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Sample records for non-steroid anti-inflammatory drugs

  1. Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.

    PubMed

    Smith, Christina E; Soti, Subada; Jones, Torey A; Nakagawa, Akihisa; Xue, Ding; Yin, Hang

    2017-02-15

    Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. While the role of NSAIDs as cyclooxygenase (COX) inhibitors is well established, other targets may contribute to anti-inflammation. Here we report caspases as a new pharmacological target for NSAID family drugs such as ibuprofen, naproxen, and ketorolac at physiologic concentrations both in vitro and in vivo. We characterize caspase activity in both in vitro and in cell culture, and combine computational modeling and biophysical analysis to determine the mechanism of action. We observe that inhibition of caspase catalysis reduces cell death and the generation of pro-inflammatory cytokines. Further, NSAID inhibition of caspases is COX independent, representing a new anti-inflammatory mechanism. This finding expands upon existing NSAID anti-inflammatory behaviors, with implications for patient safety and next-generation drug design.

  2. [Non steroidal anti-inflammatory drugs and rheumatic diseases].

    PubMed

    Cossermelli, W; Pastor, E H

    1995-01-01

    Nonsteroidal anti-inflammatory drugs (NSAID) comprise an important class of medicaments that reduced the symptoms of inflamation in rheumatic disease. This article emphasizes similarities and class characteristics of the NSAID, mechanisms of action, and drug-interactions.

  3. Non-steroidal Anti-inflammatory Drugs in Raptors

    USGS Publications Warehouse

    Oaks, J. Lindsay; Meteyer, Carol U.; Miller, R. Eric; Fowler, Murray E.

    2012-01-01

    The use of analgesia has become standard, and appropriate, practice in avian medicine. As in mammals, pain control in avian patients is usually accomplished with opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) used singly or in combination for a multimodal approach. Despite their usefulness, widespread use, and relative safety in clinical use, few controlled studies in birds have been conducted on efficacy, safety, and dosing. The guidelines for the use of NSAIDs in raptors and other birds have mainly been empirical. More recently, NSAIDs in free-living raptors have emerged as a major conservation issue with the discovery that diclofenac sodium was responsible for the population crash of three species of Gyps vultures in southern Asia. In this context, residues of veterinary NSAIDs in domestic animals are now considered environmental contaminants that can be significantly toxic to vultures and possibly other avian scavengers. Ironically, the disaster with Asian vultures has led to a considerable body of research on NSAIDs in raptors to the benefit of clinicians who now have scientific information available to help assess dosing, safety, toxicity, and pharmacokinetics of NSAIDs in their raptor patients.

  4. Non-steroidal anti-inflammatory drug gastropathy: clinical results with antacids and sucralfate.

    PubMed

    Lazzaroni, M; Sainaghi, M; Bianchi Porro, G

    1999-01-01

    The efficacy of antacids in the short- and long-term treatment of peptic ulcers, has suggested a possible use in the prevention and in the treatment of non-steroidal anti-inflammatory drug related gastroduodenal lesions. In short-term prevention studies, significant protection against ASA-related lesions was observed when antacids at high-dose were given before the administration of the offending drug. To the contrary, antacids at low dose did not prevent ASA-induced lesions of gastric and duodenal mucosa. As for long-term prophylaxis, no clinical effect was observed. In the treatment of non-steroidal anti-inflammatory drug-related mucosal lesions in patients who were able to discontinue the offending drugs, antacids proved of some use, when compared with placebo, but were significantly less effective than H2 blockers, as cimetidine. Sucralfate is an effective antiulcer drug thought to provide cytoprotective action. Although initial studies utilizing sucralfate for protection against short-term aspirin administration were encouraging, longer term studies (more than 7 days) were generally disappointing. A comparative study with misoprostol demonstrated that the PGE1 analogue was far superior for the prevention of non-steroidal anti-inflammatory drugs ulcers, and that ulceration rates in the sucralfate group were equivalent to rates in the placebo group. As far as the treatment of non-steroidal anti-inflammatory drug-related mucosal lesions is concerned, sucralfate proved superior to placebo, similar to ranitidine, but significantly less effective than omeprazole.

  5. The non-steroidal anti-inflammatory drug niflumic acid inhibits Candida albicans growth.

    PubMed

    Baker, Andrew; Northrop, Frederick D; Miedema, Hendrik; Devine, Gary R; Davies, Julia M

    2002-01-01

    The non-steroidal anti-inflammatory drug niflumic acid was found to inhibit growth of the yeast form of Candida albicans. Niflumic acid inhibited respiratory oxygen uptake and it is hypothesised that this was achieved by cytosolic acidification and block of glycolysis. Inhibitory concentrations are compatible with current practice of topical application.

  6. Comparison of beneficial actions of non-steroidal anti-inflammatory drugs to flavonoids.

    PubMed

    Conti, P; Varvara, G; Murmura, G; Tete, S; Sabatino, G; Saggini, A; Rosati, M; Toniato, E; Caraffa, A; Antinolfi, P; Pandolfi, F; Potalivo, G; Galzio, R; Theoharides, T C

    2013-01-01

    Inflammation is involved in increasing number of diseases necessitating the development of new, effective and safe treatments. Non steroidal anti-inflammatory drugs (NSAIDs) have been helpful in many instances, but they only inhibit cyclooxygenase (COX), but not the generation or actions of cytokines. Instead, some natural flavonoids have multiple anti-inflammatory effects, including COX inhibition, and a much safer profile. Increasing evidence indicates that inflammation plays a critical role in the pathogenesis of many diseases that also involve mast cells. Consequently, the need for new, effective and safe anti-inflammatory drugs is all the more urgent. Corticosteroids are quite potent, but have many adverse effects such as increased risk of infections, osteoporosis, glaucoma and depression. Biological agents such anti-TNF are useful in certain conditions, such as rheumatoid arthritis and psoriasis, but has been associated with increased risk of infection and leukemia.

  7. Renal Side Effects of Non-Steroidal Anti-Inflammatory Drugs in Neonates

    PubMed Central

    Allegaert, Karel; de Hoon, Jan; Debeer, Anne; Gewillig, Marc

    2014-01-01

    Non-steroidal anti-inflammatory drugs like ibuprofen or indomethacin are commonly prescribed drugs to induce pharmacologic closure of a patent ductus arteriosus in preterm neonates. Based on a recently published Cochrane meta-analysis, both drugs are equally effective to induce closure. Drug choice can therefore be based on differences in side effects or pharmaco-economic arguments. The current review quantifies the negative impact of either ibuprofen or indomethacin on renal function, including diuresis, glomerular filtration rate and renal tubular function. Both ibuprofen and indomethacin have a quantifiable impact on renal function. However, compared to ibuprofen, the negative impact of indomethacin is more pronounced. PMID:27713258

  8. Structural basis of non-steroidal anti-inflammatory drug diclofenac binding to human serum albumin.

    PubMed

    Zhang, Yao; Lee, Philbert; Liang, Shichu; Zhou, Zuping; Wu, Xiaoyang; Yang, Feng; Liang, Hong

    2015-11-01

    Human serum albumin (HSA) is the most abundant protein in plasma, which plays a central role in drug pharmacokinetics because most compounds bound to HSA in blood circulation. To understand binding characterization of non-steroidal anti-inflammatory drugs to HSA, we resolved the structure of diclofenac and HSA complex by X-ray crystallography. HSA-palmitic acid-diclofenac structure reveals two distinct binding sites for three diclofenac in HSA. One diclofenac is located at the IB subdomain, and its carboxylate group projects toward polar environment, forming hydrogen bond with one water molecule. The other two diclofenac molecules cobind in big hydrophobic cavity of the IIA subdomain without interactive association. Among them, one binds in main chamber of big hydrophobic cavity, and its carboxylate group forms hydrogen bonds with Lys199 and Arg218, as well as one water molecule, whereas another diclofenac binds in side chamber, its carboxylate group projects out cavity, forming hydrogen bond with Ser480.

  9. Non-steroidal anti-inflammatory drugs and colorectal cancer prevention

    PubMed Central

    Sangha, S; Yao, M; Wolfe, M

    2005-01-01

    Colorectal cancer is the second leading cause of cancer deaths in the United States. Currently, the most effective strategy available for colon cancer prevention is endoscopic screening, with polypectomy or surgical resection for advanced lesions. This intervention carries with it many concerns regarding cost, patient acceptance, and the growing burden of surveillance colonoscopies for patients with polyps. Further improvements in the understanding of the multistep model of colorectal carcinogenesis will probably lead to the development of other primary and secondary prevention strategies. Data obtained from animal and epidemiological studies and most recently from randomised, placebo controlled trials, suggest that non-steroidal anti-inflammatory drugs may prove effective chemopreventive agents in different groups of people, from patients with familial adenomatous polyposis to those with sporadic adenomas. PMID:15811884

  10. The non-steroidal anti-inflammatory drug diclofenac is readily biodegradable in agricultural soils.

    PubMed

    Al-Rajab, Abdul Jabbar; Sabourin, Lyne; Lapen, David R; Topp, Edward

    2010-12-01

    Diclofenac, 2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid, is an important non-steroidal anti-inflammatory drug widely used for human and animals to reduce inflammation and pain. Diclofenac could potentially reach agricultural lands through the application of municipal biosolids or wastewater, and in the absence of any environmental fate data, we evaluated its persistence in agricultural soils incubated in the laboratory. (14)C-Diclofenac was rapidly mineralized without a lag when added to soils varying widely in texture (sandy loam, loam, clay loam). Over a range of temperature and moisture conditions extractable (14)C-diclofenac residues decreased with half lives <5days. No extractable transformation products were detectable by HPLC. Diclofenac mineralization in the loam soil was abolished by heat sterilization. Addition of biosolids to sterile or non-sterile soil did not accelerate the dissipation of diclofenac. These findings indicate that diclofenac is readily biodegradable in agricultural soils.

