A report of two deaths from massive ibuprofen ingestion.

J Med Toxicol. 2007 Jun;3(2):52-5

Authors: Holubek W, Stolbach A, Nurok S, Lopez O, Wetter A, Nelson L

INTRODUCTION: Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. While the vast majority of exposures to the drug do not result in significant morbidity, we are reporting 2 fatalities that resulted from massive ibuprofen ingestion. CASE 1: A 17-year-old girl presented to the emergency department (ED) following an ibuprofen overdose; she was unresponsive with a metabolic acidosis and hypothermic. Her serum ibuprofen concentration was 352 microg/mL: the therapeutic range is 10-50 microg/mL. Despite intensive supportive care and continuous veno-venous hemofiltration, she expired. CASE 2: A 49-year-old man presents to the ED with a history of divalproex sodium and ibuprofen ingestion. He was unresponsive, hypotensive, and had a significant metabolic acidosis. His serum ibuprofen concentration was 260 microg/mL and serum valproate concentration was 560 microg/mL: the therapeutic range is 50-100 microg/mL. In spite of supportive care and hemodialysis, he expired. DISCUSSION: We will describe 2 cases of ibuprofen overdose characterized by cardiovascular collapse, acidosis, and hypothermia despite the use of vasopressors and renal replacement therapy. Although rarely reported, massive ibuprofen overdose may result in refractory multisystem organ failure and death.

PMID: 18072160 [PubMed - in process]

Use of neostigmine for the management of drug induced ileus in severe poisonings.

J Med Toxicol. 2005 Dec;1(1):18-22

Authors: Chan B, Whyte I, Dawson A, Downes M

Effective whole bowel irrigation may be difficult in the presence of drug-induced ileus. Neostigmine, which inhibits the enzymatic degradation of acetylcholine, has been suggested to improve drug-induced ileus. We present two poisoning cases in which neostigmine was used to facilitate gut decontamination complicated by ileus. Case Reports: A 47-year-old woman, after overdose with sodium valproate, venlafaxine, and ibuprofen, developed ileus that prevented whole bowel irrigation. Neostigmine, 2.5 mg intravenously followed by 1.25 mg three hours later, led to improved bowel transit and successful whole bowel irrigation. A 25-year-old man developed ileus after overdose with venlafaxine, dothiepin, and ethanol. Neostigmine administration led to improved intestinal motility and successful whole bowel irrigation. Discussion: We demonstrate facilitated gut decontamination temporally associated with administration of neostigmine in two patients judged to have drug-induced ileus following overdose. No significant adverse events related to neostigmine were observed.

PMID: 18072098 [PubMed - in process]

Synthesis, pharmacological activity and hydrolytic behavior of ethylenediamine and benzathine conjugates of ibuprofen.

Eur J Med Chem. 2007 Dec 6;

Authors: Chatterjee NR, Kulkarni AA, Ghulekar SP

For reducing the gastrointestinal toxicity associated with ibuprofen, its carboxylic group was masked by synthesizing its amide conjugates with ethylenediamine and benzathine (4a, 4b, respectively) by carbodiimide assisted coupling method. In vitro hydrolysis of conjugates showed that they were stable in HCl buffer (pH 1.2) indicating that the prodrugs did not break in stomach and there was no release of ibuprofen at gastric pH, whereas in phosphate buffer (pH 7.4) they undergo significant hydrolysis and thus release ibuprofen in adequate amounts following first order kinetics. The ibuprofen conjugates 4a, 4b were retaining anti-inflammatory activity intact and exhibited better analgesic activity along with much reduced ulcerogenicity. These findings suggested that both the conjugates are better in action as compared to parent drug and are advantageous in having less gastrointestinal side effects. Compound 4b however showed better analgesic activity and longer action (t(1/2)) than 4a, and hence it could be considered as a better candidate for prodrug among the two.

PMID: 18068271 [PubMed - as supplied by publisher]

Environmental assessment of Norwegian priority pharmaceuticals based on the EMEA guideline.

Ecotoxicol Environ Saf. 2007 Dec 6;

Authors: Grung M, Källqvist T, Sakshaug S, Skurtveit S, Thomas KV

An environmental risk assessment of eleven pharmaceuticals according to the guideline recommended by the European Medicines Evaluation Agency (EMEA) was performed. Cefuroxime, ciprofloxacin, cyclophosphamide, diclofenac, ethinylestradiol, ibuprofen, metoprolol, paracetamol, sulfamethoxazole, tetracycline and trimethoprim were selected for assessment by the Norwegian Pollution Control Authority. Predicted environmental concentrations (PECs) were calculated according to both the EMEA guideline and a conventional model for comparison and ranged from 0.0002 to 45mug/L. Available acute and chronic toxicity data were collected from the literature, although no data were available for cyclophosphamide. Toxicity tests showed cyclophosphamide to have relatively low acute toxicity with an EC50 for Pseudokirchneriella subcapitata >100mg/L and a Daphnia magna reproduction NOEC of 56mg/L. These and the literature data were used to derive predicted no effect concentrations (PNEC). Risk quotients (PEC/PNEC) were then calculated for all 11 pharmaceutical compounds. Risk quotients greater than 1 were obtained for ciprofloxacin, diclofenac, ethinylestradiol, sulfamethoxazole and tetracycline according to the EMEA guideline. Measured environmental concentrations (MECs) confirmed that the release of ciprofloxacin from wastewater treatment works may potentially be of environmental concern in Norway.

PMID: 18068226 [PubMed - as supplied by publisher]

Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study.

BMJ. 2007 Dec 4;

Authors: Underwood M, Ashby D, Cross P, Hennessy E, Letley L, Martin J, Mt-Isa S, Parsons S, Vickers M, Whyte K,

OBJECTIVE: To determine whether older patients with chronic knee pain should be advised to use topical or oral non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: Randomised controlled trial and patient preference study. SETTING: 26 general practices. PARTICIPANTS: People aged >/=50 with knee pain: 282 in randomised trial and 303 in preference study. INTERVENTIONS: Advice to use topical or oral ibuprofen. Primary outcome measures WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, major and minor adverse effects. RESULTS: Changes in global WOMAC scores at 12 months were equivalent. In the randomised trial the difference (topical minus oral) was two points (95% confidence interval -2 to 6); in the preference study, it was one point (-4 to 6). There were no differences in major adverse effects in the trial or study. The only significant differences in secondary outcomes were in the randomised trial. The oral group had more respiratory adverse effects (17% v 7%,95% confidence interval for difference -17% to -2%), the change in serum creatinine was 3.7 mmol/l less favourable (0.9 micromol/l to 6.5 micromol/l); and more participants changed treatments because of adverse effects (16% v 1%, -16% to -5%). In the topical group more participants had chronic pain grade III or IV at three months, and more participants changed treatment because of ineffectiveness. CONCLUSIONS: Advice to use oral or topical preparations has an equivalent effect on knee pain over one year, and there are more minor side effects with oral NSAIDs. Topical NSAIDs may be a useful alternative to oral NSAIDs. Trial registration ISRCTN 79353052.

PMID: 18056743 [PubMed - as supplied by publisher]

Influences on older people's decision making regarding choice of topical or oral NSAIDs for knee pain: qualitative study.

BMJ. 2007 Dec 4;

Authors: Carnes D, Anwer Y, Underwood M, Harding G, Parsons S,

OBJECTIVE: To explore the factors that influence older people's decision making regarding use of topical or oral ibuprofen for their knee pain. DESIGN: Qualitative interview study nested within a randomised controlled trial and a patient preference study that compared advice to use oral or topical non-steroidal anti-inflammatory drugs (NSAIDs) for knee pain in older people. SETTING: 11 general practices. PARTICIPANTS: 30 people aged >/=50 with knee pain. RESULTS: Participants' decision making was influenced by their perceptions of the associated risk of adverse effects, presence of other illness, nature of their pain, advice received, and practicality. Although participants' understanding of how the medications worked was sometimes poor their decision making about the use of NSAIDs seemed logical and appropriate. Participants' model for treatment was to use topical NSAIDs for mild, local, and transient pain and oral NSAIDs for moderate to severe, generalised, and constant pain (in the absence of other more serious illness or risk of adverse effects). Participants showed marked tolerance and normalisation of adverse effects. CONCLUSION: Participants had clear ideas about the appropriate use of oral and topical NSAIDs. Taking such views into account when prescribing may improve adherence, judgment of efficacy, and the doctor-patient relationship. Tolerance and normalisation of adverse effects in these patients indicate that closer monitoring of older people who use NSAIDs might be needed.

