Diruthenium(II, III) complexes of ibuprofen, aspirin, naproxen and indomethacin non-steroidal anti-inflammatory drugs: Synthesis, characterization and their effects on tumor-cell proliferation

[Ru-2(dNSAID)(4)Cl] and novel [Ru-2(dNSAID)(4)(H2O)(2)]PF6 complexes, where dNSAID = deprotonated carboxylate from the non-steroidal anti-inflammatory drugs (NSIDs), respectively: ibuprofen, Hibp (1) and aspirin, Hasp (2); naproxen, Hnpx (3) and indomethacin, Hind (4), have been prepared and characterized by optical spectroscopic methods. All of the compounds exhibit mixed valent Ru-2(II, III) cores where metal-metal bonds are stabilized by four drug-carboxylate bridging ligands in paddlewheel type structures. The diruthenium complexes and their parent NSAIDs showed no significant effects for Hep2 human larynx or T24/83 human bladder tumor. In contrast, the coordination of Ru-2(II,III) core led to synergistic effects that increased significantly the inhibition of C6 rat glioma proliferation in relation to the organic NSAIDs naproxen and ibuprofen, The possibility that the complexes Ru-2-ibp and Ru-2-npx may exert effects (anti-angiogenic and anti-matrix metalloprotease) that are similar to those exhibited by NAMI-A opens new horizons for in vivo C6 glioma model studies. (C) 2007 Elsevier Ltd. All rights reserved.

Non-steroidal anti-inflammatory drugs may modulate the protease activity of Candida albicans

The phenotypic pressure exerted by non-steroidal anti-inflammatory drugs (NSAIDs) on autochthonous and pathogenic microbiota remains sparsely known. In this study, we investigated if some NSAIDs increment or diminish the secretion of aspartyl-proteases (Sap) by Candida albicans grown under different phenotypes and oxygen availability using a set of SAP knock-out mutants and other set for genes (EFG1 and CPH1) that codify transcription factors involved in filamentation and protease secretion. Preconditioned cells were grown under planktonic and biofilm phenotypes, in normoxia and anoxia, in the presence of plasma concentrations of acetylsalicylic acid, diclofenac, indomethacin, nimesulide, piroxicam, ibuprofen, and acetaminophen. For diclofenac, indomethacin, nimesulide, and piroxicam the secretion rates of Sap by SAP1-6, EFG1. and CPH1 mutants were similar or, even, inferior to parental wildtype strain. This suggests that neither Sap 1-6 isoenzymes nor Efg1/Cph1 pathways may be entirely responsible for protease release when exposed to these NSAIDs. Ibuprofen and acetaminophen enhanced Sap secretion rates in three environmental conditions (normoxic biofilm, normoxic planktonic and anoxic planktonic). In other hand, aspirin seems to reduce the Sap-related pathogenic behavior of candidal biofilms. Modulation of Sap activity may occur according to candidal phenotypic state, oxygen availability, and type of NSAID to which the cells are exposed. (C) 2010 Elsevier Ltd. All rights reserved.

Treatment with paracetamol, ketorolac or etoricoxib did not hinder alveolar bone healing: a histometric study in rats

Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. OBJECTIVE: The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. MATERIAL AND METHODS: The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. RESULTS AND CONCLUSIONS: Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket.

Ovarian hyperstimulation syndrome: pathophysiology and prevention

To review and discuss the pathophysiology and prevention strategies for ovarian hyperstimulation syndrome (OHSS), which is a condition that may occur in up to 20% of the high risk women submitted to assisted reproductive technology cycles. The English language literature on these topics were reviewed through PubMed and discussed with emphasis on recent data. The role of estradiol, luteinizing hormone, human chorionic gonadotropin (hCG), inflammatory mediators, the renin-angiotensin system and vascular endothelial growth factor is discussed in the pathophysiology of OHSS. In addition we consider the prevention strategies, including coasting, administration of albumin, renin-angiotensin system blockage, dopamine agonist administration, non-steroidal anti-inflammatory administration, GnRH antagonist protocols, reducing hCG dosage, replacement of hCG and in vitro maturation of oocytes (IVM). Among the many prevention strategies that have been discussed, the current evidence points to the replacement of hCG by GnRH agonists in antagonist cycles and the performance of IVM procedures as the safest approaches.