  11. [Appropriate prescription, adherence and safety of non-steroidal anti-inflammatory drugs].

    PubMed

    Sostres, Carlos; Lanas, Ángel

    2016-03-18

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most numerous category of drugs sharing the same mechanism of action and therapeutic activities (anti-inflammatory, analgesic and anti-pyretic). Despite having similar efficacy for pain relieve, the different available NSAIDs show variability in its safety profile. The risk of gastrointestinal and cardiovascular complications varies depending on the dose of NSAID and also the presence of different risk factors. It is necessary, therefore, an individualized case assessment before establishing the indication of the best NSAID for each patient, taking account of the best gastroprotection strategy. Improved prescription and enhanced treatment adherence are central objectives to reduce NSAID-related complications. A recent consensus of the Spanish Association of Gastroenterology and the Spanish societies of Cardiology and Rheumatology intends to promote the rational use of NSAIDs according to new recent studies. This review provides additional aspects to facilitate the optimal decision-making process in the routine use of these drugs in clinical practice.

  12. Effects of non-steroidal anti-inflammatory drugs on canine neutrophil chemotaxis.

    PubMed

    Strøm, H; Thomsen, M K

    1990-06-01

    Non-steroidal anti-inflammatory drugs exhibit differences in their ability to suppress polymorphonuclear leucocyte (PMN) functions in different species. The present study investigated the in-vitro and ex-vivo effects of phenylbutazone and flunixin on leukotriene-B4-directed migration of canine PMN. Furthermore, in-vitro comparison was made to indomethacin and the 5-lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA). In vitro, flunixin and NDGA were the most potent inhibitors, with IC50S of 13 and 7 mumol/l, respectively. Phenylbutazone had an IC50 of 42 mumol/l whereas indomethacin did not achieve 50% inhibition at concentrations less than 100 mumol/l. Ex vivo, flunixin almost completely abolished the LTB4 response at 1 h, and still possessed significant inhibitory activity 24 h after a dosage of 1 mg/kg i.v. Phenylbutazone was less active ex vivo but did suppress chemotaxis by 23% (P less than 0.05) at 1 h following an i.v. dose of 20 mg/kg. It is suggested that part of the anti-inflammatory action of flunixin in dogs may be attributed to inhibition of PMN recruitment.

  13. Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy.

    PubMed

    Hussain, Muzammal; Javeed, Aqeel; Ashraf, Muhammad; Al-Zaubai, Nuha; Stewart, Alastair; Mukhtar, Muhammad Mahmood

    2012-07-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) have received considerable importance in cancer chemoprevention over the last few years. They are now being considered as prospective candidates in cancer immunotherapy because of their striking immune-enhancing impact on various effector elements of anti-tumour immunity on one hand, and to augment the efficacy of different anti-cancer immunotherapeutic strategies on the other. This review specifically discusses the role of NSAIDs in anti-tumour immunity by describing their immunomodulatory effects on different immune cells including tumour-associated macrophages (TAM), dendritic cells (DC), natural killer (NK) cells, T effector cells, and T regulatory cells (Treg). Secondly, the therapeutic perspective of NSAIDs in combination with different anti-cancer immunotherapeutic approaches, in particular the cancer vaccines, tumour-specific monoclonal antibodies, and cytokine-based therapy, has been outlined. At the end, the impact of anti-inflammatories other than NSAIDs on tumour immunity and immunotherapy, and the immunopharmacological potential of selective E-prostanoid (EP) receptor antagonists with respect to cancer immunity have also been discussed briefly.

  14. Interactions between non-steroidal anti-inflammatory drugs and lipid membranes

    NASA Astrophysics Data System (ADS)

    Boggara, Mohan; Krishnamoorti, Ramanan

    2008-03-01

    Chronic usage of Non-steroidal anti-inflammatory drugs(NSAIDs) leads to gastrointestinal toxicity and clinical evidences point the cause to direct interactions between NSAIDs and phospholipid membranes. Also, NSAIDs pre-associated with phospholipid vesicles are shown to be safer and therapeutically more effective than unmodified ones. Our initial experiments and simulations on the partitioning of Aspirin and Ibuprofen clearly indicate role played by the drug structure in drug-membrane interactions. Those results motivated systematic molecular dynamics simulations of membranes with NSAIDs of different size, structure and pKa values. Our results suggest high partition coefficients for these NSAIDs in the membrane compared to water and thinning effect on the bilayer. Our small angle neutron scattering and reflectivity studies on DMPC-Ibuprofen systems indicate that the drug affects both ˜5 nm thick bilayer and overall ˜100 nm diameter vesicle, indicating that NSAIDs affect vesicles on various length scales. We will discuss the structural perturbations to membranes due to NSAIDs at clinically relevant molar ratios and their implications on the use of vesicles as delivery vehicles for NSAIDs.

  15. Adverse effects of conventional non-steroidal anti-inflammatory drugs on the upper gastrointestinal tract.

    PubMed

    Langman, Michael J S

    2003-08-01

    This article reviews the clinical and epidemiological features of conventional non-steroidal anti-inflammatory drug (NSAID) related peptic ulcer complications, and the associated risk factors. The degree of gastrointestinal toxicity varies widely between the available drugs and with dose of each. The risk of ulcer complications can however be reduced, and perhaps completely removed, by using the lowest dose of the least toxic member of the class. Enteric coating and other delayed release formulations have not been shown to reduce risk. Estimates of the imposed disease burden have varied widely, in part through assuming that risks in selected patient groups will necessarily translate to the general population. Nevertheless, the imposed disease burden is one of the largest associated with current drug treatment. Associated risk factors such as prior ulcer, corticosteroid use and concurrent aspirin as well as general cardiovascular disease will raise the likelihood of an ulcer complication in NSAID takers and non-takers. Therefore, strategies dependent on substituting COX-selective drugs will then be only partially successful.

  16. Prevention of Renal Complications Induced by Non- Steroidal Anti-Inflammatory Drugs.

    PubMed

    Ković, Sonja Vuč; Vujović, Katarina Savić; Srebro, Dragana; Medić, Branislava; Ilic-Mostic, Tatjana

    2016-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of pain, inflamation and fever. They are usually well tolerated in healthy persons, but in patients with risk factors (advanced age, renal impairment, heart failure, liver disease, concurrent medications with antihypertensive drugs), NSAIDs can induce serious renal adverse effects. They include sodium and water retention with edema, worsening of heart failure, hypertension, hyponatremia, hyperkalemia, acute kidney injury, chronic kidney disease, renal papillary necrosis and acute interstitial nephritis. The majority of these adverse effects are due to the inhibition of prostaglandins synthesis and they are dose and duration-dependent. Acute forms of kidney injuries are transient and often reversible upon drug withdrawal. Chronic use of NSAIDs in some patients may result in chronic kidney disease. It is recommended that patients at risk should have preventative strategies in place, including the use of the "lowest effective dose" of NSAID for the "shortest possible time" and monitoring renal function, fluid retention and electrolyte abnormalities. Patients who are taking antihypertensive medications should be monitored for high blood pressure and the doses of antihypertensive medications should be adjusted if needed. In general, the combination of NSAIDs and angiotensin inhibitors should be avoided. Some other preventive measures are dietary salt restriction, use of topical NSAIDs/non-pharmacological therapies and use of calcium channel blockers for treating hypertension.

  17. Cardiovascular pharmacogenetics of anti-thrombotic agents and non-steroidal anti-inflammatory drugs.

    PubMed

    Stitham, J; Vanichakarn, P; Ying, L; Hwa, J

    2014-01-01

    The use of antithrombotic agents, particularly antiplatelet drugs like aspirin and clopidogrel, has been instrumental in decreasing the risk for adverse cardiovascular events across a wide range of patients. However, despite the established benefits, the use of these medications remains suboptimal. There is a high degree of inter-individual variation in response to these treatments, whereby patients experience occlusive thromboembolic events, in spite of maintaining an appropriate treatment regimen. This has lead to the notion of antithrombotic "resistance" or "poor responders", which has been a growing concern amongst clinicians and other healthcare providers. Compounding this matter even further, reports of increased cardiovascular risk associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, have revealed additional and unforeseen contributors to myocardial infarction and stroke. With all medications, striking a balance between the potential risks and benefits seems more art than science at times. However, given their widespread use and critical cardiovascular implications, further emphasis has been placed on understanding factors influencing antithrombotic and NSAID therapies. A major aim in cardiovascular pharmacogenetics is the discovery of genetic biomarkers that will allow for prospective screening and individualized prediction of drug efficacy and adverse reactions for these medications (both alone and together) within the context of cardiovascular disease.

  18. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome.

    PubMed

    Rogers, M A M; Aronoff, D M

    2016-02-01

    The composition of the gut microbiome with the use of non-steroidal anti-inflammatory drugs (NSAIDs) has not been fully characterized. Drug use within the past 30 days was ascertained in 155 adults, and stool specimens were submitted for analysis. Area under the receiver operating characteristic curve (AUC) was calculated in logit models to distinguish the relative abundance of operational taxonomic units (OTUs) by medication class. The type of medication had a greater influence on the gut microbiome than the number of medications. NSAIDs were particularly associated with distinct microbial populations. Four OTUs (Prevotella species, Bacteroides species, family Ruminococcaceae, and Barnesiella species) discriminated aspirin users from those using no medication (AUC = 0.96; 95% CI 0.84-1.00). The microbiome profile of celecoxib users was similar to that of ibuprofen users, with both showing enrichment of Acidaminococcaceae and Enterobacteriaceae. Bacteria from families Propionibacteriaceae, Pseudomonadaceae, Puniceicoccaceae and Rikenellaceae were more abundant in ibuprofen users than in controls or naproxen users. Bacteroides species and Erysipelotrichaceae species discriminated individuals using NSAIDs plus proton-pump inhibitors from those using NSAIDs alone (AUC = 0.96; 95% CI 0.87-1.00). Bacteroides species and a bacterium of family Ruminococcaceae discriminated individuals using NSAIDs in combination with antidepressants and laxatives from those using NSAIDs alone (AUC = 0.98; 95% CI 0.93-1.00). In conclusion, bacteria in the gastrointestinal tract reflect the combinations of medications that people ingest. The bacterial composition of the gut varied with the type of NSAID ingested.