PMID: 18056742 [PubMed - as supplied by publisher]

The p38 MAPK pathway mediates aryl propionic acid induced messenger rna stability of p75 NTR in prostate cancer cells.

Cancer Res. 2007 Dec 1;67(23):11402-10

Authors: Quann EJ, Khwaja F, Djakiew D

The p75(NTR) acts as a tumor suppressor in the prostate, but its expression is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines such as PC-3, DU-145, and LNCaP. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75(NTR) expression in PC-3 and DU-145 cells leading to p75(NTR)-mediated decreased survival. Here, we investigate the mechanism by which these drugs induce p75(NTR) expression. We show that the observed increase in p75(NTR) protein due to R-flurbiprofen and ibuprofen treatment was accompanied by an increase in p75(NTR) mRNA, and this increase in mRNA was the result of increased mRNA stability and not by an up-regulation of transcription. In addition, we show that treatment with R-flurbiprofen or ibuprofen led to sustained activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Furthermore, inhibition of the p38 MAPK pathway with the p38 MAPK-specific inhibitor SB202190 or by small interfering RNA (siRNA) knockdown of p38 MAPK protein prevented induction of p75(NTR) by R-flurbiprofen and ibuprofen. We also observed that siRNA knockdown of MAPK-activated protein kinase (MK)-2 and MK3, the kinases downstream of p38 MAPK that are responsible for the mRNA stabilizing effects of the p38 MAPK pathway, also prevented an induction of p75(NTR) by R-flurbiprofen and ibuprofen. Finally, we identify the RNA stabilizing protein HuR and the posttranscriptional regulator eukaryotic translation initiation factor 4E as two possible mechanisms by which the p38 MAPK pathway may increase p75(NTR) expression. Collectively, the data suggest that R-flurbiprofen and ibuprofen induce p75(NTR) expression by increased mRNA stability that is mediated through the p38 MAPK pathway.

PMID: 18056468 [PubMed - in process]

PLGA-based drug delivery systems: Importance of the type of drug and device geometry.

Int J Pharm. 2007 Oct 30;

Authors: Klose D, Siepmann F, Elkharraz K, Siepmann J

Different types of ibuprofen- and lidocaine-loaded, poly(lactic-co-glycolic acid) (PLGA)-based microparticles and thin, free films of various dimensions were prepared and physico-chemically characterized in vitro. The obtained experimental results were analyzed using mathematical theories based on Fick's second law of diffusion. Importantly, the initial drug loadings were low in all cases (4%, w/w), simplifying the mathematical treatment and minimizing potential effects of the acidic/basic nature of the two model drugs on polymer degradation. Interestingly, the type of drug and device geometry strongly affected the resulting release kinetics and relative importance of the involved mass transport mechanisms. For instance, the relative release rate was almost unaffected by the system size in the case of spherical microparticles, but strongly depended on the thickness of thin, free films, irrespective of the type of drug. Ibuprofen and lidocaine release was found to be primarily diffusion controlled from the investigated PLGA-based microparticles for all system sizes, whereas diffusion was only dominant in the case of the thinnest free films. Interestingly, the type of drug did not significantly affect the resulting polymer degradation kinetics. However, ibuprofen release was always much faster than lidocaine release for all system geometries and sizes. This can probably be attributed to attractive ionic interactions between protonated, positively charged lidocaine ions and negatively charged, deprotonated carboxylic end groups of PLGA, hindering drug diffusion. The determined apparent diffusion coefficients of the drugs clearly point out that the mobility of an active agent in PLGA-based delivery systems does not only depend on its own physico-chemical properties and the type of PLGA used, but also to a large extent on the size and shape of the device. This has to be carefully taken into account when developing/optimizing this type of advanced drug delivery systems.

PMID: 18055140 [PubMed - as supplied by publisher]

Source to sink tracking of selected human pharmaceuticals from two Oslo city hospitals and a wastewater treatment works.

J Environ Monit. 2007 Dec;9(12):1410-8

Authors: Thomas KV, Dye C, Schlabach M, Langford KH

The occurrence of twenty pharmaceutical compounds was quantitatively determined in effluents from two major Oslo city hospitals, Rikshospitalet and Ullev&#xE5;l, along with influent, sludge and final effluent from the city's VEAS wastewater treatment works (WTW). Composite hospital effluents were collected over a twelve week period and were showed to contain paracetamol, metoprolol, diclofenac, ibuprofen, 17beta-Estradiol, estriol, estrone, oxytetracycline, tetracycline, doxycycline, chlorotetracycline, demeclocycline, trimethoprim, ciprofloxacin, sulfamethoxazole, cyclophosphamide and ifosfamide. Three pharmaceuticals were not detected above the limit of detection; cefuroxime, 17alpha-ethinylestradiol and meclocycline. Composite influent, sludge and effluent samples were collected from VEAS WTW over a seven week period. The influent into VEAS WTW contained all of the same selected substances detected in the hospital effluents, except for oxytetracycline, chlorotetracycline, demeclocycline, cyclophosphamide and ifosfamide. The percentage of pharmaceuticals entering the works from the hospitals was <10% for all of the selected compounds. VEAS sludge samples contained a different profile of substances reflecting their physico-chemical properties. Hydrophobic antibiotics, such as oxytetracycline, tetracycline and ciprofloxacin, were detected in all of the collected sludge samples. Their absence in the collected influent samples suggests that they enter the works bound to effluent particles, with the dissolved fraction observed in the hospital effluents partitioning onto particulate matter within the sewerage network. The final effluent from VEAS WTW contained reduced concentrations of many pharmaceuticals, including paracetamol, ibuprofen and sulfamethoxazole. For other compounds, such as metoprolol, diclofenac and trimethoprim, there were often higher concentrations in the effluent than the influent. These effluent concentrations represent median inputs varying from low g day(-1) (e.g. paracetamol and ibuprofen) to nearly 200 g day(-1) (e.g. metoprolol and trimethoprim) into Oslofjord. A simple risk assessment showed that the antibiotic ciprofloxacin may at times pose an acute risk to the Oslofjord aquatic environment.

PMID: 18049781 [PubMed - in process]

Blunting of the cardiovascular effect of aspirin by ibuprofen: what is the evidence?

Clin Pharmacol Ther. 2007 Nov 28;

Authors: van Westrhenen R, Gispen-de Wied CC, Lekkerkerker JF

PMID: 18043688 [PubMed - as supplied by publisher]

Resonse to Pharmacodynamic interaction between aspirin and ibuprofen: a plausible mechanism of aspirin resistance.

Clin Pharmacol Ther. 2007 Nov 28;

Authors: Patrignani P, Renda G, Tacconelli S, Capone ML, Sacchetta D, Santarelli F, Sciulli MG, Zimarino M, Grana M, D'Amelio E, Zurro M, Patrono C, De Caterina R

PMID: 18043687 [PubMed - as supplied by publisher]

S-Ibuprofen Effectively Inhibits Thromboxane B(2) Levels and Platelet Function in an Experimental Model of Lipopolysaccharide-Stimulated and Non-Stimulated Whole Blood.

Pharmacology. 2007 Nov 28;81(2):181-186

Authors: Kaehler S, Marsik C, Heinisch B, Thallinger C, Sauermann R, Kazemi-Shirazi L, Wagner O, Joukhadar C

Objective: The present study aimed at testing the effect of S- and R-ibuprofen on thromboxane B(2) (TXB(2)), collagen-epinephrine closure time (CEPI-CT) and collagen-adenosine 5'-diphosphate closure time (CADP-CT) in lipopolysaccharide (LPS)-stimulated and non-stimulated human whole blood. Materials and Methods: Whole blood was incubated with S- or R-ibuprofen with and without prior stimulation with LPS. To verify ibuprofen's potential effects on TXB(2), varying ratios of concentrations of S- and R-ibuprofen ranging from 0 to 100% were used. TXB(2) levels were measured by ELISA. The effects of S- and R-ibuprofen enantiomers on platelet aggregability were tested utilizing a PFA-100 apparatus. Results: In non-stimulated and LPS-stimulated whole blood, S-ibuprofen markedly decreased TXB(2) levels at concentrations ranging from 10 to 200 mug/ml. R-ibuprofen showed its inhibiting effect at concentrations >100 mug/ml. In inflammatory and non-inflammatory conditions, CEPI-CT was prolonged at concentrations of 12.5 and 75 mug/ml for S-ibuprofen and at a concentration of 150 mug/ml of combined R- and S-ibuprofen. S-ibuprofen was significantly more effective than R-ibuprofen (p < 0.05). The combined use of S- and R-ibuprofen did not additively or synergistically prolong CEPI-CTs. CADP-CTs remained unaffected by both enantiomers. Conclusions: S-ibuprofen was more effective than the R-ibuprofen enantiomer in inhibiting TXB(2) plasma levels and aggregability of thrombocytes in non-inflammatory and inflammatory conditions. Copyright (c) 2008 S. Karger AG, Basel.

