Action Of Non-steroidal Anti-inflammatory Drugs Research Articles

Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

Cell membranes often constitute the first biological structure encountered by drugs, and binding or interactions of drugs with lipid components of the membrane may explain part of their mechanism of activity or their side effects. The present study provides evidence of alterations in the structural properties of phospholipid bilayers at acidic conditions that can be correlated with the mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) and with their local action effect on the gastrointestinal tract lipids, aiming a molecular biophysical approach to the interaction of these drugs with lipid membranes. In this context, the structural modifications of the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine bilayers at pH 5.0, induced by increasing concentrations of five NSAIDs (piroxicam, meloxicam, tolmetin, indomethacin, and nimesulide), were studied by small-angle and wide-angle X-ray scattering. Results obtained highlight the effect of each NSAID in modulating the membrane structure properties. All the NSAIDs promoted distinct biophysical effects by perturbing the membrane arrangement to different degrees that are intimately related to their different physicochemical properties as well as with the initial organization of the lipids, depending if they are in the gel (L(β')) or in the liquid-crystalline phase (L(α)).

Abstract 833: Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/beta-catenin/cyclin D1 signaling pathway in rats

Abstract Colorectal cancer is the third leading cause of death from cancer worldwide. Evidence support the protective role of non-steroidal anti-inflammatory drugs (NSAIDs) and statins. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon adenocarcinoma (AdCa) formation. Also, we evaluated colonic AdCa inhibitory action of atorvastatin and NSAIDs in regulating the expression of key protein markers and cytokines. F344 rats were fed AIN-76A diet and colon AdCa were induced with azoxymethane (AOM). One week after AOM-treatment (adenoma-stage) groups of rats were fed AIN-76A diet containing atorvastatin (200 ppm), sulindac (100 ppm) or naproxen (150 ppm), or their combinations with atorvastatin (100 ppm) for 45 weeks. We found that rats fed experimental diets were comparable body weights and without any observable toxicity. Most of AOM-treated control-diet fed rats developed AdCa (74.2% incidence) at 45 weeks. Administration of sulindac and naproxen individually had modest inhibitory (∼25% incidence and ∼33% multiplicity) effect on colon AdCa. However, 200 ppm atorvastatin significantly suppressed both AdCa incidence (>52%, p<0.005) and multiplicity (59%, p<0.003). Importantly, colon AdCa incidence was significantly decreased when rats were given low-dose atorvastatin with either sulindac (p<0.001) or naproxen (p <0.0005). Also, colon AdCa multiplicities were profoundly reduced (80-85%, p<0.0001) when rats were given low-dose atorvastatin with either sulindac or naproxen. The staining of proliferation markers, PCNA, cyclin D1 and beta-catenin indicated that the tumors from the control group had the strong positive staining in the cells, whereas sulindac, naproxen, atorvastatin, and/or combinations had much weaker positive staining. Importantly, colon AdCa from atorvastatin and NSAIDs fed animals showed reduced expression of key inflammatory markers as well as nuclear staining for phospho-p65, a key molecule in the NF-kB pathway. In addition, atorvastatin and NSAIDs combination decreased mucosal and colonic tumor levels of the pro-inflammatory cytokines, TNF- alpha, IL-1 beta, IL-4 and IL-10. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low dose sulindac or naproxen, which greatly suppress the colon AdCa incidence and multiplicity. Also, our results suggest that decreased inflammatory cytokines and signaling molecules, particularly inhibition of nuclear p65, beta-catenin and cyclin D1 are responsible for suppression of colonic AdCa. In summary, low-dose atorvastatin with sulindac or naproxen might potential useful combinations for colon cancer prevention in humans. (Supported by NCI-N01-CN-53300 and R01-CA94962) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 833. doi:10.1158/1538-7445.AM2011-833

Molecular Mechanisms and Therapeutic Application of NSAIDs and Derived Compounds in Alzheimers Disease