  19. Are antacids necessary as routine prescriptives with non-steroidal anti-inflammatory drugs?

    PubMed

    See, Y; Ng, S C; Tho, K S; Teo, S K

    1998-03-01

    In Singapore, there exists a local habit to routinely prescribe antacids with non-steroidal anti-inflammatory drugs (NSAIDs) perhaps in the belief that gastrointestinal (GI) symptoms and complications are common, and that antacids protect from them. We prospectively studied 140 adults in an orthopaedic clinic who were prescribed a short course of NSAIDs (1 to 4 weeks) without antacids to determine the frequency and severity of GI symptoms. Symptomatic patients were then given antacids to determine their effect on the GI symptoms and followed up by telephone interview. These patients had mild inflammation, soft tissue rheumatism, injury or degenerative disease. All were otherwise well with no known peptic ulcer disease or major illness and were not on ulcerogenic drugs. Only 13 (9.3%) had significant GI symptoms, of which 6 (4.2%) of the total took antacid and 5 (3.5%) had partial or total relief. In this study, GI symptoms were not common with short course NSAIDs in otherwise well patients. Antacids may afford symptomatic relief for GI symptoms. However, because antacids may offer no significant protection against NSAID-induced peptic ulcer, may dangerously mask symptoms of GI irritation, may be troublesome to take and costly on a large scale, we should stop routine prescription of antacids in patients requiring only short-term NSAIDs and not at risk for peptic ulcer disease.

  20. Molecular Basis for Cyclooxygenase Inhibition by the Non-steroidal Anti-inflammatory Drug Naproxen

    SciTech Connect

    Duggan, Kelsey C.; Walters, Matthew J.; Musee, Joel; Harp, Joel M.; Kiefer, James R.; Oates, John A.; Marnett, Lawrence J.

    2010-11-15

    Naproxen ((S)-6-methoxy-{alpha}-methyl-2-naphthaleneacetic acid) is a powerful non-selective non-steroidal anti-inflammatory drug that is extensively used as a prescription and over-the-counter medication. Naproxen exhibits gastrointestinal toxicity, but its cardiovascular toxicity may be reduced compared with other drugs in its class. Despite the fact that naproxen has been marketed for many years, the molecular basis of its interaction with cyclooxygenase (COX) enzymes is unknown. We performed a detailed study of naproxen-COX-2 interactions using site-directed mutagenesis, structure-activity analysis, and x-ray crystallography. The results indicate that each of the pendant groups of the naphthyl scaffold are essential for COX inhibition, and only minimal substitutions are tolerated. Mutation of Trp-387 to Phe significantly reduced inhibition by naproxen, a result that appears unique to this inhibitor. Substitution of S or CH2 for the O atom of the p-methoxy group yielded analogs that were not affected by the W387F substitution and that exhibited increased COX-2 selectivity relative to naproxen. Crystallization and x-ray analysis yielded structures of COX-2 complexed to naproxen and its methylthio analog at 1.7 and 2.3 {angstrom} resolution, respectively. The combination of mutagenesis, structure analysis, and x-ray crystallography provided comprehensive information on the unique interactions responsible for naproxen binding to COX-2.

  1. Non-steroidal anti-inflammatory drugs in the watercourses of Elbe basin in Czech Republic.

    PubMed

    Marsik, Petr; Rezek, Jan; Židková, Monika; Kramulová, Barbora; Tauchen, Jan; Vaněk, Tomáš

    2017-03-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) belong to most used pharmaceuticals in the human and veterinary medicine. The widespread consumption of NSAIDs has led to their ubiquitous occurrence in water environment including large river systems. In the present study, concentrations of the five most frequently used NSAIDs (ibuprofen, diclofenac, naproxen, ketoprofen and indomethacin) were determined in the watercourses of the river Elbe basin in Czech Republic. The presence of the pharmaceuticals was measured at 29 sampling sites including urban and rural areas, small creeks and main tributaries of the Elbe monthly from April to December of 2011. For the NSAIDs quantitation, the comprehensive analytical method combing pentafluorobenzyl bromide (PFBBr) derivatization with highly sensitive two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-TOFMS) was developed. Although the content of all NSAIDs varied at the particular sampling points significantly, total amount of particular compounds was relatively stable during all monitored periods with only non-significant increase in the spring and autumnal months. Ibuprofen was found to be the most abundant drug with maximum concentration of 3210 ng/L, followed by naproxen, diclofenac and ketoprofen (1423.8 ng/L, 1080 ng/L and 929.8 ng/L, respectively). Indomethacin was found only at several sampling sites (maximum concentration of 69.3 ng/L). Concentrations of all compounds except ibuprofen were significantly higher at sampling sites with low flow rates (creeks), followed by the biggest watercourses.

  2. Environmental fate of non-steroidal anti-inflammatory drugs in river water/sediment systems.

    PubMed

    Koumaki, Elena; Mamais, Daniel; Noutsopoulos, Constantinos

    2017-02-05

    Laboratory tests were conducted with four non-steroidal anti-inflammatory drugs (naproxen, ibuprofen, diclofenac and ketoprofen) under different redox conditions (aerobic, anoxic, anaerobic and sulfate-reducing conditions) in order to assess abiotic and biotic degradation in a river water/sediment system. The river water was sampled from Sperchios River and the sediment was collected from the banks of a rural stream where the discharge point of a wastewater treatment plant is located. To quantitatively describe degradation kinetics of the selected compounds, pseudo first-order kinetics were adopted. According to the results, it can be stated that the concentration of the substances remained constant or decreased only marginally (p≥0.05) in the sterile experiments and this excludes abiotic processes such as hydrolysis or sorption as major removal mechanisms of the target compounds from the water phase and assign their removal to microbial action. Results showed that the removal rate of the compounds decreases as dissolved oxygen concentration in the river water/sediment system decreases. All compounds were found to be biodegradable under aerobic conditions at dissipation half-lives between 1.6 and 20.1days, while dissipation half-lives for naproxen and ketoprofen increase by a factor of 2 under all tested conditions in the absence of oxygen.

  3. Influence of non-steroidal anti-inflammatory drugs on Drosophila melanogaster longevity.

    PubMed

    Danilov, Anton; Shaposhnikov, Mikhail; Shevchenko, Oksana; Zemskaya, Nadezhda; Zhavoronkov, Alex; Moskalev, Alexey

    2015-08-14

    Most age-related diseases and aging itself are associated with chronic inflammation. Thus pharmacological inhibition of inflammatory processes may be effective antiaging strategy. In this study we demonstrated that treatment of Drosophila melanogaster with 10 non-steroidal anti-inflammatory drugs (NSAIDs: CAY10404, aspirin, APHS, SC-560, NS-398, SC-58125, valeroyl salicylate, trans-resveratrol, valdecoxib, licofelone) leads to extension of lifespan, delays age-dependent decline of locomotor activity and increases stress resistance. The effect of the lifespan increase was associated with decrease of fecundity. Depending on the concentration, NSAIDs demonstrated both anti- and pro-oxidant properties in Drosophila tissues. However, we failed to identify clear correlation between antioxidant properties of NSAIDs and their pro-longevity effects. The lifespan extending effects of APHS, SC-58125, valeroyl salicylate, trans-resveratrol, valdecoxib, and licofelone were more pronounced in males, valdecoxib and aspirin - in females. We demonstrated that lifespan extension effect of NSAIDs was abolished in flies with defective genes involved in Pkh2-ypk1-lem3-tat2 pathway.

  4. Altered membrane lipid dynamics and chemoprevention by non-steroidal anti inflammatory drugs during colon carcinogenesis.

    PubMed

    Singh Kanwar, S; Vaish, V; Nath Sanyal, S

    2011-01-01

    The present work focuses on the anti-neoplastic role of non steroidal anti-inflammatory drugs (NSAIDs) in modulating the biophysical parameters of the colonic membranes in 1,2-dimethylhydrazine dihydrochloride (DMH) induced carcinogenesis. The steady-state fluorescence polarization technique was applied to assess membrane fluidity, membrane polarity and lipid phase states. The decline in cholesterol content, biosynthesis and cholesterol: phospholipids ratio with DMH treatment indicates more fluidity associated with carcinogenesis. The DMH group had shown lower order parameter indicating more fluidity whereas NSAIDs resulted in increasing the membrane lipid order. The converging effects of these changes were more in membrane phase separations and membrane phase state. In DMH treatment membrane shows lesser phase separation or high polarity, and more liquid crystalline state while for NSAID groups membranes have higher phase separations or low polarity, and more of the gel phase. Further, NSAIDs induced anti-proliferative effects were evidently observed by apoptosis in the colonocytes by using acridine orange-ethidium bromide fluorescent staining and Terminal de-oxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The results suggest that NSAIDs induced alteration in the membrane biophysical parameters may be an important initiating event for the chemopreventive action.