PMID: 18043009 [PubMed - as supplied by publisher]

Millimetre wave therapy for pain relief after total knee arthroplasty: A randomised controlled trial.

Eur J Pain. 2007 Nov 23;

Authors: Usichenko TI, Edinger H, Witstruck T, Pavlovic D, Zach M, Lange J, Gizhko V, Wendt M, Koch B, Lehmann C

Millimetre wave therapy (MWT) is a promising complementary method for pain relief, however rigorous investigations of its effectiveness are needed. The purpose of this study was to examine if MWT can reduce opioid requirement compared to sham procedure applied for relief of acute pain in patients after total knee arthroplasty (TKA). Eighty patients undergoing TKA were randomly assigned to receive MWT or sham procedure. Patients and evaluators were blinded to the group allocation. MWT consisted of six sessions, each session of 30min duration. During each session the knee wound was exposed to electromagnetic waves with frequency 50-75GHz and power density 4.2mW/cm(2). Postoperative analgesia with piritramide, a weak opioid with 0.7 potency of morphine delivered via patient-controlled analgesia pump, was directed to achieve pain intensity of less than 40 on a 100mm visual analogue scale (VAS). The primary outcome measure was postoperative piritramide requirement for three days after surgery. Secondary outcome measures were: total ibuprofen requirement from the fourth postoperative day to discharge; success of patients' blinding; patients' satisfaction with pain relief; incidence of analgesia-related side effects; heart rate and blood pressure. Piritramide requirement was similar in both groups whereby all patients reported adequate pain relief measured on a VAS. Secondary outcome measures were also comparable in both groups. The majority of patients in both groups believed they had received true MWT and wanted to repeat it in future. Millimetre waves applied to surfaces of surgical wounds did not reduce opioid requirement compared to the sham procedure after TKA.

PMID: 18042413 [PubMed - as supplied by publisher]

p53 is important for the anti-proliferative effect of ibuprofen in colon carcinoma cells.

Biochem Biophys Res Commun. 2008 Jan 25;365(4):698-703

Authors: Janssen A, Schiffmann S, Birod K, Maier TJ, Wobst I, Geisslinger G, Gr&#xF6;sch S

S-ibuprofen which inhibits the cyclooxygenase-1/-2 and R-ibuprofen which shows no COX-inhibition at therapeutic concentrations have anti-carcinogenic effects in human colon cancer cells; however, the molecular mechanisms for these effects are still unknown. Using HCT-116 colon carcinoma cell lines, expressing either the wild-type form of p53 (HCT-116 p53(wt)) or being p(HCT-116 p53(-/-)), we demonstrated that both induction of a cell cycle block and apoptosis after S- and R-ibuprofen treatment is in part dependent on p53. Also in the in vivo nude mice model HCT-116 p53(-/-) xenografts were less sensitive for S- and R-ibuprofen treatment than HCT-116 p53(wt) cells. Furthermore, results indicate that induction of apoptosis in HCT-116 p53(wt) cells after ibuprofen treatment is in part dependent on a signalling pathway including the neutrophin receptor p75(NTR), p53 and Bax.

PMID: 18036557 [PubMed - in process]

Purification and application of a lipase from Penicillium expansum PED-03.

Appl Biochem Biotechnol. 2007 Aug;142(2):194-9

Authors: Lianghua T, Liming X, Min S, Huaying G

An extracellular lipase was purified from the fermentation broth of Penicillium expansum PED-03 by DEAE-Sepharose chromatography, followed by sephacryl S-200 chromatography. The enzyme was purified 81.8-fold with 19.8% recovery and a specific activity of 85.94 U/mg. The molecular weight of the homogeneous enzyme was about 28 kDa, determined by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. The enzymatic resolution of racemic ibuprofen was carried out by the lipase from P. expansum PED-03, and the conversion reached 46% with excellent enantioselectivity(E > 200), which showed a good application potential in the production of optically pure ibuprofen.

PMID: 18025580 [PubMed - in process]

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.

Eur J Med Chem. 2007 Oct 6;

Authors: Amir M, Kumar H, Javed SA

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.

PMID: 18023930 [PubMed - as supplied by publisher]

High-temperature ultra-performance liquid chromatography coupled to hybrid quadrupole time-of-flight mass spectrometry applied to ibuprofen metabolites in human urine.

Rapid Commun Mass Spectrom. 2007;21(24):4079-85

Authors: Plumb RS, Rainville PD, Potts WB, Castro-Perez JM, Johnson KA, Wilson ID

The application of sub-2 microm porous particle liquid chromatography (LC) operated at elevated temperatures, coupled with time-of-flight mass spectrometry (MS), to the separation and identification of metabolites of ibuprofen present in human urine following oral administrations is illustrated. The LC/MS system generated a high-resolution analytical separation that, with an analysis time of 20 min, provided a peak capacity in the order of ca. 350. Using this system a total of nine glucuronides of the drug and its metabolites were detected, including a number of isomeric acyl glucuronides of ibuprofen itself, a side-chain-oxidized carboxylic acid acyl glucuronide and a number of acyl glucuronides of various hydroxylated metabolites. The identities of the metabolites were confirmed by their accurate mass values and the presence of the common fragment ions from ibuprofen. Copyright (c) 2007 John Wiley & Sons, Ltd.

PMID: 18022959 [PubMed - in process]

In vivo glycyrrhizin accelerates liver regeneration and rapidly lowers serum transaminase activities in 70% partially hepatectomized rats.

Eur J Pharmacol. 2007 Nov 1;

Authors: Kimura M, Moro T, Motegi H, Maruyama H, Sekine M, Okamoto H, Inoue H, Sato T, Ogihara M

The in vivo effects of glycyrrhizin on restoration of liver mass and recovery of liver function were compared with those of epidermal growth factor (EGF), ibuprofen and dexamethasone in 70% partially hepatectomized rats. Hepatic regenerative activity was assessed based on the ratio of liver weight to 100 g body weight, and 5-bromo-2'-deoxyuridine (BrdU) incorporation into hepatocyte DNA in the remnant liver. Glycyrrhizin (50 mg/kg/day, i.p.)- or EGF (1.0 mug/kg/day, i.p.)-treated rats showed an approx. 1.4-fold increase in liver weight/100 g body weight ratio over saline-treated control rats on days 2 and 3 after 70% partial hepatectomy. BrdU labeling index in the remnant regenerating liver was significantly higher in glycyrrhizin- or EGF-treated rats when compared with saline-treated control rats on days 0.5 and 1. Ibuprofen (100 mg/kg/day, i.p.) and dexamethasone (0.1 mg/kg/day, i.p.) did not significantly increase either liver weight/100 g body weight ratio or BrdU labeling index. Serum activity of liver-related transaminases, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), elevated rapidly on day 1 and decreased to near pre-operative levels on day 5 after 70% partial hepatectomy in saline-treated control rats. Injection of glycyrrhizin or EGF significantly decreased the elevated serum ALT and AST activities on days 2 and 3 after hepatectomy when compared with saline-treated control rats. The transaminase-lowering effects of glycyrrhizin or EGF were smaller than those of ibuprofen and dexamethasone. These results demonstrate that injection of glycyrrhizin or EGF significantly enhances regeneration of liver mass and function, as well as recovery from the liver damage induced by surgical resection.

PMID: 18022618 [PubMed - as supplied by publisher]

[Answers to the questions on application of ibuprofen and acetaminophen in children with fever]

Zhonghua Er Ke Za Zhi. 2007 Sep;45(9):649

Authors: Hu YJ, Sun GM

PMID: 18021552 [PubMed - in process]

The influence of mobile phase demixion on thin-layer chromatographic enantioseparation of ibuprofen and naproxen.