Alzheimer's disease (AD) is the most common form of neurodegenerative dementias worldwide. Amyloid-β deposition, neurofibrillary tangle formation and Neuroinflammation are the major pathogenetic mechanisms that in concert lead to memory dysfunction and decline of cognition. To date, there is no curative treatment for AD. Epidemiological analysis support the notion that sustained intake of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delay the onset of AD. In contrast, therapeutic studies testing NSAID efficacy in AD patients have not yielded positive results. This suggests that either the investigated drugs have not addressed the mechanism of action required for mediating beneficial effects or that NSAIDs are effective at stages way before clinical onset of symptoms. The NSAIDs concerned are pleiotrophic in nature and interact with more than one pathomechanism. Therefore evidence for more than one neuroprotective action of NSAIDs has been put forward and it seems likely that some of the drugs act at multiple levels through more than one molecular mechanism. Some, even may not only be beneficial, but negative actions may be overruled by protective effects. Within these mechanisms, modulation of γ-secretase activity, the activation of the peroxisome proliferator-activated receptor-γ, binding to prostaglandin receptors or interactions at the blood-brain barrier may account for the observed protection from AD. This article reviews the current knowledge and views on the above mechanisms and critically discusses current obstacles and the potential as future AD therapeutics.

Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxibetc.) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer's diseases still continues to attract investigations on the development of COX-2 inhibitors. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships.

Symptomatic therapy for chronic joint diseases

The paper depicts the aspects of symptomatic therapy for chronic inflammatory diseases of joints and the mechanisms of action of nonsteroidal anti-inflammatory drugs. It gives the data available in the literature on the efficacy of Voltaren (diclofenac sodium) and pharmacodynamic differences of original Voltaren and its generics.

Indirect role of β2-adrenergic receptors in the mechanism of analgesic action of nonsteroidal antiinflammatory drugs

Adrenal gland hormones have been shown to have a role in the antiinflammatory effect mechanism of nonsteroidal antiinflammatory drugs. This study investigates whether the analgesic effects of indomethacin, diclofenac sodium, aspirin, and nimesulide (IDAN; upper case letters of the four drugs we used) are also related to adrenal gland hormones. The analgesic effects of IDAN were studied in the carrageenan-induced inflammatory pain model using both intact and adrenalectomized rats. Paw withdrawal tests were performed in adrenalectomized rats that had been pretreated with phenoxybenzamine, propranolol, and metoprolol. This study was performed in Pharmacology and Biochemistry Laboratories of Faculty of Medicine. A total of 306 (114 intact and 192 adrenalectomized) male Albino Wistar rats were used. Adrernalectomy, drug administrations, pain model induction and pain threshold measurements were performed during the study. Although the analgesic effects of nonsteroidal antiinflammatory drugs were lost in adrenalectomized rats, they exerted significant analgesia in adrenalectomized rats that had been pretreated with prednisolone and adrenalin. All these drugs were found to decrease serum adrenalin concentration but did not change serum cortisole (corticosterone in rats) concentration. Prednisolone and adrenalin inhibited carrageenan-induced hyperalgesia in adrenalectomized rat groups pretreated with metoprolol or phenoxybenzamine, but not in rats given propranolol. Propranolol also negated the analgesic effects of IDAN in intact rats. The analgesic effects provided by either prednisolone or adrenalin could not be inhibited by the alpha1, alpha2, or beta1 blockers but disappeared when beta2 receptors were blocked. The analgesic effects of nonsteroidal antiinflammatory drugs appear to be related to endogenous adrenalin and cortisole. We have demonstrated that adrenalin and prednisolone play important roles in the analgesic effect mechanism of IDAN. Prednisolone and adrenalin produce analgesic effects through beta2-adrenergic receptors, suggesting an indirect role for beta2-adrenergic receptors in the analgesic effect mechanism of the nonsteroidal antiinflammatory drugs mentioned.

Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors

Anti-inflammatory efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been related to their properties as inhibitors of cyclooxygenase (COX)-mediated prostaglandin (PG) synthesis. However, recent studies have suggested that variations of the in vivo anti-inflammatory actions among different NSAIDs could not be solely explained by COX inhibition. Here, we have analyzed the effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole anti-inflammatory drugs with different potencies as COX-2 inhibitors, namely E-6087, E-6232, E-6231, E-6036 and E-6259 as well as the chemically related COX-2 inhibitor Celecoxib. These drugs inhibited mitogen-mediated T cell proliferation as well as Interleukin (IL)-2, tumor necrosis factor (TNF)-α and Interferon (IFN)-γ synthesis by activated T cells, independently of their ability to inhibit COX-2 enzymatic activity. Immunosuppressive effects of these drugs seem to be due to their interference on transcription factor activation as induced transcription from Nuclear Factor (NF)-κB and Nuclear Factor of Activated T cells (NFAT)-dependent enhancers was inhibited in a dose-dependent manner, being the latter effect the most sensitive to the action of those compounds. Both NFAT dephosphorylation, required for its nuclear translocation, as well as transcriptional activity of a GAL4-NFAT chimera were diminished in the presence of these compounds. These findings provide new insights into the molecular mechanisms involved in the immunomodulatory and anti-inflammatory actions of NSAIDs, which may have important implications in anti-inflammatory therapy, through inhibition of NFAT.