  5. Management of gastroduodenal ulcers caused by non-steroidal anti-inflammatory drugs.

    PubMed

    Hawkey, C J

    2000-02-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are a major cause of morbidity and mortality, probably resulting in the death of 1200 patients per annum in the UK. The main mechanism of toxicity involves an inhibition of prostaglandin synthesis that results in mucosal erosion as a result of the abrogation of defence mechanisms. However, acid peptic attack can deepen this initial injury. Thus, logical treatments include prostaglandin analogues as 'replacement therapy', acid suppression, enteric coating to avoid topical effects and the use of safer NSAIDs, including those that have little or no effect on gastric mucosal prostaglandin synthesis. There is less logic to the strategy of Helicobacter pylori (H. pylori) eradication, and the status of this approach is controversial. Overall, proton pump inhibitors have the best profile of efficacy and side-effects for the healing and prevention of NSAID-associated ulcers. Misoprostol is also effective and appears to be superior to proton pump inhibitors for superficial erosive injury. Early indications are that selective inhibitors of the inducible cyclooxygenase-2 enzyme have little or no effect in causing ulcers. Growing experience with these agents will probably revolutionize the management of patients with arthritic conditions. However, the increasing use of low-dose aspirin for cardiovascular prophylaxis means that gastroenterologists will have to continue to grapple with the problems of NSAID-associated ulcers for some time to come.

  6. Influence of non-steroidal anti-inflammatory drugs on Drosophila melanogaster longevity

    PubMed Central

    Danilov, Anton; Shaposhnikov, Mikhail; Shevchenko, Oksana; Zemskaya, Nadezhda; Zhavoronkov, Alex; Moskalev, Alexey

    2015-01-01

    Most age-related diseases and aging itself are associated with chronic inflammation. Thus pharmacological inhibition of inflammatory processes may be effective antiaging strategy. In this study we demonstrated that treatment of Drosophila melanogaster with 10 non-steroidal anti-inflammatory drugs (NSAIDs: CAY10404, aspirin, APHS, SC-560, NS-398, SC-58125, valeroyl salicylate, trans-resveratrol, valdecoxib, licofelone) leads to extension of lifespan, delays age-dependent decline of locomotor activity and increases stress resistance. The effect of the lifespan increase was associated with decrease of fecundity. Depending on the concentration, NSAIDs demonstrated both anti- and pro-oxidant properties in Drosophila tissues. However, we failed to identify clear correlation between antioxidant properties of NSAIDs and their pro-longevity effects. The lifespan extending effects of APHS, SC-58125, valeroyl salicylate, trans-resveratrol, valdecoxib, and licofelone were more pronounced in males, valdecoxib and aspirin - in females. We demonstrated that lifespan extension effect of NSAIDs was abolished in flies with defective genes involved in Pkh2-ypk1-lem3-tat2 pathway. PMID:26305987

  7. Selection of topically applied non-steroidal anti-inflammatory drugs for oral cancer chemoprevention.

    PubMed

    Sood, Sandeep; Shiff, Steven J; Yang, Chung S; Chen, Xiaoxin

    2005-07-01

    Topical delivery of non-steroidal anti-inflammatory drugs through the oral mucosa has been used for oral cancer chemoprevention. Local permeation of these agents has been one of the major concerns. Here we propose an approach to predict the permeability of topically applied agents for oral cancer chemoprevention. In theory, the total flux through the oral mucosa (Jmax) can be estimated by adding the transcellular flux (JTC) and the paracellular flux (JPC). To target the Cox-2 enzyme in oral epithelial cells, it is desirable to maximize the theoretical activity index, the ratio of JTC and IC50 of a Cox-2 inhibitor (JTC/IC50-Cox-2). Among the 12 commonly used NSAIDs, celecoxib, nimesulide and ibuprofen had the highest values and may be the agents of choice to target Cox-2 in oral epithelial cells through topical application. Based on these calculations, a long-term chemopreventive experiment using celecoxib (3% or 6%) through topical application was performed in a DMBA induced hamster oral cancer model. Both 3% and 6% reduced the incidence of squamous cell carcinoma at the post-initiation stage.

  8. Esters of some non-steroidal anti-inflammatory drugs with cinnamyl alcohol are potent lipoxygenase inhibitors with enhanced anti-inflammatory activity.

    PubMed

    Theodosis-Nobelos, Panagiotis; Kourti, Malamati; Tziona, Paraskevi; Kourounakis, Panos N; Rekka, Eleni A

    2015-11-15

    Novel esters of non steroidal anti-inflammatory drugs, α-lipoic acid and indol-3-acetic acid with cinnamyl alcohol were synthesised by a straightforward method and at high yields (60-98%). They reduced acute inflammation more than the parent acids and are potent inhibitors of soybean lipoxygenase. Selected structures decreased plasma lipidemic indices in Triton-induced hyperlipidemia to rats. Therefore, the synthesised compounds may add to the current knowledge about agents acting against various inflammatory disorders.

  9. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage?

    PubMed Central

    Bessone, Fernando

    2010-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with anti-infectious agents, list on the top for causes of Drug-Induced Liver Injury (DILI). The incidence of liver disease induced by NSAIDs reported in clinical studies is fairly uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to 9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk of liver-related hospitalizations was reported (3-23 per 100 000 patients). NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic, transient, hyper-transaminasemia to fulminant hepatic failure. However, under-reporting of asymptomatic, mild cases, as well as of those with transient liver-tests alteration, in conjunction with reports non-compliant with pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies, jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity. Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been withdrawn from the market due to hepatotoxicity; others like nimesulide were never marketed in some countries and withdrawn in others. Indeed, the controversy concerning the actual risk of severe liver disease persists within NSAIDs research. The present work intends (1) to provide a critical analysis of the dissimilar results currently available in the literature concerning the epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of hepatotoxicity for each one of the most commonly employed compounds of the NSAIDs family, based on past and recently published data. PMID:21128314

  10. New insights into the use of currently available non-steroidal anti-inflammatory drugs

    PubMed Central

    Brune, Kay; Patrignani, Paola

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs), which act via inhibition of the cyclooxygenase (COX) isozymes, were discovered more than 100 years ago. They remain a key component of the pharmacological management of acute and chronic pain. The COX-1 and COX-2 isozymes have different biological functions; analgesic activity is primarily (although not exclusively) associated with inhibition of COX-2, while different side effects result from the inhibition of COX-1 and COX-2. All available NSAIDs, including acetaminophen and aspirin, are associated with potential side effects, particularly gastrointestinal and cardiovascular effects, related to their relative selectivity for COX-1 and COX-2. Since all NSAIDs exert their therapeutic activity through inhibition of the COX isozymes, strategies are needed to reduce the risks associated with NSAIDs while achieving sufficient pain relief. A better understanding of the inhibitory activity and COX-1/COX-2 selectivity of an NSAID at therapeutic doses, based on pharmacokinetic and pharmacodynamic properties (eg, inhibitory dose, absorption, plasma versus tissue distribution, and elimination), and the impact on drug tolerability and safety can guide the selection of appropriate NSAIDs for pain management. For example, many NSAIDs with moderate to high selectivity for COX-2 versus COX-1 can be administered at doses that maximize efficacy (~80% inhibition of COX-2) while minimizing COX-1 inhibition and associated side effects, such as gastrointestinal toxicity. Acidic NSAIDs with favorable tissue distribution and short plasma half-lives can additionally be dosed to provide near-constant analgesia while minimizing plasma concentrations to permit recovery of COX-mediated prostaglandin production in the vascular wall and other organs. Each patient’s clinical background, including gastrointestinal and cardiovascular risk factors, should be taken into account when selecting appropriate NSAIDs. New methods are emerging to assist

  11. Effects of non-steroidal anti-inflammatory drug (NSAID) diclofenac exposure in mussel Mytilus galloprovincialis.

    PubMed

    Gonzalez-Rey, Maria; Bebianno, Maria João

    2014-03-01

    In recent years, research studies have increasingly focused on assessing the occurrence of active pharmaceutical ingredients (APIs) in ecosystems. However, much remains unknown concerning the potential effects on APIs on non-target organisms due to the complexity of the mode of action, reactivity and bioconcentration potential for each specific drug. The non-steroidal anti-inflammatory drug (NSAID) diclofenac (DCF) is one of the most frequently detected APIs in surface waters worldwide and has recently been included in the list of priority substances under the European Commission. In this study, mussels (Mytilus galloprovincialis) were exposed to an environmentally relevant nominal concentration of DCF (250 ng L(-1)) over 15 days. The responses of several biomarkers were assessed in the mussel tissues: condition index (CI); superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and phase II glutathione-S-transferase (GST) activities, lipid peroxidation levels (LPO) associated with oxidative stress, acetylcholinesterase (AChE) activity related to neurotoxic effects and vitellogenin-like proteins linked to endocrine disruption. This study demonstrated significant induction of SOD and GR activities in the gills in addition to high CAT activity and LPO levels in the digestive gland. Phase II GST remained unaltered in both tissues, while the up-regulation of the AChE activity was directly related to the vitellogenin-like protein levels in exposed females, indicating an alteration in the estrogenic activity, rather than a breakdown in cholinergic neurotransmission function. This study confirmed that DCF at a concentration often observed in surface water induces tissue-specific biomarker responses. Finally, this study also revealed the importance of a multi-biomarker approach when assessing the potentially deleterious effects in a species that may be vulnerable to the continuously discharge of APIs into the ecosystems; this approach provides crucial new

  12. H1N1 pneumonitis associated with long-term non-steroidal anti-inflammatory drug abuse

    PubMed Central

    Prower, Emma; Hasnain, Ozair; Oscier, Chris

    2015-01-01

    This case series discusses two similar presentations of H1N1 influenza in young patients with a background history of long-term non-steroidal anti-inflammatory drug (NSAID) abuse. Both patients presented with type 1 respiratory failure requiring intensive care unit admission and subsequent organ support. This report reviews the immunosuppressive effects of long-term NSAID use and highlights a potential link to the significant morbidity seen. PMID:25870210