J Chromatogr Sci. 2007 Sep;45(8):500-6

Authors: Sajewicz M, Kaczmarski K, Gontarska M, Kiszka S, Kowalska T

In our earlier article we presented the results of tracing the enantioseparation of the two test analytes (ibuprofen and naproxen) by means of video densitometry and scanning densitometry. In that way we demonstrated an excellent performance of this combined approach to the thin-layer chromatographic detection in the area of enantioseparation. In this paper we study an impact of the four different mobile phases on the enantioseparation of the scalemic mixtures of ibuprofen and naproxen on the silica gel layers impregnated with L-arginine as chiral selector. The main component of all the investigated mobile phases is 2-propanol. Mobile phase 1 consists of pure 2-propanol, while mobile phases 2-4 contain, respectively, ca. 0.66, 1.32, and 1.98 g/L of glacial acetic acid in 2-propanol. Acetic acid is used to protonate L-arginine, as the involved retention mechanism consists of the ion pair formation between L-arginine in the cationic form and the chiral 2-arylpropionic acids (2-APAs), ibuprofen and naproxen, in the anionic form. It is shown that in the absence of glacial acetic acid no enantioseparation can be obtained. Then with adding of 0.66 g/L glacial acetic acid partial enantioseparation of the naproxen and ibuprofen antimers is obtained, with a simultaneous effect of the mobile phase demixion. With the amount of acetic acid increasing, the effect of demixion becomes increasingly perceptible. In that case the displacement effect is observed (and mathematically modeled), which results in compressing of the antimer pairs by the second front of mobile phase. The obtained results allow a deeper insight into the mechanism of enantioseparation with the two test 2-APAs. A combined impact of the crystalline chirality of silica gel and the molecular chirality of L-arginine on the vertical and the horizontal enantioseparation of ibuprofen and naproxen is also discussed.

PMID: 18019559 [PubMed - in process]

Current therapies in childhood and adolescent migraine.

J Child Neurol. 2007 Nov;22(11):1288-92

Authors: Pakalnis A

This review summarizes recent guidelines for diagnosis of migraine in children and adolescents and inherent issues regarding their headaches that influence evaluation of therapies. With the shorter duration of pediatric migraine attacks and the prominent placebo responder rate, design of randomized clinical trials becomes more problematic than in the adult population. Regarding abortive therapies, several agents have appreciable efficacy in randomized controlled trials. Ibuprofen, acetaminophen, and sumatriptan nasal spray are probably beneficial and safe to use in pediatric migraine. For the minority of children who should be candidates for prophylactic therapy, there is a limited amount of information available for clinicians to make judicious treatment decisions.

PMID: 18006958 [PubMed - in process]

Cytosolic phospholipase A2 and arachidonic acid metabolites modulate ventilator-induced permeability increases in isolated mouse lungs.

J Appl Physiol. 2007 Nov 15;

Authors: Miyahara T, Hamanaka K, Weber DS, Anghelescu M, Frost JR, King JA, Parker JC

We have previously reported that the cytosolic phospholipase A2 (cPLA2) pathway is involved in ventilator-induced lung injury (VILI) produced by high peak inflation pressures (PIP) (Yoshikawa S, J. Appl. Physiol. 98:1264-71, 2005), but the relative contributions of the various downstream products of cPLA2 on the acute permeability response was not determined. Therefore, we investigated the role of cPLA2 and the downstream products of arachidonic acid metabolism on the high PIP ventilation induced increase in vascular permeability. We perfused isolated mouse lungs and measured the capillary filtration coefficient (Kfc) after 30-min periods of ventilation with PIP of 9, 25, and 35 cmH2O. In high PIP ventilated lungs, Kfc increased significantly by 2.7-fold after ventilation with 35 cmH2O PIP compared to paired baseline values and low PIP ventilated lungs. Also, an increased phosphorylation of lung cPLA2 suggested enzyme activation after high PIP ventilation. However, treatment with 40 mg/kg arachidonyl trifluoromethyl ketone, an inhibitor of cPLA2, or a combination of 30 microM ibuprofen, a cyclooxygenase inhibitor, 100 microM nordihydroguaiaretic acid, a lipoxygenase inhibitor, and 10 microM 17-octadecynoic acid, a cytochrome P450 epoxygenase inhibitor, prevented the high PIP induced increase in Kfc. Combinations of only one or two of the inhibitors of cyclooxygenase, lipoxygenase or P450 epoxygenase did not prevent significant increases in Kfc even though bronchoalveolar lavage levels of the cyclooxygenase or lipoxygenase products were significantly reduced. These results suggest that multiple mediators from each pathway contribute to the acute ventilator-induced permeability increase in isolated mouse lungs by mutual potentiation. Key words: ventilator-induced lung injury, cyclooxygenase, arachidonic acid, lipoxygenase, P450.

PMID: 18006865 [PubMed - as supplied by publisher]

Analgesic synergy between topical opioids and topical non-steroidal anti-inflammatory drugs in the mouse model of thermal pain.

Eur J Pharmacol. 2007 Oct 16;

Authors: Kolesnikov Y, S&#xF5;ritsa D

The main aim of the study was to examine analgesic effects of the topical opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in a radiant heat tail-flick nociception model. Also, we have tested whether the addition of lauric acid to propylene glycol improves skin permeation for the opioids and NSAIDs. We found that the addition of lauric acid to propylene glycol dramatically improves the penetration of the drugs, measured by the drug's ED(50). We observed a significant dose response shift to the left for all tested drugs. So, morphine's ED(50) was decreased by 19-fold. The duration of the analgesic activity of morphine dissolved in a combination of propylene glycol and lauric acid was much longer compared with the same dose of the drug dissolved in propylene glycol only. Methadone and hydrocodone also produced analgesic activity in this experimental paradigm. We then assessed potential interactions between opioids, ibuprofen and diclofenac using a fixed, low dose of each. The inclusion of either S-ibuprofen or diclofenac to a fixed, low dose of morphine raised the analgesic response from around 20% to 50% and 80%, respectively. Topical methadone and diclofenac alone produced analgesia in 30% of mice. The combination produced analgesia in 100% of mice (100% versus 60%, P<0.001) and the analgesic effect was observed for 90 min. Alone, topical methadone and S-ibuprofen produced analgesia in 25% and 30% of mice, respectively. The combination elicited analgesia in 100% of mice (100% versus 55%, P<0.001) and this analgesic effect lasted for 120 min. Our current findings support the supra-additive interaction of topical mu opioids, S-ibuprofen and diclofenac in a model of moderate to severe pain, radiant heat tail-flick assay.

PMID: 18001710 [PubMed - as supplied by publisher]

[Consumption of nonsteroidal anti-inflammatory agents in primary care in Costa Rica: changing patterns and geographical variability.]

Gac Sanit. 2007 Nov-Dec;21(6):458-64

Authors: Morera Salas M, Aparicio Llanos A, Xirinachs Salazar Y, Barber Pérez P

OBJECTIVE: To determine changing patterns and variability in consumption of classic nonsteroidal anti-inflammatory drugs (NSAIDs) among the health areas in Costa Rica between 2000 and 2005. METHODS: The drugs studied were ibuprofen, indomethacin, penicillamine, sulindac, tenoxicam, and diclofenac sodium. To measure consumption, we used the defined daily dose per 1,000 inhabitants per day (DID). To analyze variability, the coefficient of variation weighed by the population size (CVw), extremal ratio, interquartile ratio, dot plot and map graphs were used. RESULTS: From 2000-2005, NSAID consumption increased by 48% and the annual cost rose by 184%. The drugs with greatest consumption and participation in cost were sulindac and indomethacin. NSAID consumption varied between 0.1 and 61.8 DID according to health areas, with a CVw of 66.8%. Variability was greatest with penicillamine (CVw = 449.89%) and tenoxicam (CVw = 315.26%). CONCLUSIONS: Clearly differentiated geographical patterns in NSAID consumption were found in Costa Rica, with very different rates within the same region. According to the results obtained, two factors associated with this variability were the supply of health services and the percentage of the population aged 65 years or more within the catchment area.

PMID: 18001658 [PubMed - in process]

Desorption electrospray ionization of aerosol particles.

Rapid Commun Mass Spectrom. 2007;21(24):3995-4000

Authors: Dong J, Rezenom YH, Murray KK

We have applied desorption electrospray ionization to aerosol particles. Ions were formed from aerosols by merging suspended dry particles with an electrospray of solvent in a modified ion trap mass spectrometer. Dry aerosol particles were generated using a fluidized bed powder disperser and directed toward the inlet of the mass spectrometer. A nanospray source was used to create a spray of solvent droplets directed at the inlet and at a right angle with respect to the aerosol. Ions generated by the interaction of the particles and electrospray were transferred into the ion trap mass spectrometer. Using this method, pure samples of caffeine and erythromycin A were analyzed. In addition, commonly available food and drug powders including instant cocoa powder, artificial sweetener and ibuprofen were analyzed. Copyright (c) 2007 John Wiley & Sons, Ltd.