A role for COX2-derived PGE2 and PGE2-receptor subtypes in head and neck squamous carcinoma cell proliferation

The overexpression of cyclooxygenase (COX)-2 is a frequent event in squamous cell carcinomas of the head and neck (HNSCC), and non-steroidal anti-inflammatory drugs, which are potent inhibitors of COX-1 and COX-2, exert chemopreventive effects on HNSCC cancer development. COX-2 promotes the release of the pro-inflammatory mediator prostaglandin E2 (PGE2), which acts on its cell surface G protein-coupled receptors EP1, EP2, EP3, and EP4. Here, we investigated the role of PGE2 and its receptors in cellular proliferation in HNSCC. The expression of COX-2 and EP1-4 was examined in immortalized oral epithelial cells and in a representative panel of HNSCC cell lines, and based on these data EP1-EP3 and COX-2 expression were evaluated by immunohistochemistry in a large clinical sample collection using HNSCC tissue microarrays. The ability of selective COX-2 inhibition to block PGE2 secretion was measured by ELISA specific assays. The effects of PGE2 on cell proliferation were evaluated using PGE2, its stable analog, and EP2 and EP3-specific synthetic agonists. The results presented here show that HNSCC tumoral lesions and their derived cell lines constitutively express COX-2 and the EP1, EP2 and EP3 receptors for PGE2. HNSCC cells secrete PGE2, which can be suppressed by low concentrations of COX-2 selective inhibitors, without inhibiting cell proliferation. Exogenously added stable PGE2 and EP3-specific agonists induce DNA synthesis in all HNSCC cell lines tested. Overall, our study supports the emerging notion that PGE2 produced in the tumor microenvironment by the overexpression of COX-2 in tumoral and inflammatory cells may promote the growth of HNSCC cells in an autocrine and paracrine fashion by acting on PGE2 receptors that are widely expressed in most HNSCC cancer cells. In particular, our findings suggest that EP3 receptor may play a more prominent role in HNSCC cell growth promotion, thus providing a rationale for the future evaluation of this PGE2 receptor as a target for HNSCC prevention strategies. Published by Elsevier Ltd.

Effects of short-term acetaminophen and celecoxib treatment on orthodontic tooth movement and neuronal activation in rat

Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for pain relief in orthodontics, but clinical studies reported that they may reduce tooth movement (TM). By other side, TM seems to activate brain structures related to nociception, but the effects of NSAIDs in this activation have not been studied yet. We analyzed the effect of short-term treatment with acetaminophen or celecoxib in the separation of rat upper incisors, as well as in neuronal activation of the spinal trigeminal nucleus, following tooth movement. Thirty rats (400-420 g) were pretreated through oral gavage (1 ml/dose)with acetaminophen (200 mg/kg), celecoxib (50 mg/kg) or vehicle (carboxymethylcellulose 0.4%). After 30 min, they received an activated (30 g) orthodontic appliance for TM. In controls, this appliance was immediately removed after its introduction. Rats received ground food, and every 12 h, one of the drugs or vehicle. After 48 h, they were anesthetized, maxilla was radiographed, and were perfused with 4% paraformaldehyde. Brains were further processed for Fos immunohistochemistry. TM induced incisor distalization (p < 0.05) and neuronal activation of the spinal trigeminal nucleus. Treatment with both drugs did not affect tooth movement, but reduced c-fos expression in the caudalis subnucleus. No changes in c-fos expression were seen in the oralis and interpolaris subnuclei. We conclude that neither celecoxib nor acetaminophen seems to affect tooth movement, when used for 2 days, but both drugs are able to reduce the activation of brain structures related to nociception. Short-term treatment with celecoxib, thus, may be a therapeutic alternative to acetaminophen when the latter is contra indicated. (C) 2009 Elsevier Inc. All rights reserved.