In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1.

The detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC50, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy.

Clopidogrel: mechanisms of action and review of the evidence relating to use during skin surgery procedures

Patients who have skin surgery may be taking medication that increases the likelihood of bleeding, such as clopidogrel, aspirin, warfarin, heparin and nonsteroidal anti-inflammatory drugs (NSAIDS). All of these may increase the risk of perioperative and postoperative bleeding. This article examines the mechanism of action of clopidogrel, current practice, and evidence for or against continuing its use during skin surgery. The mechanisms of action of aspirin, warfarin, heparin and NSAIDS will also be briefly discussed.

Clinical outcomes of systemic therapy for patients with deep fibromatosis (desmoid tumor)

In the current study, the authors examined the outcomes of patients with desmoid tumors who received systemic therapy at a single institution to provide a basis for the examination of newer agents. Records of patients with desmoid tumors who were treated with chemotherapy at the study institution were reviewed. The activity of nonsteroidal anti-inflammatory drugs was not addressed. Patients without measurable disease and those receiving therapy could not be documented, and those receiving prophylactic therapy were excluded. A total of 68 patients received 157 lines of therapy. At the time of last follow-up, 9 patients had died, 7 of progressive disease. The cohort was 62% female, with a median age of 32.5 years. Approximately 32% of the patients had Gardner syndrome. The median follow-up was 63 months, and patients received a median of 2 lines of therapy. An intra-abdominal primary tumor location was the most common (44%). The greatest Response Evaluation Criteria in Solid Tumors (RECIST) response rate was observed with anthracyclines and hormonal therapy and the lowest response was noted with single-agent dacarbazine/temozolomide or tyrosine kinase inhibitors, principally imatinib. On multivariate analysis, macroscopic nodular morphology and the presence of Gardner syndrome were the only tumor factors found to be associated with a greater time to disease progression. Compared with other agents, antiestrogens and anthracycline-containing regimens appear to be associated with a higher radiological response rate against desmoid tumors. Systemic therapy can be successful in patients with desmoid tumors, and is a viable option in lieu of morbid or disabling surgery.

Abstract 2274: Effect of myeloperoxidase inhibitor resorcinol on colon tumorigenesis in APCmin/+ mice

Abstract Beneficial actions of non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer progression are well accepted. Nevertheless, NSAIDs have had only a minor impact in primary or secondary prevention - even in high risk populations - for at least two reasons. First, NSAIDs are contra-indicated in some high risk conditions, such as colitis-associated colorectal cancer, because of their corrosive actions in the gut. Second, publicity about the cardiovascular safety of NSAIDs has thwarted their potential in primary or secondary prevention of sporadic polyps. Thus, we sought to identify molecular targets and agents that might work in these situations. Myeloperoxidase (MPOx) from neutrophils is distantly related to the cyclooxygenase (COX) enzymes. MPOx and its relative, eosinophil peroxidase (EPOx) constitute part of the innate immune process in the normal gut, and the pathology of colitis. Hypochlorite generated by MPOx oxidizes amino acids (serine, threonine) and polyunsaturated fatty acids (arachidonic acid). Several of these oxidative by-products generated by MPOx - hypochlorite are non-prostaglandin E2 (PGE2) mediators that enhance β-catenin signaling. Thus, we hypothesized that MPOx and its by-products may promote intestinal malignancy, comparable to the actions of COX and PGE2. Using APCmin/+ mice we tested the effect of resorcinol, an irreversible MPOx inhibitor, under two experimental conditions: 1) colorectal and intestinal tumor promotion accompanying inflammation induced with dextran sodium sulfate (DSS); and 2) tumor formation in the normal intestine, without colitis, but with basal “inflammation” (para-inflamation) due to commensal bacteria in the gut. For APCmin/+ mice with DSS induced inflammation, 1.25mg/kg intraperitoneal (IP) resorcinol caused a 30% reduction in colorectal adenoma numbers, and a 40% reduction in average adenoma size (p<0.05). Small intestinal polyp numbers were also reduced by 20%. Surprisingly, in APCmin/+ mice without DSS-induced colitis, but with basal “inflammation” of the normal gut, resorcinol 1.25mg/kg IP caused a modest, but detectable increase in adenoma formation. To reconcile these results we hypothesize that anti-inflammatory effects dominate the high intensity inflammation in the DSS colitis-APCmin/+ mouse, and manifest as reduced colitis-associated tumor formation. Conversely, we hypothesize that anti-inflammatory action in the lesser basal “inflammation” of normal APCmin/+ mice suppresses innate immune surveillance and elimination processes, which spares aberrant crypt foci. Alternatively, oxidation of resorcinol in the gut of normal APCmin/+ mice may be generating tumor promoting quinine metabolites. We are breeding an MPOx null-APCmin/+ mouse to help distinguish between these two alternatives. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2274.

