the UK, USA, Israel, Italy, France and Portugal. These studies compared five types of topical NSAIDs (0.1% indomethacin, 0.03% flurbiprofen, 0.5% ketorolac, 1% indomethacin, 0.1% diclofenac) to control (consisting of standard care and in four studies used placebo eye drops). Overall, the studies were at an unclear or high risk of bias (particularly selection and reporting bias). None of the included studies reported the primary outcome measures of this review, namely participant-reported pain intensity reduction of 30% or more or 50% or more at 24 hours. Four trials, that included data on 481 participants receiving NSAIDs or control (placebo/standard care), reported on the use of 'rescue' analgesia at 24 hours as a proxy measure of pain control. Topical NSAIDs were associated with a reduction in the need for oral analgesia compared with control (risk ratio (RR) 0.46, 95% confidence interval (CI) 0.34 to 0.61; low-certainty evidence). Approximately 4 out of 10 people in the control group used rescue analgesia at 24 hours. No data were available on the use of analgesia at 48 or 72 hours.One trial (28 participants) reported on the proportion of abrasions healed after 24 and 48 hours. These outcomes were similar in both arms of the trial. (at 24 hours RR 1.00 (0.81 to 1.23); at 48 hours RR 1.00 (0.88 to 1.14); low-certainty evidence). In the control group nine out of 10 abrasions were healed within 24 hours and all were healed by 48 hours. Complications of corneal abrasions were reported in 6 studies (609 participants) and were infrequently reported (4 complications, 1 in NSAID groups (recurrent corneal erosion) and 3 in control groups (2 recurrent corneal erosions and 1 corneal abscess), very low-certainty evidence). Possible drug-related adverse events (AEs) were reported in two trials (163 participants), with the number of adverse events low (4 AEs, 3 in NSAID group, including discomfort/photophobia on instillation, conjunctival hyperaemia and urticaria, and 1 in the control group, corneal abscess) very low-certainty evidence. The findings of the included studies do not provide strong evidence to support the use of topical NSAIDs in traumatic corneal abrasions. This is important, since NSAIDs are associated with a higher cost compared to oral analgesics. None of the trials addressed our primary outcome measure of participant-reported pain intensity reduction of 30% or more or 50% or more at 24 hours.