  13. Non-steroidal anti-inflammatory drugs attenuate the vascular responses in aging metabolic syndrome rats

    PubMed Central

    Rubio-Ruiz, María Esther; Pérez-Torres, Israel; Diaz-Diaz, Eulises; Pavón, Natalia; Guarner-Lans, Verónica

    2014-01-01

    Aim: Metabolic syndrome (MS) and aging are low-grade systemic inflammatory conditions, and inflammation is a key component of endothelial dysfunction. The aim of this study was to investigate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) upon the vascular reactivity in aging MS rats. Methods: MS was induced in young male rats by adding 30% sucrose in drinking water over 6, 12, and 18 months. When the treatment was finished, the blood samples were collected, and aortas were dissected out. The expression of COX isoenzymes and PLA2 in the aortas was analyzed using Western blot analysis. The contractile responses of aortic rings to norepinephrine (1 μmol/L) were measured in the presence or absence of different NSAIDs (10 μmol/L for each). Results: Serum levels of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in control rats were remained stable during the aging process, whereas serum IL-6 in MS rats were significantly increased at 12 and 18 months. The levels of COX isoenzyme and PLA2 in aortas from control rats increased with the aging, whereas those in aortas from MS rats were irregularly increased with the highest levels at 6 months. Pretreatment with acetylsalicylic acid (a COX-1 preferential inhibitor), indomethacin (a non-selective COX inhibitor) or meloxicam (a COX-2 preferential inhibitor) decreased NE-induced contractions of aortic rings from MS rats at all the ages, with meloxicam being the most potent. Acetylsalicylic acid also significantly reduced the maximum responses of ACh-induced vasorelaxation of aortic rings from MS rats, but indomethacin and meloxicam had no effect. Conclusion: NSAIDs can directly affect vascular responses in aging MS rats. Understanding the effects of NSAIDs on blood vessels may improve the treatment of cardiovascular diseases and MS in the elders. PMID:25263337

  14. Role of Non-Steroidal Anti-Inflammatory Drugs in Exacerbations of Inflammatory Bowel Disease

    PubMed Central

    Long, Millie D.; Kappelman, Michael D.; Martin, Christopher F.; Chen, Wenli; Anton, Kristen; Sandler, Robert S.

    2015-01-01

    GOALS To determine the role of NSAIDs in activation of IBD. BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) may activate inflammatory pathways in inflammatory bowel disease (IBD). STUDY Crohn’s and Colitis Foundation of American (CCFA) Partners is an ongoing cohort study of patients living with IBD. All data are self-reported via the internet. We identified a sub-cohort of participants whose disease activity, based on short Crohn’s Disease Activity Index (sCDAI) and simple clinical colitis activity index (SCCAI), indicated remission. Pattern of use of NSAIDs was measured at baseline, and disease activity assessment was performed 6 months later. We used multivariate binomial regression to determine effects of NSAIDs on disease activity. RESULTS A total of 791 individuals in remission had baseline and follow data available for analysis. Of these, 247 Crohn’s disease (CD) patients (43.2%) and 89 ulcerative colitis (UC) patients (40.6%) reported NSAID use. CD patients with NSAID use ≥ 5 times/monthly had greater risk of active disease at follow-up (23% v. 15%, p=0.04); (adjusted risk ratio (RR) 1.65; 95% confidence interval (CI) 1.12–2.44). No effect was observed in patients with UC (22% vs 21%, p=0.98; adjusted RR 1.25; 95% CI, 0.81–1.92). Acetaminophen use was associated with active disease at follow-up in CD (adjusted RR 1.72, 95% CI 1.11–2.68). CONCLUSIONS Regular (≥ 5 times/monthly) NSAID and acetaminophen use were associated with active CD, but not UC. Less frequent NSAID use was not associated with active CD or UC. These findings indicate that regular NSAID use may increase CD activity, or that NSAID use may be a marker of a less robust remission; thus reflecting subclinical disease activity. PMID:26485106

  15. [Cardiovascular side effects of non-steroidal anti-inflammatory drugs in the light of recent recommendations. Diclofenac is not more dangerous].

    PubMed

    Horváth, Viktor József; Tabák, Gy Ádám; Szabó, Gergely; Putz, Zsuzsanna; Koós, Csaba Géza; Lakatos, Péter

    2015-03-29

    Among their beneficial effects, non-steroidal anti-inflammatory drugs may also exert several side effects which depend on the dosage and the type of these medications. The most frequent gastrointestinal side effects usually develop shortly after the beginning of their administration, but others such as cardiovascular interactions (which are present much less frequently than gastrointestinal side effects) can also occur after the beginning of drug administration without a latency period. For a long-term treatment, non-steroidal anti-inflammatory drugs are most frequently used in the elderly population where patients typically have high cardiovascular risk and take other medicines, e.g. low dose acetylsalicylic acid that can interact with non-steroidal anti-inflammatory drugs; in this aspect diclofenac may cause less side effects. In this review, the authors briefly review cardiovascular side effects of non-steroidal anti-inflammatory drugs, the processes which potentially influence them, therapeutic consequences and their interaction with acetylsalicylic acid.

  16. Oxidation of non-steroidal anti-inflammatory drugs with aqueous permanganate.

    PubMed

    Rodríguez-Álvarez, Tania; Rodil, Rosario; Quintana, José Benito; Triñanes, Sara; Cela, Rafael

    2013-06-01

    Potassium permanganate is a strong oxidant widely used in drinking water treatment, that can react with organic micropollutants. Thus, the oxidation kinetics and transformation route of seven non-steroidal anti-inflammatory drugs (NSAIDs) upon reaction with potassium permanganate was investigated. A liquid chromatography-quadrupole-time-of-flight-mass spectrometry (LC-Q-TOF-MS) system was used to follow the time course of pharmaceuticals concentrations and for the identification of their by-products. Under strong oxidation conditions (2 mg L(-1) KMnO4, 24 h), only two NSAIDs were significantly degraded: indomethacine and diclofenac. The degradation kinetics of these two drugs was investigated at different concentrations of permanganate, chlorides, phosphates and sample pH by means of a full factorial experimental design. Depending on these factors, half-lives were in the range: 2-270 h for indomethacine and 3-558 h for diclofenac, equivalent to apparent second order constants between 0.65 and 9.5 M(-1) s(-1) and 0.27 and 7.4 M(-1) s(-1), respectively. Permanganate concentration was the most significant factor on NSAIDs oxidation kinetics, but the pH also played a significant role in diclofenac reaction, being faster at acidic pH. In the case of indomethacine, the dose of permanganate seemed also to play an autocatalytic effect. The use of an accurate-mass high resolution LC-Q-TOF-MS system permitted the identification of a total of 13 by-products. The transformation path of these drugs consisted mainly of hydroxylations, decarboxylations and oxidation of aromatic double bonds, with ring opening. The software predicted toxicity of these products indicates that they are expected not to be more toxic than the NSAIDs, with the exception of two indomethacine by-products. Reaction in real samples was slower and/or incomplete for both pharmaceuticals, depending on the organic matter content of the sample. However, still all transformation products could be detected for

  17. Non-steroidal anti-inflammatory drugs affect the methotrexate transport in IEC-6 cells.

    PubMed

    Sosogi, Aiko; Gao, Feng; Tomimatsu, Takashi; Hirata, Koji; Horie, Toshiharu

    2003-06-13

    Methotrexate (MTX) is used not only for the cancer chemotherapy but also for the treatment of rheumatic disease, often together with non-steroidal anti-inflammatory drugs (NSAIDs). MTX is actively cotransported with H(+) in the small intestine, mediated by a reduced folate carrier (RFC). The coadministration of some NSAIDs with MTX to rats caused a decrease of MTX absorption through the small intestine. This may be due to the uncoupling effect of oxidative phosphorylation of the NSAIDs. The present study investigated whether flufenamic acid, diclofenac and indomethacin, NSAIDs, decreased ATP content of rat-derived intestinal epithelial cell line IEC-6 cells and affected the MTX transport in IEC-6 cells. The MTX uptake in IEC-6 cells was dependent on medium pH and maximum around pH 4.5-5.5. The MTX uptake was composed of a transport inhibited by 4, 4'-diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS) and a non-saturable one. The DIDS-sensitive component in the MTX uptake showed a saturation kinetics (Michaelis-Menten constant (Km): 3.91 +/- 0.52 microM, Maximum velocity (Vmax): 94.66 +/- 6.56 pmol/mg protein/5 min). The cellular ATP content in IEC-6 cells decreased significantly at 30 min after the cells were started to incubate with the NSAIDs (250 microM flufenamic acid, 500 microM diclofenac and 500 microM indomethacin). The MTX uptake in IEC-6 cells in the presence of the NSAIDs decreased with the reduction of cellular ATP content and showed a good correlation with the ATP content (correlation coefficient: 0.982). Thus it seems likely that the ATP content in IEC-6 cells with the NSAIDs decreased due to the uncoupling effect of oxidative phosphorylation of the NSAIDs, resulting in the inhibition of the secondary active transport of MTX in IEC-6 cells. The present results also suggest that IEC-6 cells are useful to evaluate the drug interaction relating to this carrier system.

  18. Endoscopic evaluation of the gastroduodenal mucosa following non-steroidal anti-inflammatory drug administration in the dog.