Mechanisms of Action of Non-Steroidal Anti-Inflammatory Drugs for the Prevention of Alzheimers Disease

Alzheimer's disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDs). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDs cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD subjects have failed, and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review.

Non-opioid tolerance in juvenile and adult rats

It has recently been shown that antinociceptive tolerance develops by repeated systemic administration of non-steroidal anti-inflammatory drugs (NSAIDs) metamizol and lysine-acetylsalicylate. This is similar to the tolerance observed with opioid-induced analgesia [Vanegas and Tortorici, 2002, Cell and Mol. Neurobiol. 22, 655–661]. In the present study, we investigated the development of tolerance to the analgesic effects of the additional NSAIDs analgine, ketorolac and xefocam in juvenile and adult rats. After injection of each drug, tail-flick latencies were significantly elevated on the first day followed by a progressive decrease in tail-flick latency (i.e., tolerance) over the 5-day period, as well as cross-tolerance to morphine-induced analgesia. Tolerance to the analgesic effect of all three NSAIDs developed more rapidly in juvenile compared to adult rats. Pretreatment with naloxone completely prevented the analgesic effects of these drugs in tail-flick and hot plate tests for both juvenile and adult rats. Moreover, each NSAID exhibited cross-tolerance when tolerance to morphine had been induced by systemic morphine delivered repeatedly over 5-day period in both age groups. Our data confirm other recent findings that tolerance to the analgesic action of NSAIDs may depend on an opiate-mediated mechanism.

Abstract C96: The effect of non-steroidal anti-inflammatory drugs (NSAIDs) in ovarian cancer cells

Abstract Epidemiological and laboratory studies have suggested a protective role for non-steroidal anti-inflammatory drugs (NSAIDs) against various neoplasms, including ovarian cancer. In an attempt to clarify the mechanisms and molecular targets of tumor prevention by NSAIDs, we have studied the effects of multiple NSAIDs in several ovarian cancer cell lines. NSAID treatment decreased the viability of all the ovarian cancer cell lines examined. To determine the effect of NSAIDs on the cell cycle, flow cytometry analysis was performed. Cells treated with indomethacin, ibuprofen or celecoxib were arrested in G1 phase, while cells treated with diclofenac underwent an S/G2 arrest. In addition, induction of apoptosis was cell line specific. The levels of several cell cycle regulatory and apoptosis proteins were examined. The levels of phosphorylated Rb protein decreased and phospho-p53 increased upon treatment with NSAIDs, suggesting an involvement of these proteins in the response of ovarian cancer cells to NSAID treatment. In order to further clarify the mechanisms of action of NSAIDs in ovarian cancer cells, gene expression profiling experiments were performed. Ovarian cancer cell lines Hey, OVCAR5, and UCI101 were treated with diclofenac, indomethacin, celecoxib, and ibuprofen, and microarray analysis was performed. A large number of gene expression changes were observed in the different cell lines treated with various NSAIDs. Among the most consistent and reproducible changes observed, S-phase kinase associated protein 2 (Skp2) was found to be downregulated at the mRNA and protein levels in all cell lines with all NSAIDs tested. In addition, Damage inducible transcript-4 (DDIT4) was found to be upregulated in all cell lines upon treatment with diclofenac, indomethacin and celecoxib. Skp2 forms part of the SCF ubiquitin ligase and is involved in the targeting for degradation of several proteins, including the cyclin dependent kinase inhibitors p21 and p27, therefore facilitating S-phase entry. DDIT-4, is transcriptionally activated upon p53 activation and it is known to inhibit mTOR signaling. In conclusion, we have identified a number of target genes that may be important for the NSAID-induced cell cycle arrest and apoptosis and their exact roles are currently being investigated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C96.