Human monocytes but not dendritic cells are killed by blocking of autocrine cyclooxygenase activity

Dendritic cells (DCs), in peripheral tissues, derive mostly from blood precursors that differentiate into DCs under the influence of the local microenvironment. Monocytes constitute the main known DC precursors in blood and their infiltration into tissues is up-regulated during inflammation. During this process, the local production of mediators, like prostaglandins (PGs), influence significantly DC differentiation and function. In the present paper we show that treatment of blood adherent mononuclear cells with 10 mu M indomethacin, a dose achieved in human therapeutic settings, causes monocytes` progressive death but does not affect DCs viability or cell surface phenotype. This resistance of DCs was observed both for cells differentiated in vitro from blood monocytes and for a population with DCs characteristics already present in blood. This phenomenon could affect the local balance of antigen-presenting cells, influence the induction and pattern of immune responses developed under the treatment with non-steroidal anti-inflammatory drugs and, therefore, deserves further investigation. (C) 2009 Elsevier Inc. All rights reserved.

Airway epithelium mediates the anti-inflammatory effects of exercise on asthma

Airway epithelium plays an important role in the asthma physiopathology. Aerobic exercise decreases Th2 response in murine models of allergic asthma, but its effects on the structure and activation of airway epithelium in asthma are unknown. BALB/c mice were divided into control, aerobic exercise, ovalbumin-sensitized and ovalbumin-sensitized plus aerobic exercise groups. Ovalbumin sensitization occurred on days 0, 14, 28, 42, and aerosol challenge from day 21 to day 50. Aerobic exercise started on day 22 and ended on day 50. Total cells and eosinophils were reduced in ovalbumin-sensitized group submitted to aerobic exercise. Aerobic exercise also reduced the oxidative and nitrosative stress and the epithelial expression of Th2 cytokines, chemokines, adhesion molecules, growth factors and NF-kB and P2X7 receptor. Additionally, aerobic exercise increased the epithelial expression of IL-10 in non-sensitized and sensitized animals. These findings contribute to the understanding of the beneficial effects of aerobic exercise for chronic allergic airway inflammation, suggesting an immune-regulatory role of exercise on airway epithelium. (C) 2011 Elsevier B.V. All rights reserved.

Novel 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazones: Orally effective anti-inflammatory drug candidates

We described herein the molecular design of novel in vivo anti-inflammatory 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives (1) planned by applying the molecular hybridization approach. This work also points out to the discovery of LASSBio-930 (1c) as a novel anti-inflammatory and anti-hyperalgesic prototype, which was able to reduce carrageenan-induced rat paw edema with an ED(50) of 97.8 mu mol/kg, acting mainly as a non-selective COX inhibitor. (C) 2009 Elsevier Ltd. All rights reserved.

Intestinal Anti-Inflammatory Activity of Baccharis dracunculifolia in the Trinitrobenzenesulphonic Acid Model of Rat Colitis

Baccharis dracunculifolia DC (Asteraceae) is a Brazilian medicinal plant popularly used for its antiulcer and anti-inflammatory properties. This plant is the main botanical source of Brazilian green propolis, a natural product incorporated into food and beverages to improve health. The present study aimed to investigate the chemical profile and intestinal anti-inflammatory activity of B. dracunculifolia extract on experimental ulcerative colitis induced by trinitrobenzenosulfonic acid (TNBS). Colonic damage was evaluated macroscopically and biochemically through its evaluation of glutathione content and its myeloperoxidase (MPO) and alkaline phosphatase activities. Additional in vitro experiments were performed in order to test the antioxidant activity by inhibition of induced lipid peroxidation in the rat brain membrane. Phytochemical analysis was performed by HPLC using authentic standards. The administration of plant extract (5 and 50 mgkg(-1)) significantly attenuated the colonic damage induced by TNBS as evidenced both macroscopically and biochemically. This beneficial effect can be associated with an improvement in the colonic oxidative status, since plant extract prevented glutathione depletion, inhibited lipid peroxidation and reduced MPO activity. Caffeic acid, p-coumaric acid, aromadendrin-4-O-methyl ether, 3-prenyl-p-coumaric acid, 3,5-diprenyl-p-coumaric acid and baccharin were detected in the plant extract.