    PubMed

    Forsyth, S F; Guilford, W G; Lawoko, C R

    1996-10-01

    The gastroduodenal mucosa of 30 healthy dogs was examined by endoscope after 7 days of oral non-steroidal anti-inflammatory drug administration. The dogs were divided into five groups. One group received ketoprofen (1 mg/kg every 24 h), one group copper-indomethacin (0.2 mg/kg every 12 h), one group 1 mg of prednisolone and 200 mg of cinchophen (1 tablet per 20 kg every 12 h), one group aspirin (15 mg/kg every 12 h) and one group gelatin (1 capsule every 12 h). Occult blood was not detected in the faeces either prior to or after non-steroidal anti-inflammatory drug administration. Packed cell volume, total plasma protein and buccal mucosal bleeding times did not significantly change after non-steroidal antiinflammatory drug administration. Gastroduodenal lesions were observed in 22 dogs. There was no significant difference in lesions between the ketoprofen, copper-indomethacin and prednisolone-cinchophen groups, but the gelatin group had significantly (p

  19. Non-steroidal anti-inflammatory drug gastropathy: causes and treatment.

    PubMed

    Hawkey, C J

    1996-01-01

    Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) almost invariably cause acute gastroduodenal injury and probably account for approximately 12,000 ulcer bleeding episodes and 1200 deaths per annum in the United Kingdom. Clinically significant intestinal toxicity is also recognized but less clearly defined. The main risk factors for NSAID-related peptic ulcer complications are age, past history, use of higher risk individual NSAIDs, drug dose, concurrent use of warfarin or corticosteroids. The underlying reason for NSAID use and Helicobacter pylori status is not clearly associated with increased risk. Whether NSAIDs cause drug-induced non-ulcer dyspepsia is also controversial. Acute injury occurs more readily with aspirin than with non-aspirin NSAIDs, and the spectrum of acute injury is of little value in predicting clinically significant end points in comparison with different NSAIDs. However, acute studies of co-prescribed protective agents are highly predictive of performance in clinical practice. Gastric mucosal integrity is maintained by the interplay of three protective networks: prostaglandin synthesis, nitric oxide synthesis and the activity of the enteric nervous system. Aspirin and NSAIDs act by inhibiting prostaglandin synthesis catalysed by two cyclooxygenase enzymes. Most existing NSAIDs are unselective and inhibit the activity of the constitutive cyclooxygenase (COX) 1 enzyme in the stomach as much as the cyclooxygenase (COX) 2 enzyme which is induced at sites of inflammation such as joint disease. There are, however, prospects for selective cyclooxygenase 2 inhibitors. Some NSAIDs, particularly aspirin, have additional topical toxicity, which may in part reflect mucosal trapping. Some data favor an effect of NSAIDs in inhibiting mitochondrial oxidative phosphorylation. The principal physiological mechanisms which are compromised by NSAID use are mucosal blood flow, secretion of mucus and bicarbonate and maintenance of a

  20. Neuronal zinc stores are modulated by non-steroidal anti-inflammatory drugs: an optical analysis in cultured hippocampal neurons.

    PubMed

    Love, Rachal; Salazar, Gloria; Faundez, Victor

    2005-11-02

    Zinc chelation and non-steroidal anti-inflammatory drugs (NSAIDs) have been explored as potential neuroprotective agents. However, it remains unknown whether NSAIDs and zinc chelation may converge on a similar cellular process. Using two-photon microscopy to observe hippocampal neurons labeled with a zinc-sensitive dye, we provide evidence that three chemically unrelated NSAIDs, niflumic acid, ibuprofen, and naproxen, acutely increase intracellular zinc stores from extracellular metal pools. Phospholipase A2 inhibitors triggered similar responses, suggesting that NSAIDs likely control zinc stores by their activity as cyclooxygenase inhibitors. These results provide evidence for a new link between cyclooxygenase metabolites and the mechanisms controlling neuronal zinc pools.

  1. Modulation of non steroidal anti-inflammatory drug induced membrane fusion by copper coordination of these drugs: anchoring effect.

    PubMed

    Majumdar, Anupa; Chakraborty, Sreeja; Sarkar, Munna

    2014-12-04

    Membrane fusion, an integral event in several biological processes, is characterized by several intermediate steps guided by specific energy barriers. Hence, it requires the aid of fusogens to complete the process. Common fusogens, such as proteins/peptides, have the ability to overcome theses barriers by their conformational reorganization, an advantage not shared by small drug molecules. Hence, drug induced fusion at physiologically relevant drug concentrations is rare and occurs only in the case of the oxicam group of non steroidal anti-inflammatory drugs (NSAIDs). To use drugs to induce and control membrane fusion in various biochemical processes requires the understanding of how different parameters modulate fusion. Also, fusion efficacy needs to be enhanced. Here we have synthesized and used Cu(II) complexes of fusogenic oxicam NSAIDs, Meloxicam and Piroxicam, to induce fusion in model membranes monitored by using DSC, TEM, steady-state, and time-resolved spectroscopy. The ability of the complexes to anchor apposing model membranes to initiate/facilitate fusion has been demonstrated. This results in better fusion efficacy compared to the bare drugs. These complexes can take the fusion to its final step. Unlike other designed membrane anchors, the role of molecular recognition and strength of interaction between molecular partners is obliterated for these preformed Cu(II)-NSAIDs.

  2. Breast Cancer Stem Cell Potent Copper(II)-Non-Steroidal Anti-Inflammatory Drug Complexes.

    PubMed

    Boodram, Janine N; Mcgregor, Iain J; Bruno, Peter M; Cressey, Paul B; Hemann, Michael T; Suntharalingam, Kogularamanan

    2016-02-18

    The breast cancer stem cell (CSC) potency of a series of copper(II)-phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4, selectivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis.

  3. Non-Steroidal Anti-Inflammatory Drugs in Alzheimer's Disease and Parkinson's Disease: Reconsidering the Role of Neuroinflammation

    PubMed Central

    Moore, Amy H.; Bigbee, Matthew J.; Boynton, Grace E.; Wakeham, Colin M.; Rosenheim, Hilary M.; Staral, Christopher J.; Morrissey, James L.; Hund, Amanda K.

    2010-01-01

    Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases with age as the greatest risk factor. As the general population experiences extended life span, preparation for the prevention and treatment of these and other age-associated neurological diseases are warranted. Since epidemiological studies suggested that non-steroidal anti-inflammatory drug (NSAID) use decreased risk for AD and PD, increasing attention has been devoted to understanding the costs and benefits of the innate neuroinflammatory response to functional recovery following pathology onset. This review will provide a general overview on the role of neuroinflammation in these neurodegenerative diseases and an update on NSAID treatment in recent experimental animal models, epidemiological analyses, and clinical trials. PMID:27713331

  4. Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.

    PubMed Central

    Lang, J; Price, A B; Levi, A J; Burke, M; Gumpel, J M; Bjarnason, I

    1988-01-01

    Operative small bowel resection specimens received over a period of 16 years were reviewed to assess whether any intestinal disease could be directly attributed to the use of non-steroidal anti-inflammatory drugs (NSAID). Seven cases of intestinal disease associated with the use of NSAID were identified, all of which occurred in the final six years of the survey, which may reflect the increasing use of these compounds. A spectrum of patterns was found from multiple pathognomonic ileal mucosal diaphragms to broad strictures similar to those seen as a complication of enteric potassium. It seems likely that the formation of diaphragm lesions requires an additional factor, but what is not known as yet is whether the effects of NSAID are local or systemic. Images Fig 1 Fig 2 Fig 3 Fig 4 Fig 5 Fig 6 Fig 7 Fig 8 Fig 9 Fig 10 PMID:3384981

  5. Carbon nanotube-impeded transport of non-steroidal anti-inflammatory drugs in Xiangjiang sediments.

    PubMed

    Yan, Jin; Gong, Ji-Lai; Zeng, Guang-Ming; Song, Biao; Zhang, Peng; Liu, Hong-Yu; Huan, Shuang-Yan; Li, Xiao-Dong

    2017-03-06

    Carbon nanotubes (CNTs), usually with a superior affinity with organic chemicals, are expected to ultimately released to the environment through their manufacturing, usage, and eventual disposal, which will influence the mobility and environmental risk of nonsteroidal anti-inflammatory drugs (NSAIDs). In this study, batch and column experiments were performed to examine the effects of two kinds of multi-walled carbon nanotubes (MWCNTs: MWCNT2040, MWCNT0815) and one kind of single-walled carbon nanotubes (SWCNTs) on the environmental fate of two NSAIDs, paracetamol (PA) and diclofenac sodium (DS), in sediments. Impact ways of CNTs including addition in inflow and mixing with sediments were investigated. The adsorption capacity of NSAIDs on sediments increased with increasing CNTs/sediments ratios and in an order of MWCNT2040

  6. Expression of pleiotrophin, an important regulator of cell migration, is inhibited in intestinal epithelial cells by treatment with non-steroidal anti-inflammatory drugs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs for the suppression of inflammation and pain. However, the analgesic properties of NSAIDs are also associated with significant negative side effects, most notably in the gastrointestinal (GI) tract. Increasingly, evi...

  7. Chemopreventive action of non-steroidal anti-inflammatory drugs on the inflammatory pathways in colon cancer.

    PubMed

    Ghanghas, Preety; Jain, Shelly; Rana, Chandan; Sanyal, S N

    2016-03-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development by cellular proliferation and by promoting apoptosis. Inflammation is principal cause of colon carcinogenesis. A missing link between inflammation and cancer could be the activation of NF-κB, which is a hallmark of inflammatory response, and is commonly detected in malignant tumors. Therefore, targeting pro-inflammatory cyclooxygenase enzymes and transcription factors will be profitable as a mechanism to inhibit tumor growth. In the present study, we have studied the role of various pro-inflammatory enzymes and transcription factors in the development of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer and also observed the role of three NSAIDs, viz., Celecoxib, Etoricoxib and Diclofenac. Carcinogenic changes were observed in morphological and histopathological studies, whereas protein regulations of various biomolecules were identified by immunofluorescence analysis. Apoptotic studies was done by TUNEL assay and Hoechst/PI co-staining of the isolated colonocytes. It was found that DMH-treated animals were having an over-expression of pro-inflammatory enzymes, aberrant nuclear localization of activated cell survival transcription factor, NF-κB and suppression of anti-inflammatory transcription factor PPAR-γ, thereby suggesting a marked role of inflammation in the tumor progression. However, co-administration of NSAIDs has significantly reduced the inflammatory potential of the growing neoplasm.