Pharmacokinetic of Diclofenac in the Presence and Absence of Glibenclamide in the Rat

There is evidence that the sulfonylurea antidiabetic agent glibenclamide reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. Therefore, in view of the vast clinical uses and interactions of NSAIDs with commonly used therapeutic agents, the interaction of the NSAID diclofenac and glibenclamide was investigated about pharmacokinetic profile and antinociceptive effect in rats. Antinociception was assessed using the formalin test. Fifty microliters of diluted formalin was injected s.c. into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection. Rats were treated with oral administration of vehicle or increasing doses of diclofenac (3-18 mg/kg) before formalin injection. To determine the pharmacodynamic interaction between diclofenac and glibenclamide, the effect of oral administration of glibenclamide (1-30 mg/kg) on the antinociceptive effect induced by diclofenac (18 mg/kg, p.o.) was assessed. To evaluate the pharmacokinetic interaction between diclofenac and glibenclamide, the effect of glibenclamide (10 mg/kg, p.o.) on the pharmacokinetic of diclofenac (18 mg/kg, p.o.) was studied in the rat. Blood samples were taken over 8 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of diclofenac. Pharmacokinetic parameters were estimated using noncompartmental analysis. Systemic administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Systemic treatment with glibenclamide prevented diclofenac-induced antinociception. In pharmacokinetic interaction study, no significant (P>0.05) change in diclofenac concentration-time profiles in the presence of glibenclamide was detected. The experimental findings suggest that systemic glibenclamide is able to block the diclofenac-induced antinociception in the rat formalin test. Besides, this antagonism was not produced by diminution in the bioavailability of diclofenac. Likewise, the validated assay had sufficient accuracy and precision for pharmacokinetic determination of diclofenac in the rat.

Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critique

Chondroitin sulphate (CS) has attracted much interest over the past two decades or so as a biological agent for use in the relief of pain and joint symptoms in osteoarthritis. Earlier clinical investigations produced variable, if encouraging results. This variability was partly due to limitations on the study designs and the lack of availability of standardized CS. Recently, high quality and fully standardized CS (Condrosulf) has become available and its effects have been studied in large-scale osteoarthritis trials, which are discussed here. There is now evidence for symptom- and structure-modifying (radiologically-observed) effects. These studies show that CS (a) has slow onset of response and that relief of pain may not be like that of the direct analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs), (b) there are indications of reduced need for intake of analgesics (e.g. NSAIDs) in patients taking CS, and (c) quality of life and cost-benefits may be associated with use of CS. Safety evaluations show that the incidence of adverse reactions is low. Pharmacokinetic studies indicate that although oral absorption is relatively fast CS has moderate oral bioavailability (15-24%) and that depolymerised and degraded CS that is evident after absorption, together with CS itself, may take some time to accumulate in target joints. The pharmacodynamic actions of CS indicate that it has anti-inflammatory effects that include multiple actions involving reduction of catabolic reactions and enhanced anabolic (proteoglycan) synthetic reactions in cartilage and may block osteoclast activation in bone. Further studies are required to (a) establish the effects of depolymerised and degraded CS on degradation of cartilage and bone in vitro, and (b) MRI and other investigations of the effects in osteoarthritis of long-term CS treatment. The findings from this review show there may be potential value of CS in reducing the dependence on intake of NSAIDs and analgesics in patients with osteoarthritis, while at the same time having favourable safety.

Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critique

Abstract Objectives Chondroitin sulphate (CS) has attracted much interest over the past two decades or so as a biological agent for use in the relief of pain and joint symptoms in osteoarthritis. Earlier clinical investigations produced variable, if encouraging results. This variability was partly due to limitations on the study designs and the lack of availability of standardized CS. Recently, high quality and fully standardized CS (Condrosulf) has become available and its effects have been studied in large-scale osteoarthritis trials, which are discussed here. Key findings There is now evidence for symptom - and structure-modifying (radio-logically-observed) effects. These studies show that CS (a) has slow onset of response and that relief of pain may not be like that of the direct analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs), (b) there are indications of reduced need for intake of analgesics (e.g. NSAIDs) in patients taking CS, and (c) quality of life and cost-benefits may be associated with use of CS. Safety evaluations show that the incidence of adverse reactions is low. Pharmacokinetic studies indicate that although oral absorption is relatively fast CS has moderate oral bioavailability (15–24%) and that depolymerised and degraded CS that is evident after absorption, together with CS itself, may take some time to accumulate in target joints. The pharmacodynamic actions of CS indicate that it has anti-inflammatory effects that include multiple actions involving reduction of catabolic reactions and enhanced anabolic (proteoglycan) synthetic reactions in cartilage and may block osteoclast activation in bone. Further studies are required to (a) establish the effects of depolymerised and degraded CS on degradation of cartilage and bone in vitro, and (b) MRI and other investigations of the effects in osteoarthritis of long-term CS treatment. Summary The findings from this review show there may be potential value of CS in reducing the dependence on intake of NSAIDs and analgesics in patients with osteoarthritis, while at the same time having favourable safety.