Analgesic and Anti-Inflammatory Activities of Salicylaldehyde 2-Chlorobenzoyl Hydrazone (H(2)LASSBio-466), Salicylaldehyde 4-Chlorobenzoyl Hydrazone (H(2)LASSBio-1064) and Their Zinc(II) Complexes

Salicylaldehyde 2-chlorobenzoyl hydrazone (H(2)LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H(2)LASSBio-1064) and their complexes [Zn(LASSBio-466) H(2)O](2) (1) and [Zn(HLASSBio-1064) Cl](2) (2) were evaluated in animal models of peripheral and central nociception, and acute inflammation. All studied compounds significantly inhibited acetic acid-induced writhing response. Upon coordination the anti-nociceptive activity was favored in the complex 1. H(2)LASSBio-466 inhibited only the first phase of the formalin test, while 1 was active in the second phase, like indomethacin, indicating its ability to inhibit nociception associated with the inflammatory response. Hence coordination to zinc(II) altered the pharmacological profile of H(2)LASSBio-466. H(2)LASSBio-1064 inhibited both phases but this effect was not improved by coordination. The studied compounds did not increase the latency of response in the hot plate model, indicating their lack of central anti-nociceptive activity. All compounds showed levels of inhibition of zymosan-induced peritonitis comparable or superior to indomethacin, indicating an expressive anti-inflammatory profile.

Quantification of some nonsteroidal anti-inflammatory drugs as reducing agents of Cu(II)/4,4 '-dicarboxy-2,2 '-biquinoline complexes in cationic micellar medium

A simple method was developed for spectrophotometric determination of some nonsteroidal anti-inflammatory drugs (meloxicam, piroxicam and tenoxicam) based on the reduction of copper(II) in buffered solution (pH 7.0) and micellar medium containing 4,4'-dicarboxy-2,2'-buffered solution (pH 7.0) and micellar medium containing 4,4'-dicarboxy-2,2'-biquinoline acid. The-biquinoline acid. The absorbance values at 558 nm, characteristic of the formed Cu(I)/4,4'-dicarboxy-2,2'-biquinoline complexes, are linear with the concentrations (5.7-40 mmol L(-1), n = 5) of these oxicams (meloxicam r = 0.998; piroxicam and tenoxicam r = 0.999). The limit of detection values, in mmol L(-1), calculated for meloxicam (2.7), piroxicam (1.2) and tenoxicam (1.3) was obtained with 99% confidence level and the relative standard deviations for meloxicam (3.1%), piroxicam (5.1%) and tenoxicam (1.2%) were calculated using a 25 mmol L(-1) solution (n = 7). Mean recovery values for meloxicam, piroxicam and tenoxicam forms were 100 +/- 6.9, 98.6 +/- 3.6 and 99.4 +/- 2.5%, respectively. The conditional potential of Cu(II)/Cu(I) in complex medium of 7.5 mmol L(-1) BCA was determined to be 629 +/- 11 mV vs. NHE.