PMID: 18000959 [PubMed - in process]

IgE-mediated hypersensitivity after ibuprofen administration.

Ann Clin Lab Sci. 2007;37(4):362-5

Authors: Bluth MH, Beleza P, Hajee F, Jord&#xE3;o MJ, Figueiredo J, Almeida F, Smith-Norowitz T

Although many immunoglobulin-related drug sensitivities have been described, there is a paucity of reports regarding IgE-related drug sensitivities. Here we describe a case of a patient who demonstrated IgE-mediated sensitivity to ibuprofen.

PMID: 18000294 [PubMed - in process]

Luminescence functionalization of mesoporous silica with different morphologies and applications as drug delivery systems.

Biomaterials. 2008 Feb;29(6):692-702

Authors: Yang P, Quan Z, Lu L, Huang S, Lin J

Ordered mesoporous silica (MCM-41) particles with different morphologies were synthesized through a simple hydrothermal process. Then these silica particles were functionalized with luminescent YVO(4):Eu(3+) layers via the Pechini sol-gel process. The obtained YVO(4):Eu(3+)and MCM-41 composites, which maintained the mesoporous structure of MCM-41 and the red luminescence property of YVO(4):Eu(3+), were investigated as drug delivery systems using ibuprofen (IBU) as model drug. The physicochemical properties of the samples were characterized by X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), N(2) adsorption, and photoluminescence (PL) spectra, respectively. It is found that the specific surface area and pore volume, which are directly correlated with the drug-loading amount and drug release rate, decrease in sequence after the deposition of YVO(4):Eu(3+) layer and the further incorporation of IBU. Additionally, the drug release test indicated that the IBU release rate could be controlled by regulating the morphology of the materials. It is worth noting that the IBU-incorporated samples still exhibit red luminescence under UV irradiation. Furthermore, the emission intensities of Eu(3+) can be tailored as a function of the released amount of IBU, thus making the drug release be easily tracked and monitored.

PMID: 17996294 [PubMed - as supplied by publisher]

Analysis of the risk factors and their combinations in acute gastroduodenal ulcer bleeding: A case-control study.

Scand J Gastroenterol. 2007 Dec;42(12):1395-403

Authors: Udd M, Miettinen P, Palmu A, Heikkinen M, Janatuinen E, Pasanen P, Tarvainen R, Mustonen H, Julkunen R

Objective. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) including ASA for thrombosis prophylaxis (ASA-TP), for pain medication (ASA-P) or non-ASA NSAIDs (NANSAIDs), Helicobacter pylori infection, CagA strains of H. pylori and smoking are reported risk factors for peptic ulcer bleeding (PUB), but the combined and the dose effects of these factors are controversial. The aim of this study was to estimate the significance of these risk factors and their combinations in PUB. Material and methods. PUB patients (n=94) were compared with an age- (+/-5 years) and gender-matched control group of non-ulcer patients (n=94) attending elective endoscopy. A questionnaire on the possible risk factors (previous gastric and duodenal ulcer, use of ASA-TP, ASA-P, NANSAIDs, warfarin, alcohol and smoking) was completed. H. pylori infection was determined as positive if histology and/or urease tests were positive. CagA antibodies of IgG class were determined using an immunoblot method. Results. H. pylori infection (odds ratio (OR) 8.8), the use of ASA-P (OR 3.5), ASA-TP (OR 4.07), NANSAIDs with >/=1 defined daily dose (OR 6.56), smoking >/=20 cigarettes daily (OR 6.43) and previous duodenal ulcer (DU) (OR 8.96) were independent risk factors for PUB. At least two risk factors were present in 65% of PUB patients. CagA strains were detected in 97% of the H. pylori-positive cases and in 96% of the respective controls. ASA, ibuprofen, ketoprofen and smoking were dose-dependent risk factors for PUB. Conclusions. Previous DU, H. pylori, the use of any ASA and smoking explained the majority of the PUB episodes. CagA strains of H. pylori were not associated with PUB. Two-thirds of the PUB patients had at least two risk factors, but their combination did not potentiate the risk.

PMID: 17994466 [PubMed - in process]

Quantitative Assessment of the Degree of Ductal Steal Using Celiac Artery Blood Flow to Left Ventricular Output Ratio in Preterm Infants.

Neonatology. 2007 Nov 9;93(3):206-212

Authors: El-Khuffash A, Higgins M, Walsh K, Molloy EJ

Background: Determining the significance of a patent ductus arteriosus (PDA) remains difficult in preterm neonates and current echocardiographic markers give little information about ductal steal. We hypothesized that the relationship between celiac artery flow (CAF) and left ventricular output (LVO) in the presence of a PDA may determine haemodynamic significance. Objectives: To examine CAF to LVO ratio (CAF:LVO) in the presence and the absence of a PDA in preterm neonates, and to compare CAF:LVO to current echocardiographic markers of a significant PDA. Methods: This was a prospective observational study of neonates <1,500 g. Echocardiography was performed at 12 h and day 3. PDA, LVO and CAF were measured by echocardiography. The infants were divided into those who developed a significant PDA (PDA >1.4 mm and left atrial to aortic ratio >1.5 on day 3) and controls. A further assessment was carried out following successful PDA treatment with ibuprofen or surgical ligation. Results: A total of 33 infants were enrolled. 19 infants had a PDA (median gestation 27 weeks, birth weight 915 g), and 14 controls (gestation 28.7 weeks, birth weight 1,110 g). At 12 h, there was no difference in CAF, LVO or CAF:LVO. On day 3, there was a significant difference in CAF:LVO between PDA versus control groups. CAF:LVO significantly correlated with conventional markers of ductal significance. A CAF:LVO value of 0.10 had a sensitivity of 93% and a specificity of 78% for the presence of a significant PDA. Following successful PDA treatment CAF:LVO returned to levels similar to controls. Conclusion: CAF:LVO may be used to determine which PDA warrants treatment and serve as a marker of treatment success. Trials are needed to correlate CAF:LVO with outcome and the impact of basing PDA treatment on this ratio. Copyright (c) 2007 S. Karger AG, Basel.

PMID: 17992021 [PubMed - as supplied by publisher]

Cyclooxygenase Inhibitors Affect Bone Mineralization in Rat Fetuses.

Cells Tissues Organs. 2007 Nov 9;

Authors: Burdan F, Rozylo-Kalinowska I, Szumilo J, Dudka J, Klepacz R

Intrauterine growth retardation, increased incidence of developmental variations, lack of cartilage and joint developmental side effects were previously reported for nonselective (ibuprofen, piroxicam, tolmetin) and selective (DFU) cyclooxygenase (COX)-2 inhibitors, also known as nonsteroidal anti-inflammatory drugs. The aim of the present study was to evaluate the lumbar vertebra mineralization in fetuses prenatally exposed to COX inhibitors. All the tested compounds were administered intragastrically to pregnant rats from gestational days 8 to 21. Fetuses were delivered on gestational day 21, and after digital radiological examination were double-stained with alcian blue and alizarin. Decrease of alizarin staining, as a qualitative sign of mineralization, was significantly greater in groups exposed to the highest doses of the nonselective COX inhibitors. Decrease of vertebra mineralization in drug-exposed groups was also revealed using quantitative radiological analysis. However, significant differences were noted only for the fifth and sixth lumbar vertebrae in the group exposed to the highest dose of tolmetin. Strong influence of the total protein level in maternal sera on the fetal bone optic density was found. It should be stressed that unlike DFU, the examined nonselective COX inhibitors decreased fetal bone mineralization when administered in high maternal toxic doses. Moreover, maternal health status determined fetal bone mineralization. Copyright (c) 2007 S. Karger AG, Basel.

PMID: 17992008 [PubMed - as supplied by publisher]

The undesirable side-effects of non-steroidal anti-inflammatory drugs.