  8. Molecular dynamics in liquid and glassy states of non-steroidal anti-inflammatory drug: ketoprofen.

    PubMed

    Sailaja, U; Shahin Thayyil, M; Krishna Kumar, N S; Govindaraj, G

    2013-05-13

    Ketoprofen is a well known nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic effects. It acts by inhibiting the body's production of prostaglandin. The molecular mobility of amorphous ketoprofen has been investigated by broadband dielectric spectroscopy (BDS) covering wide temperature and frequency range. Multiple relaxation processes were observed. Besides the primary α-relaxation, one secondary relaxation, γ-have been identified. The γ-process visible in the dielectric spectra at very low temperature is non-JG relaxation, and has an activation energy E=37.91 kJ/mol typical for local mobility. Based on Ngai's coupling model smaller n or a larger Kohlrausch exponent (1-n) of the α-relaxation associated with larger τβ (Tg). In the case of ketoprofen we conclude that the secondary relaxation (β) emerging from intermolecular motions, is hidden under the dominant α-peak. The temperature dependence of the relaxation time of the α-process can be described over the entire measured range by a single Vogel-Fulcher-Tammann (VFT) equation. From VFT fits, the glass transition temperature (Tg) was estimated as 267.07 K, and a fragility or steepness index m=86.57 was calculated, showing that ketoprofen is a fragile glass former. Our differential scanning calorimetry (DSC) study shows that ketoprofen is a non-crystallizing compound. To confirm the hydrogen bond patterns of ketoprofen FTIR spectroscopy was applied in both crystalline and amorphous phases. Solubility test performed at 37 °C proved that amorphous phase is more soluble than the crystalline phase.

  9. Reduction of Breast Cancer Relapses with Perioperative Non-Steroidal Anti-Inflammatory Drugs: New Findings and a Review

    PubMed Central

    Retsky, Michael; Demicheli, Romano; Hrushesky, William J.M; Forget, Patrice; Kock, Marc De; Gukas, Isaac; Rogers, Rick A; Baum, Michael; Sukhatme, Vikas; Vaidya, Jayant S

    2013-01-01

    To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. Most relapses in breast cancer are in the early category. Recent data from Forget et al. suggest an unexpected mechanism. They retrospectively studied results from 327 consecutive breast cancer patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Relapse hazard updated Sept 2011 are presented. A common Non-Steroidal Anti-Inflammatory Drug (NSAID) analgesic used in surgery produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Transient systemic inflammation accompanying surgery could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. PMID:23992307

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

    PubMed

    Paul, Mithun; Dastidar, Parthasarathi

    2016-01-18

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

  11. Nitroxide derivatives of non-steroidal anti-inflammatory drugs exert anti-inflammatory and superoxide dismutase scavenging properties in A459 cells

    PubMed Central

    Flores-Santana, Wilmarie; Moody, Terry; Chen, Weibin; Gorczynski, Michael J; Shoman, Mai E; Velázquez, Carlos; Thetford, Angela; Mitchell, James B; Cherukuri, Murali K; King, S Bruce; Wink, David A

    2012-01-01

    BACKGROUND AND PURPOSE Inflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox-active nitroxide group. TEMPO-aspirin (TEMPO-ASA) and TEMPO-indomethacin (TEMPO-IND) were synthesized and evaluated in the lung cancer cell line A549. EXPERIMENTAL APPROACHES We evaluated physico-chemical properties of TEMPO-ASA and TEMPO-IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase-like properties was assayed by measuring cytochrome c reduction and anti-inflammatory effects were assayed by measuring production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo. KEY RESULTS MTD were: TEMPO (140 mg·kg−1), ASA (100 mg·kg−1), indomethacin (5 mg·kg−1), TEMPO-ASA (100 mg·kg−1) and TEMPO-IND (40 mg·kg−1). While TEMPO-ASA was as well tolerated as ASA, TEMPO-IND showed an eightfold improvement over indomethacin. TEMPO-IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO-ASA and TEMPO-IND inhibited production of PGE2 and LTB4 in A549 cells with maximum effects at 100 µg·mL−1 or 10 µg·mL−1 respectively. CONCLUSIONS AND IMPLICATIONS The nitroxide-NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti-inflammatory effects, inhibiting cyclooxygenase and 5-lipoxygenase enzymes. These redox-modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID-associated toxicity. PMID:21658022

  12. Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs

    PubMed Central

    Keeble, J E; Moore, P K

    2002-01-01

    This review examines the biological significance, therapeutic potential and mechanism(s) of action of a range of nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAID) and related nitric oxide-releasing donating drugs (NODD). The slow release of nitric oxide (NO) from these compounds leads to subtle changes in the profile of pharmacological activity of the parent, non-steroidal anti-inflammatory drugs (NSAID). For example, compared with NSAID, NO-NSAID cause markedly diminished gastrointestinal toxicity and improved anti-inflammatory and anti-nociceptive efficacy. In addition, nitroparacetamol exhibits hepatoprotection as opposed to the hepatotoxic activity of paracetamol. The possibility that NO-NSAID or NODD may be of therapeutic benefit in a wide variety of disease states including pain and inflammation, thrombosis and restenosis, neurodegenerative diseases of the central nervous system, colitis, cancer, urinary incontinence, liver disease, impotence, bronchial asthma and osteoporosis is discussed. PMID:12237248

  13. Effect of non-steroidal anti-inflammatory drugs and new fenamate analogues on TRPC4 and TRPC5 channels.

    PubMed

    Jiang, Hongni; Zeng, Bo; Chen, Gui-Lan; Bot, David; Eastmond, Sarah; Elsenussi, Sandra E; Atkin, Stephen L; Boa, Andrew N; Xu, Shang-Zhong

    2012-04-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used anti-inflammatory therapeutic agents, among which the fenamate analogues play important roles in regulating intracellular Ca²⁺ transient and ion channels. However, the effect of NSAIDs on TRPC4 and TRPC5 is still unknown. To understand the structure-activity of fenamate analogues on TRPC channels, we have synthesized a series of fenamate analogues and investigated their effects on TRPC4 and TRPC5 channels. Human TRPC4 and TRPC5 cDNAs in tetracycline-regulated vectors were transfected into HEK293 T-REx cells. The whole cell current and Ca²⁺ movement were recorded by patch clamp and calcium imaging, respectively. Flufenamic acid (FFA), mefenamic acid (MFA), niflumic acid (NFA) and diclofenac sodium (DFS) showed inhibition on TRPC4 and TRPC5 channels in a concentration-dependent manner. The potency was FFA>MFA>NFA>DFS. Modification of 2-phenylamino ring by substitution of the trifluoromethyl group in FFA with F, CH₃, OCH₃, OCH₂CH₃, COOH, and NO₂ led to the changes in their channel blocking activity. However, 2-(2'-methoxy-5'-methylphenyl)aminobenzoic acid stimulated TRPC4 and TRPC5 channels. Selective COX1-3 inhibitors (aspirin, celecoxib, acetaminophen, and indomethacin) had no effect on the channels. Longer perfusion (> 5 min) with FFA (100 μM) and MFA (100 μM) caused a potentiation of TRPC4 and TRPC5 currents after their initial blocking effects that appeared to be partially mediated by the mitochondrial Ca²⁺ release. Our results suggest that fenamate analogues are direct modulators of TRPC4 and TRPC5 channels. The substitution pattern and conformation of the 2-phenylamino ring could alter their blocking activity, which is important for understanding fenamate pharmacology and new drug development targeting the TRPC channels.

  14. Capillary electrochromatography and capillary electrochromatography-electrospray mass spectrometry for the separation of non-steroidal anti-inflammatory drugs.

    PubMed

    Desiderio, C; Fanali, S

    2000-10-20

    In this study capillary electrochromatography (CEC) was utilized for the separation of ten non-steroidal anti-inflammatory drugs (NSAIDs). Experiments were carried out in a commercially available CE instrument using a packed capillary with RP-18 silica particles where the stationary phase completely filled the capillary. The mobile phase consisted of a mixture of ammonium formate buffer pH 2.5 and acetonitrile. Selectivity and resolution were studied changing the pH and the concentration of the buffer, the acetonitrile content mobile phase and the capillary temperature. The optimum experimental conditions for CEC separation of the studied drug mixture were found using 50 mM ammonium formate pH 2.5-acetonitrile (40:60) at 25 degrees C. The CEC capillary was coupled to an electrospray mass spectrometer for the characterization of the NSAIDs. A mobile phase composed by the same buffer but with a higher concentration of acetonitrile (90%) was used in order to speed up the separation of analytes.

  15. The effect of a systemically-administered non-steroidal anti-inflammatory drug (flurbiprofen) on experimental gingivitis in humans.

    PubMed

    Heasman, P A; Seymour, R A

    1989-10-01

    Non-steroidal anti-inflammatory drugs reduce the acute inflammatory reaction and alveolar bone loss of experimental periodontitis in dogs by mechanism thought to be associated with the inhibition of prostaglandin synthesis. 25 healthy volunteers abstained from tooth cleaning for 21 days. Experimental gingivitis developed in all subjects. On day 21, the subjects were divided into 3 treatment groups: oral flurbiprofen (100 mg/day)/toothbrushing (A), placebo+toothbrushing (B) and oral flurbiprofen (100 mg/day) only (C). Treatment continued for 6 days. Plaque indices (PI), gingival indices (GI) and probing pocket depths (PPD) were recorded at 6 points on each of 6 maxillary teeth on days 1. 22, 23, 24 and 27. Crevicular fluid flow (CFF) was quantified with a Periotron on days 1, 22 and 27 in groups A and B, and on days 1 and 27 in group C. There were no changes in PPD throughout the study. A reduction of GI occurred between days 22 and 27 for all treatment groups. CFF was also reduced between days 22 and 27 in groups A and B. The differences between the 3 treatments were very small. It is concluded that systemic flurbiprofen (100 mg/day) can reduce the signs of an experimental gingivitis over 6 days. This effect may be seen when the drug is used alone and as an adjunct to toothbrushing.