Antinociceptive and anti-inflammatory properties of 7-hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain

Objectives In the present study we investigated the anti nociceptive, anti-inflammatory and antipyretic effects of 7-hydroxycoumarin (7-HC) in animal models. Methods The effects of oral 7-HC were tested against acetic acid-induced writhing, formalin test, tail flick test, complete Freund`s adjuvant (CFA)-induced hypemociception, carrageenan-induced paw oedema, lipopolysaccharide-induced fever and the rota rod test. Key findings 7-HC (3-60 mg/kg) produced a dose-related antinociception against acetic acid-induced writhing in mice and in the formalin test. In contrast, treatment with 7-HC did not prevent thermal nociception in the tail flick test. A single treatment with 7-HC, 60 mg/kg, produced a long-lasting antinociceptive effect against CFA-induced hypernociception, a chronic inflammatory pain stimulus. Notably, at 60 mg/kg per day over 4 days the administration of 7-HC produced a continuous antinociceptive effect against CFA-induced hypernociception. 7-HC (30-120 mg/kg) produced anti-inflammatory and antipyretic effects against carrageenan-induced inflammation and lipopolysaccharide-induced fever, respectively. Moreover, 7-HC was found to be safe with respect to ulcer induction. In the rota rod test, 7-HC-treated mice did not show any motor performance alterations. Conclusions The prolonged antinociceptive and anti-inflammatory effects of 7-HC, in association with its low ulcerogenic activity, indicate that this molecule might be a good candidate for development of new drugs for the control of chronic inflammatory pain and fever.

Further sesquiterpene lactones from viguiera robusta and the potential anti-inflammatory activity of a heliangolide: Inhibition of human neutrophil elastase release

In addition to known heliangolides, a new eudesmanolide was isolated from the leaf rinse extract of Viguiera robusta (Asteraceae). Structural elucidation was based oil spectral analysis. It is the first report on eudesmanolides in members of the subgenus Calanticaria of Viguiera. In this work, the main isolated compound, the furanoheliangolide budlein A, besides its previously, reported in vitro and in vivo anti-inflammatory activities, inhibited human neutrophil elastase release. The inhibition was at the concentration of (16.83 +/- 1.96) mu M for formylated bacterial tripeptide (fMLP) stimulation and (11.84 +/- 1.62) mu M for platelet aggregation factor (PAF) stimulation, being slightly less active than the reference drug parthenolide. The results are important to demonstrate the potential anti-inflammatory activities of sesquiterpene lactones and corroborate the previous studies using other targets.

Anti-inflammatory and antinociceptive effects of Baccharis dracunculifolia DC (Asteraceae) in different experimental models

Aim of the study: The aerial parts of Baccharis dracunculifolia D.C., popularly known as ""alecrim do campo"" are used in folk medicine as anti-inflammatory. The aim of the present study was to evaluate the anti-inflammatory and antinociceptive activities of the crude hydroalcoholic extract obtained from leaves of Baccharis dracunculifolia (BdE), which have not been reported. Matetials and methods: BdE was analyzed by HPLC and in vivo evaluated (doses ranging from 50 to 400 mg/kg, p.o.) by using the acetic acid-induced abdominal constrictions, paw oedema induced by carrageenan or histamine, overt nociception models using capsaicin, glutamate or phorbol myristate acetate (PMA), formalin-induced nociception and mechanical hypernociception induced by carrageenan or complete Freund adjuvant (CFA). As positive controls it was used paracetamol in both acetic acid and formalin tests; dipyrone in capsaicin, glutamate and PMA-induced nociception; indomethacin in CFA and carrageenan-induced hypernociception models. In addition, the in vitro effects of BdE on COX-2 activity and on the activation of NF-kappa B were also evaluated. Results: BdE (50-400 mg/kg, p.o.) significantly diminished the abdominal constrictions induced by acetic acid, glutamate and CFA. Furthermore, BdE also inhibited the nociceptive responses in both phases of formalin-induced nociception. BdE, administered orally, also produced a long-lasting anti-hypernociceptive effect in the acute model of inflammatory pain induced by carrageenan. It was also observed the inhibition of COX-2 activity by BdE. Conclusion: In summary, the data reported in this work confirmed the traditional anti-inflammatory indications of Baccharis dracunculifolia leaves and provided biological evidences that Baccharis dracunculifolia, like Brazilian green propolis, possess antinociceptive and anti-inflammatory activities. (C) 2009 Elsevier Ireland Ltd. All rights reserved.