Ortop Traumatol Rehabil. 2001 Mar 30;3(1):126-8

Authors: Hamera-S&#x142;ynarska M, Słynarski K

Non-steroidal anti-inflammatory drugs (NSAD) are among the most commonly used medications. Many of them, such as ibuprofen, naproxen and aspirin, are widely advertised in the media and available without prescription. NSADs have anti-inflammatory effects, and some of them (aspirin, ibuprofen) are also antipyretic. The basic mechanism of their action is based on the inhibition of the enzyme cascade in the metabolism of arachidonid acid - cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) - and as a result inhibition of prostaglandin production. The undesirable side-effects of NSADs are primarily a direct result of the anti-inflammatory mechanism, and increase proportionally with the dosage. The article presents undesirable side-effects in the digestive system, the kidneys, and elsewhere. In conclusions the author point to the need for caution in using drugs of this kind.

PMID: 17986975 [PubMed - in process]

Drug rash with eosinophilia and systemic symptoms after ibuprofen intake.

J Investig Allergol Clin Immunol. 2007;17(5):347-8

Authors: Kucharewicz I, Kemona-Chetnik I, Reduta T, Wierzbicka I, Flisiak R, Bodzenta-Lukaszyk A

PMID: 17982931 [PubMed - in process]

Chitosan-polycarbophil complexes in swellable matrix systems for controlled drug release.

Curr Drug Deliv. 2007 Oct;4(4):257-63

Authors: Lu Z, Chen W, Hamman JH

A prerequisite for progress in the design of novel drug delivery systems is the development of excipients that are capable of fulfilling multifunctional roles such as controlling the release of the drug according to the therapeutic needs. Although several polymers have been utilised in the development of specialised drug delivery systems, their scope in dosage form design can be enlarged through combining different polymers. When a polymer is cross-linked or complexed with an oppositely charged polyelectrolyte, a three-dimensional network is formed in which the drug can be incorporated to control its release. The swelling properties and release kinetics of two model drugs with different water solubilities (i.e. diltiazem and ibuprofen) from monolithic matrix tablets consisting of an interpolyelectrolyte complex between chitosan and polycarbophil are reported. Matrix tablets consisting of this polymeric complex without drug or excipients exhibited extremely high swelling properties that are completely reversible upon drying. The drug release from matrix systems with different formulations depended on the concentration of the chitosan-polycarbophil interpolyelectrolyte complex and approached zero order release kinetics for both model drugs. The chitosan-polycarbophil interpolyelectrolyte complex has demonstrated a high potential as an excipient for the production of swellable matrix systems with controlled drug release properties.

PMID: 17979647 [PubMed - indexed for MEDLINE]

Preparation and evaluation of Ibuprofen solid dispersion systems with kollidon particles using a pulse combustion dryer system.

Chem Pharm Bull (Tokyo). 2007 Nov;55(11):1545-50

Authors: Xu L, Li SM, Sunada H

Solid dispersions (SDs) of ibuprofen (IBU) were prepared with four carriers: Kollidon 25, Kollidon 30, Kollidon VA64, and Kollidon CL, using a newly developed pulse combustion dryer system, HYPULCON. Physicochemical properties of the SDs obtained were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscope (SEM), and Fourier transformation IR spectroscopy (FT-IR). Powder X-ray diffraction (PXRD) showed that the crystal diffraction peaks of IBU in SDs disappeared completely, and in differential scanning calorimetry (DSC) curves, the endothermic peaks of IBU in SDs were not observed. Fourier transformation IR spectroscopy (FT-IR) proved that interactions between the drug and carrier existed. These findings demonstrated that IBU changed to an amorphous form in the SDs with the four carriers using the pulse combustion dryer system. The dissolution property of IBU in the SDs was markedly enhanced. The dissolution test showed that after 5 min of dissolution, the concentrations of IBU in the SDs with Kollidon CL as the carrier was 43.81 mug/ml, corresponding to 13.0 times that of pure IBU. So, it is demonstrated that the pulse combustion dryer system is very useful for preparing SDs of IBU with Kollidon of different grades as carriers.

PMID: 17978509 [PubMed - in process]

Design and study of ibuprofen disintegrating sustained-release tablets comprising coated pellets.

Eur J Pharm Biopharm. 2007 Oct 29;

Authors: Abbaspour MR, Sadeghi F, Afrasiabi Garekani H

One challenge in tableting of sustained-release multiparticulates is maintaining the desired drug release after compaction. The aim of this study was to design sustained-release ibuprofen tablets which upon oral ingestion rapidly disintegrate into sustained-release pellets in which the integrity of the pellet core and/or coat is preserved. First free films composed of Eudragit RS 30D and RL 30D in 4:1 ratio and containing different levels of triethyl citrate (TEC) were prepared and tested to optimize the plasticizer level. Cured Eudragit based pellets with 60% ibuprofen loading which in our previous study showed proper mechanical properties for compression were coated with Eudragit RS 30D/RL 30D (4:1) containing 20% triethyl citrate at different coating levels. The mechanical properties of the coated pellets were tested. Polymer coated pellets were compacted into tablets either alone or with a blend of excipients comprising Avicel, PEG 4000, cross-linked PVP. A 3(2) full factorial design was used to optimize the filler blend composition. Effects of pellet to filler ratio, compression force and granulation of filler on tablet characteristics were investigated. Results of mechanical test showed that the coating of cured pellets had no significant effect on yield point and elastic modulus of the pellets. In the case of 5% coating level sustained release of ibuprofen over a period of 24h was achieved. The results obtained from tableting procedure showed that by selecting suitable filler blend (60% Avicel, 10% cross-linked PVP and 30% PEG 4000), compression force, and granulation of filler it was possible to prepare sustained-release tablets containing high ratio of coated pellets (even 80%) with desirable strength, disintegration time, and drug release rate. It was observed that compression force, pellet to filler ratio, composition of filler blend and granulation of fillers had no effect on drug release rate from compacted pellets but had significant influence on tablet strength, friability, and disintegration time. SEM graphs and in vitro release profiles for compacted pellets showed no apparent damage to the coated pellets as a result of the compaction process.

PMID: 17977701 [PubMed - as supplied by publisher]

Effect of absorption rate on pharmacokinetics of ibuprofen in relation to chiral inversion in humans.

J Pharm Pharmacol. 2007 Nov;59(11):1509-13

Authors: Ding G, Liu Y, Sun J, Takeuchi Y, Toda T, Hayakawa T, Fukushima S, Kishimoto S, Lin W, Inotsume N

The effect of absorption rate on the pharmacokinetics of ibuprofen enantiomers was investigated in 12 healthy Han Chinese male volunteers following oral administration of immediate-release (IR) and sustained-release (SR) preparations containing racemic ibuprofen (rac-ibuprofen). The area under the curve of the plasma concentration-time curve (AUC; (mean+/-s.d.) values for rac-ibuprofen were 192.90+/-43.47 for the SR preparation and 195.90+/-31.69 microg h mL(-1) for the IR preparation. AUC values for the enantiomers after administration of the SR formulation were 55.38+/-17.79 and 92.51+/-30.68 microg h mL(-1) for R- and S-ibuprofen, respectively, and were 65.94+/-20.06 and 100.81+/-32.28 microg h mL(-1) for R- and S-ibuprofen after administration of the IR preparation. These values did not differ significantly. C(max) values were significantly decreased with the SR preparation: 25.11+/-5.71, 12.24+/-3.79 and 12.38+/-3.55 microg h mL(-1) for rac-, R-, and S-ibuprofen, respectively, after administration of the SR preparation, vs 46.21+/-8.20, 20.82+/-5.90 and 23.46+/-7.30 microg h mL(-1) for rac-, R-, and S-ibuprofen, respectively, after administration of the IR preparation. Mean residence time was significantly increased: 7.01+/-1.29, 5.52+/-1.25 and 7.04+/-1.30 h for rac-, R-, and S-ibuprofen, respectively, after administration of the SR preparation vs 4.34+/-0.89, 3.43+/-0.64 and 4.51+/-0.79 h for rac-, R-, and S-ibuprofen, respectively, after administration of the IR preparation. AUC values for S-ibuprofen were significantly larger than those for R-ibuprofen in both preparations, indicating unidirectional chiral inversion. The S/R ratio of serum concentrations of enantiomers was 1.78-fold higher at 6 h after administration of the SR preparation compared with the IR preparation (P<0.01). These results indicate that ibuprofen undergoes pre-systemic chiral inversion in parallel with a systemic process and that the clinical effects of rac-ibuprofen in humans depend on the absorption rate.

PMID: 17976261 [PubMed - in process]

Effect of anandamide on erythrocyte survival.