Mechanisms of non-steroid anti-inflammatory drugs action on acid-sensing ion channels of hippocampal interneurons

306 The inhibitiory action of non-steroid anti-inflammatory drugs (diclofenac, ibuprofen, aspirin and salicylic acid) was investigated on acid-sensing ion channels (ASIC) in isolated hippocampal interneurons and on recombinant homoand heteromeric ASICs expressed in CHO cells. Diclofenac and ibuprofen inhibited proton-induced currents in a range of concentrations from 100 μ M to 3 mM (IC 50 were 622 ± 34 μ M and 3.42 ± 0.50 mM respectively). The non-competitive inhibition was fast and fully reversible for both drugs. Aspirin and salicylic acid were ineffective up to 500 μ M. Diclofenac and ibuprofen decreased the amplitude of proton-evoked currents and slowed the rate of currents decay with a good correlation between these two effects ( r = 0.99, p < 0.05 for both drugs). Simultaneous application of acid solution (pH = 5.5) and diclofenac was required for its inhibitory action. Unlike amiloride, nonselective inhibitor of ENaC/Deg family of sodium channels, the action of diclofenac was voltage-independent. No competition was found between diclofenac and amiloride. Analysis of the action of diclofenac and ibuprofen on activation and desensitization of ASICs showed that diclofenac but not ibuprofen shifted the steady-state desensitization curve to more alkaline pH values. The reason for this shift was slowing down the recovery from desensitization of ASICs. Thus, diclofenac may serve as a neuroprotective agent during pathological conditions associated with acidification of extracellular environment.

Computer design of trans-stilbene derivatives with pronounced anti-inflammatory activity and low toxicity

Using models developed for predicting the anti-inflammatory activity of nonsteroidal anti-inflammatory drugs (NSAIDs) and their selectivity in inhibiting isomeric forms of cyclooxygenases, the structure of resveratrol has been analyzed for the presence of fragments that influence negatively the anti-inflammatory activity. Based on this analysis, five potential NSAIDs with modified resveratrol structures that possess pronounced anti-inflammatory activity and low toxicity are proposed. These compounds are recommended for synthesis and in vitro and in vivo investigations.

New Insights on the Possible Role of Mast Cells in Aspirin-Induced Asthma

Nonsteroidal anti-inflammatory drugs (NSAIDs) are major drugs used in the treatment of inflammation and pain in a wide variety of disorders. The best-known mechanism of action of NSAIDs is the inhibition of prostaglandin synthesis as a result of their action on cyclooxygenase (COX) enzymes. However, data have been accumulating through the years indicating that NSAIDs also act on other targets in cell signaling. It has been established that NSAIDs induce anti-inflammatory effects independent of COX. Acetylsalicylic acid (ASA) and other inhibitors of COX induce severe bronchospasms and asthmatic attacks in a significant population of asthmatic patients. The etiology of ASA induced asthma is complex and not fully understood, but most evidence points towards an abnormality of arachidonic acid (AA) metabolism. Since doses of ASA necessary to treat chronic inflammatory diseases appeared much higher than those required to inhibit PG synthesis, COX-independent mechanisms of NSAIDs were postulated. Recently, we have shown that NSAIDs induced expression of heat shock proteins specially HSP70. Heat shock proteins (HSPs) are normal intracellular proteins that are produced in greater amounts when cells are subjected to stress or injury. Interestingly, a potential pathogenic role for heat shock proteins in diseases such as autoimmune disease, vascular disease has been reported. Because mast cells have been reported to play a role in the pathogenesis of ASA induced asthma, a link between heat shock proteins and this disease could postulated. In this review, an overview is given on aspirin-induced asthma and the cells and mediators that may play a role therein. Mast cell signaling with regard to interaction with NSAIDs and heat shock proteins (HSPs) and toll-like receptors (TLRs) is further highlighted.