Cell Physiol Biochem. 2007;20(6):1033-42

Authors: Bentzen PJ, Lang F

The endocannabinoid anandamide (Arachidonylethanolamide, AEA) is known to induce apoptosis in a wide variety of nucleated cells. The present study explored whether anandamide induces suicidal death of erythrocytes or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Eryptotic cells are phagocytosed and thus cleared from circulating blood. Triggers of eryptosis include increase of cytosolic Ca2+ activity, formation of PGE(2), oxidative stress and excessive cell shrinkage. Erythrocyte Ca2+ activity was estimated from Fluo3 fluorescence, phosphatidylserine exposure from annexin V binding, and erythrocyte volume from forward scatter in FACS analysis. Exposure of erythrocytes to anandamide (= 2.5 microM) increased cytosolic Ca2+ activity, enhanced the percentage of annexin V binding erythrocytes and decreased erythrocyte forward scatter, effects significantly blunted in the presence of cycloxygenase inhibitors acetylsalicylic acid (50 microM) or ibuprofen (100 microM) and in the nominal absence of extracellular Ca2+. Anandamide further enhanced the stimulating effects of hypertonic (addition of 550 mM sucrose) or isotonic (isosmotic replacement of Cl- with gluconate) cell shrinkage on annexin V binding. The present observations demonstrate that anandamide increases cytosolic Ca2+ activity, thus leading to cell shrinkage and cell membrane scrambling of mature erythrocytes.

PMID: 17975305 [PubMed - in process]

Celecoxib prevented development of heterotopic ossification better than Ibuprofen after total hip replacement.

J Bone Joint Surg Am. 2007 Nov;89(11):2556

Authors: Dunbar MJ

PMID: 17974907 [PubMed - in process]

Immune Reconstitution Inflammatory Syndrome Presenting as Pericarditis and Pericardial Effusion.

Cardiology. 2007 Oct 17;110(2):142-144

Authors: Rapose A, Sarvat B, Sarria JC

Immune reconstitution inflammatory syndrome (IRIS) affects 30-43% of HIV and tuberculosis (TB) co-infected patients after starting highly active antiretroviral therapy (HAART). Pericarditis and pericardial effusion are rare manifestations of IRIS. We report a case of HIV-TB related IRIS that developed pericardial involvement. This complication resolved after treatment with ibuprofen. Antituberculous treatment and HAART were not interrupted. Copyright (c) 2007 S. Karger AG, Basel.

PMID: 17971663 [PubMed - as supplied by publisher]

Synthesis and evaluation of the antiinflammatory activity of N-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-thiazolidin-3-yl]-nicotinamide.

Arzneimittelforschung. 2007;57(9):616-22

Authors: Kalia R, Rao CM, Kutty NG

A new molecule incorporating nicotinoyl moiety, thiazolidin-4-one ring and 3,5-di-tert-butyl-4-hydroxyphenyl group (a potent antioxidant moiety) was synthesized and evaluated for anti-inflammatory activity in acute as well as chronic phase models of inflammation. The compound exhibited significant anti-inflammatory activity in three experimental models of inflammation, comparable to the positive control drug, ibuprofen (CAS 15687-27-1). It is suggested that besides the hypolipidemic and anti-oxidant potential of the molecule, its anti-inflammatory action could possibly act as an additional mechanism of its hypothesized anti-atherosclerotic activity.

PMID: 17966761 [PubMed - indexed for MEDLINE]

Indomethacin decreases optic nerve oxygen tension by a mechanism other than cyclooxygenase inhibition.

Br J Ophthalmol. 2007 Oct 26;

Authors: Noergaard MH, Pedersen DB, Bang K, Jensen PK, Kiilgaard JF, Stefansson E, la Cour M

Aims/Background: We investigated the effect of several Non-Steroidal Anti-Inflammatory Drugs, NSAIDs, on the pre-optic nerve oxygen tension (ONPO2), as indomethacin previously has demonstrated a strong decreasing effect on ONPO2. We tested whether these NSAIDs, like indomethacin, also reduces the increasing effect of dorzolamide on ONPO2. Methods: ONPO2 was measured 0.5 mm above the optic disc in 23 domestic pigs (26-36 kg) with a polarographic oxygen-sensitive electrode. One of the following NSAIDs was administered intravenously as increasing doses or as one large dose: Indomethacin, ibuprofen, diclofenac, ketoprofen, parecoxib and lornoxicam. Indomethacin was both tested alone and after preceding administration of the other NSAIDs. Dorzolamide was also tested after preceding administration of NSAIDs different from indomethacin. Results: Indomethacin decreased ONPO2 significantly in a dose-dependent manner. None of the other NSAIDs produced any effect on the ONPO2 (P >> 0.05; n =17). No difference was found between the effect of indomethacin injected alone, and after preceding administration of the other NSAIDs. Intravenous dorzolamide (500 mg) increased ONPO2 by 32 +/- 7 % (n = 7; P < 0.001) after preceding administration of several NSAIDs different from indomethacin. Conclusions: Indomethacin decreased ONPO2, while the other NSAIDs showed no effect on ONPO2, and they did not affect the effect of indomethacin. The hypoxic effect of indomethacin must be due to another mechanism than cyclooxygenase inhibition. The effect of dorzolamide on ONPO2 is not related to prostaglandin production.

PMID: 17965100 [PubMed - as supplied by publisher]

Ibuprofen does not affect levels of tumor necrosis factor alpha and soluble tumor necrosis factor receptor types I and II in Gabonese children with uncomplicated Plasmodium falciparum malaria.

Eur Cytokine Netw. 2007 Dec;18(4):201-5

Authors: Matsiegui PB, Missinou MA, Issifou S, Necek M, Mavoungou E

We assessed the ability of ibuprofen to modulate tumor necrosis factor alpha (TNF-alpha), soluble tumor necrosis factor receptor type I (sTNFR-I), and soluble tumor necrosis factor receptor type II (sTNFR-II) responses during the treatment of fever in uncomplicated Plasmodium falciparum malaria, in a placebo-controlled, randomized, double-blind study of 50 pediatric patients in Lambar&#xE9;né, Gabon. Treatment of the malaria involved the patients receiving intravenous quinine (12 mg/kg of quinine dihydrochloride every 12 h for 72 h) followed by a single dose of oral sulfadoxine/pyrimethamine (25 mg and 1.25 mg/kg). Fever was treated by mechanical treatment plus either ibuprofen (7 mg/kg every 8 h) or placebo during the hospitalization period. We determined serum concentrations of TNF-alpha, sTNFR-I, and sTNFR-II in peripheral blood throughout the treatment period in the two groups: ibuprofen and placebo groups. TNF-alpha levels were found to be positively correlated with body temperature. In contrast, TNF receptors levels did not differ between the two groups and the antipyretic effect of ibuprofen was not correlated with specific changes in sTNFR-I and sTNFR-II production. Our data suggest that TNF-alpha is involved in malarial fever, but soluble TNF receptors play no major role in fever modulation.

PMID: 17964975 [PubMed - in process]

Ibuprofen therapy and nasal polyposis in cystic fibrosis patients.

J Otolaryngol. 2007 Oct;36(5):309-14

Authors: Lindstrom DR, Conley SF, Splaingard ML, Gershan WM

OBJECTIVE: To assess the effects on nasal polyposis from high-dose ibuprofen therapy used in children with cystic fibrosis (CF) pulmonary disease. DESIGN: Retrospective case series. MAIN OUTCOME MEASURE: Presence or absence of nasal polyps. RESULTS: Twenty-two patients treated with high-dose ibuprofen therapy to benefit pulmonary function were identified from 235 patients with CF. Sinonasal disease was present in 19 patients, of whom 12 had nasal polyposis. All 12 patients had observed absence of nasal polyps at some point during their ibuprofen course. Nasal polyps were present in five patients during ibuprofen therapy, and all resolved with increased ibuprofen doses. Polyps occurred in six of eight patients after ibuprofen therapy ceased. Five of the 12 patients required endoscopic sinus surgery for polyposis. CONCLUSION: High-dose ibuprofen therapy chronically administered at appropriate weight-based dosing is a possible treatment option for children and young adults with CF polyposis. More testing is indicated.

PMID: 17963671 [PubMed - in process]

Inflammatory response and meningioma tumorigenesis and the effect of cyclooxygenase-2 inhibitors.

Neurosurg Focus. 2007;23(4):E7

Authors: Ragel BT, Jensen RL, Couldwell WT

In this article the authors discuss the rationale and research supporting the hypothesis that meningioma tumorigenesis may, in part, be driven by overexpression of cyclooxygenase-2 (Cox-2) and that treatment with celecoxib, a selective Cox-2 inhibitor, may hold therapeutic promise. Because therapies for recurrent or aggressive meningiomas (atypical or malignant subtypes) such as chemotherapy and radiotherapy generally offer little therapeutic benefit, interest in targeting Cox-2 has grown. This rate-limiting enzyme of prostaglandin synthesis can be inhibited with nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and celecoxib. Treatment with NSAIDs has been shown to curb the tumorigenic properties of prostaglandins in several cancer models via both Cox-2-dependent and -independent mechanisms. In addition, celecoxib is well tolerated in humans, making its use as a chronic therapy for meningiomas attractive.

PMID: 17961044 [PubMed - indexed for MEDLINE]

Theoretical study of ibuprofen phototoxicity.

J Phys Chem B. 2007 Nov 22;111(46):13345-52

Authors: Musa KA, Eriksson LA

The photochemical properties and degradation of the common nonsteroid anti-inflammatory drug ibuprofen is studied by means of hybrid density functional theory. Computed energies and properties of various species show that the deprotonated form dominates at physiological pH, and that the species will not be able to decarboxylate from a singlet excited state. Instead, decarboxylation will occur, with very high efficiency, provided the deprotonated compound can undergo intersystem crossing from an excited singlet to its excited triplet state. In the triplet state, the C-C bond connecting the carboxyl group is elongated, and the CO2 moiety detaches with a free energy barrier of less than 0.5 kcal/mol. Depending on the local environment, the decarboxylated product can then either be quenched through intersystem crossing (involving the possible formation of singlet oxygen) and protonation, or serve as an efficient source for superoxide anions and the formation of a peroxyl radical that will initiate lipid peroxidation.

PMID: 17958415 [PubMed - in process]

Equilibrium solubilization of lipophilic therapeutic agents by aqueous solutions of products of catalytic oxyethylation of Croda-type lanolin as model excipients of the class of non-ionic surface active agents.

Polim Med. 2007;37(2):33-50

Authors: Zgoda MM, Lukosek M, Nachajski MJ

Research was conducted into the properties and identity of the products of Croda-type hypoallergenic lanolin, which were obtained with the use of a selective catalyst (K-4) and a standard alkaline catalyst (Na/NaOH). The 1HNMR method was employed to assess the content of oxyethylated segments and the analytic level of hydrophilic-lipophilic balance (HLB). Surface activity of products soluble in water with n(TE) > or = 40 was examined and the thermodynamic potential for micelle formation deltaGm(o) was calculated. Basic viscosity and hydrodynamic values were determined for the solubilizers and their micellar adduct with ibuprofen, ketoprofen and naproxen. In addition, the amount of solubilized therapeutic agents c/s/ was examined by means of the spectroscopic method and the micellar partition coefficient--Kw(m) was estimated. The results obtained in the course of research served as a basis for determining the solubilization mechanism and the stability of the micellar adduct for the purpose of application. This enabled the commencement of technological work on the design and manufacture of a model dosage form administered to the skin and containing the products of lanolin oxyethylation.

PMID: 17957947 [PubMed - indexed for MEDLINE]

Dr Brian Gibberd (1931-2006): a pioneering clinician in Refsum's disease.

Biochem Soc Trans. 2007 Nov;35(Pt 5):862-4

Authors: Wierzbicki AS, Lloyd MD

Branched-chain fatty acids are common components of the human diet (phytanic acid) or are produced endogenously (bile acids), and are also used as medicines (ibuprofen). Owing to their branched-chain structure, they are metabolized in peroxisomes. In the case of phytanic acid, the presence of a 3-methyl group prevents beta-oxidation, and instead it undergoes one round of alpha-oxidation to allow further metabolism. Defects in this process give rise to neurological diseases and cancer. Dr Brian F. Gibberd was one of the first U.K. physicians to recognize the importance of these peroxisomal metabolic pathways in clinical medicine, and pioneered their study. This obituary recognizes his many achievements in neurology and especially in the treatment of peroxisomal disorders. The following four papers from this mini-symposium entitled 'Advances in peroxisomal alpha-, beta- and omega-oxidation' describe work done in this area as part of a collaborative study in which Dr Gibberd played a key role. This work was presented as part of the Cardiovascular Bioscience focused topic at the Life Sciences 2007 conference, and this mini-symposium was dedicated to Dr Gibberd and his important contributions to this field.

PMID: 17956233 [PubMed - in process]

Cocrystal architecture and properties: design and building of chiral and racemic structures by solid-solid reactions.

Faraday Discuss. 2007;136:167-78; discussion 213-29

Authors: Frisci&#x107; T, Jones W

The concept of the so-called "supramolecular synthon" has been employed to construct chiral and centrosymmetric cocrystals with predictable short-range order. The reactants included nicotinamide, mandelic acid and ibuprofen. In order to maximize the efficiency of cocrystal synthesis, the solids were constructed using the liquid-assisted grinding approach. The predictability of the cocrystal architecture was further employed to study in detail the effects of chirality upon physical properties of the synthesized materials, especially the melting point. The combined results of crystallographic and thermochemical studies enable, at least partially, the rationalisation of cocrystal thermal behaviour with respect to the corresponding cocrystal formers.

PMID: 17955809 [PubMed - indexed for MEDLINE]

Control of Drug Release through the In Situ Assembly of Stimuli-Responsive Ordered Mesoporous Silica with Magnetic Particles.

Chemphyschem. 2007 Dec 3;8(17):2478-2483

Authors: Zhu S, Zhou Z, Zhang D

A site-selective controlled delivery system for controlled drug release is fabricated through the in situ assembly of stimuli-responsive ordered SBA-15 and magnetic particles. This approach is based on the formation of ordered mesoporous silica with magnetic particles formed from Fe(CO)(5) via the surfactant-template sol-gel method and control of transport through polymerization of N-isopropyl acrylamide inside the pores. Hydrophobic Fe(CO)(5) acts as a swelling agent as well as being the source of the magnetic particles. The obtained system demonstrates a high pore diameter (7.1 nm) and pore volume (0.41 cm(3) g(-1)), which improves drug storage for relatively large molecules. Controlled drug release through the porous network is demonstrated by measuring the uptake and release of ibuprofen (IBU). The delivery system displays a high IBU storage capacity of 71.5 wt %, which is almost twice as large as the highest value based on SBA-15 ever reported. In vitro testing of IBU loading and release exhibits a pronounced transition at around 32 degrees C, indicating a typical thermosensitive controlled release.

PMID: 17952885 [PubMed - as supplied by publisher]

[Ibuprofen versus indomethacin in the preterm persistent patent ductus arteriosus therapy: review and meta-analysis.]

An Pediatr (Barc). 2007 Oct;67(4):309-18

Authors: Gimeno Navarro A, Modesto Alapont V, Morcillo Sopena F, Fern&#xE1;ndez Gilino C, Izquierdo Macián I, Gutiérrez Laso A

INTRODUCTION: Persistent patent ductus arteriosus (PDA) is a common pathology in the preterm whose traditional treatment has been indomethacin. Recently, ibuprofen has shown its effectiveness in closing the PDA with less hemodynamic effects. The objective of this paper is to review the current literature in order to determine if there is any benefit of ibuprofen versus indomethacin in the PDA therapy. MATERIAL AND METHODS: Eleven trials comparing intravenous ibuprofen versus indomethacin in the treatment of PDA confirmed by echocardiography in < 35 weeks preterm or < 1,500 g birth weight were included. A meta-analysis of the trials data was performed. RESULTS: No trial show statistically significant differences in the failure of closing PDA, neither the meta-analysis (RR 0.96 [CI 95 %: 0.74-1.26], with a power of 0.995). No differences were found in the rate of reopening and surgical ligation. Complications were similar, except for a significant lower incidence of oliguria in the ibuprofen group (RR 0.23 [CI 95 %: 0.10-0.51]). There were no differences in the respiratory outcomes (RR of bronchopulmonary dysplasia (BPD) at 28 days 1.32 [CI 95 %: 0.99-1.76]). CONCLUSIONS: In our revision ibuprofen was as effective as indomethacin in closing PDA. No significant differences were found in the incidence of complications except for less renal impairment with ibuprofen. A higher risk of BPD in the ibuprofen group is not confirmed, although more studies are needed.

PMID: 17949640 [PubMed - in process]