  16. Transcriptional and cellular effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in experimentally exposed mussels, Mytilus galloprovincialis.

    PubMed

    Mezzelani, M; Gorbi, S; Fattorini, D; d'Errico, G; Benedetti, M; Milan, M; Bargelloni, L; Regoli, F

    2016-11-01

    The aim of the present investigation was to provide new insights on accumulation and possible adverse effects of various non-steroidal anti-inflammatory drugs (NSAIDs) in mussels, Mytilus galloprovincialis, exposed to an environmentally realistic concentration (0.5μg/L) of individual compounds, Acetaminophen (AMP), Diclofenac (DIC), Ibuprofen (IBU), Ketoprofen (KET) or Nimesulide (NIM). The measurement of drugs in mussel tissues was integrated with both functional alterations at cellular level and transcriptomic responses. Results indicated the capability of mussels to accumulate DIC and NIM, while AMP, IBU and KET were always below detection limit. A large panel of ecotoxicological biomarkers revealed the early onset of alterations induced by tested NSAIDs on immunological responses, lipid metabolism and DNA integrity. The gene transcription analysis through DNA microarrays, supported cellular biomarker results, with clear modulation of a large number of genes involved in the arachidonic acid and lipid metabolism, immune responses, cell cycle and DNA repair. The overall results indicated an ecotoxicological concern for pharmaceuticals in M. galloprovincialis, with transcriptional responses appearing as sensitive exposure biomarkers at low levels of exposure: such changes, however, are not always paralleled by corresponding functional effects, suggesting caution when interpreting observed effects in terms of perturbed cellular pathways. Fascinating similarities can also be proposed in the mode of action of NSAIDs between bivalves and vertebrate species.

  17. Non-steroidal anti-inflammatory drug for pulmonary administration: design and investigation of ketoprofen lysinate fine dry powders.

    PubMed

    Stigliani, Mariateresa; Aquino, Rita P; Del Gaudio, Pasquale; Mencherini, Teresa; Sansone, Francesca; Russo, Paola

    2013-05-01

    Pulmonary inflammation is an important therapeutic target in cystic fibrosis (CF) patients, aiming to limit and delay the lung damage. The purpose of the present research was to produce respirable engineered particles of ketoprofen lysinate, a non-steroidal anti-inflammatory drug able to fight lung inflammatory status by direct administration to the site of action. Micronized drug powders containing leucine as dispersibility enhancer were prepared by co-spray drying the active compound and the excipient from water or hydro-alcoholic feeds. Microparticles were fully characterized in terms of process yield, particle size distribution, morphology and drug content. The ability of the drug to reach the deepest airways after aerosolization of spray-dried formulations was evaluated by Andersen cascade impactor, using the monodose DPI as device. In order to investigate the behaviour of the drug once in contact with lung fluid, an artificial CF mucus was prepared. Drug permeation properties were evaluated interposing the mucus layer between the drug and a synthetic membrane mounted in Franz-type diffusion cells. Finally, the effect of the engineered particles on vitality of human airway epithelial cells of patients homozygous for ΔF 508 CF (CuFi1) was studied and compared to that of raw active compound. Results indicated that powders engineering changed the diameter and shape of the particles, making them suitable for inhalation. The mucus layer in the donor compartment of vertical diffusion cells slowed down drug dissolution and permeation, leucine having no influence. Cell proliferation studies evidenced that the spray drying process together with the addition of leucine reduced the cytotoxic effect of ketoprofen lysine salt as raw material, making the ketoprofen lysinate DPI a very promising product for the inflammation control in CF patients.

  18. Non-steroidal anti-inflammatory drugs and prostaglandin effects on pepsinogen secretion by dispersed human peptic cells.

    PubMed Central

    Lanas, A I; Nerín, J; Esteva, F; Sáinz, R

    1995-01-01

    The effects of aspirin and ibuprofen on pepsinogen secretion were studied in isolated human peptic cells prepared from endoscopically obtained biopsy specimens after collagenase digestion, mechanical disruption, and percoll gradient centrifugation. Pharmacological concentrations of aspirin and ibuprofen (10(-8)-10(-4) M), potentiated histamine (10(-6)-10(-4)M) and forskolin (10(-5)M) stimulated pepsinogen secretion without affecting basal secretion, acetylcholine (10(-6)M) stimulated pepsinogen secretion or cell vitality. Augmentation of secretagogue stimulated pepsinogen secretion was dependent on extracellular calcium because potentiation was abolished by calcium depletion of the medium. Cimetidine inhibited the potentiation effect on histamine but not on forskolin stimulated pepsinogen secretion, thus suggesting that this augmentation was independent of histamine H2 receptors. Of interest, potentiation was also independent of endogenous prostaglandin inhibition because exogenous addition of prostaglandin E2 and D2 increased both basal and acetylcholine stimulated pepsinogen secretion in a dose dependent way, but they did not modify histamine or histamine plus aspirin or ibuprofen stimulated pepsinogen secretion. In conclusion, aspirin and ibuprofen potentiate secretagogue stimulated pepsinogen secretion by dispersed human peptic cells and this might be an additional mechanism of non-steroidal anti-inflammatory drug (NSAID) induced gastric injury. This potentiation effect is regulated by calcium, independent of endogenous prostaglandin inhibition and seems to act on pepsinogen secretion at a post-receptor site. PMID:7797113

  19. Charge transfer complex studies between some non-steroidal anti-inflammatory drugs and π-electron acceptors

    NASA Astrophysics Data System (ADS)

    Duymus, Hulya; Arslan, Mustafa; Kucukislamoglu, Mustafa; Zengin, Mustafa

    2006-12-01

    Charge transfer (CT) complexes of some non-steroidal anti-inflammatory drugs, naproxen and etodolac which are electron donors with some π-acceptors, such as tetracyanoethylene (TCNE), 2,3-dichloro-5,6-dicyano- p-benzoquinone (DDQ), p-chloranil ( p-CHL), have been investigated spectrophotometrically in chloroform at 21 °C. The coloured products are measured spectrophotometrically at different wavelength depending on the electronic transition between donors and acceptors. Beer's law is obeyed and colours were produced in non-aqueous media. All complexes were stable at least 2 h except for etodolac with DDQ stable for 5 min. The equilibrium constants of the CT complexes were determined by the Benesi-Hildebrand equation. The thermodynamic parameters Δ H, Δ S, Δ G° were calculated by Van't Hoff equation. Stochiometries of the complexes formed between donors and acceptors were defined by the Job's method of the continuous variation and found in 1:1 complexation with donor and acceptor at the maximum absorption bands in all cases.

  20. Non-steroidal anti-inflammatory drugs and amyotrophic lateral sclerosis: results from five prospective cohort studies.

    PubMed

    Fondell, Elinor; O'Reilly, Éilis J; Fitzgerald, Kathryn C; Falcone, Guido J; McCullough, Marjorie L; Thun, Michael J; Park, Yikyung; Kolonel, Laurence N; Ascherio, Alberto

    2012-10-01

    Animal and pathological studies suggest that inflammation may contribute to amyotrophic lateral sclerosis (ALS) pathology and that non-steroidal anti-inflammatory drugs (NSAIDs) might be protective. However, there are no prospective data on the relation between NSAID use and ALS risk in humans. The relation between NSAID use and ALS risk was explored in five large prospective cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health - AARP Diet and Health Study). Detailed NSAID information was sought from 780,000 participants, 708 of whom developed ALS during follow-up. Cox proportional hazards models were used within each cohort and cohort-specific estimates were pooled with random effects models. Results showed that neither non-aspirin NSAID use, nor aspirin use was associated with ALS risk overall. The multivariable, pooled relative risk was 0.96 (95% CI 0.76-1.22) among non-aspirin NSAID users compared with non-users. Duration of NSAID use in years and frequency of NSAID use were not associated with ALS risk overall. In conclusion, the results do not support an overall effect of NSAIDs on ALS risk, but because NSAIDs have heterogeneous effects, a role of individual compounds cannot be excluded.

  1. Functionalized carbon nanotubes as the pseudostationary phase for capillary EKC separation of non-steroidal anti-inflammatory drugs.

    PubMed

    Huang, Yi-Jin; Wang, Guan-Ren; Huang, Kuan-Pin; Hsieh, Yu-Fang; Liu, Chuen-Ying

    2009-11-01

    Functionalized multiwalled carbon nanotubes (f-MWCNTs) can serve as the pseudostationary phase (PSP) for the capillary EKC separation of non-steroidal anti-inflammatory drugs (NSAIDs). To increase their hydrophilicity, we treated MWCNTs, with a sonochemical process in a concentrated nitric/sulfuric acid mixture. The oxidized MWCNTs were then characterized by FT-IR, transmission electron microscopy, and X-ray photoelectron spectroscopy. We evaluated the potential of the PSP and the effects of buffer composition, pH, addition of organic modifier, and injection temperature on the NSAID separation. The PSP created a network structure of pi-pi interactions, hydrophobic forces, hydrogen bonding, and electrostatic interactions to separate NSAIDs, providing a different separation mode from SDS micelles. We achieved complete separation of six NSAIDs using a mixture of a borate buffer (75 mM, pH 10) with methanol (5%, v/v) containing 0.02 mg/mL f-MWCNTs, an applied voltage of +12 kV and detection at 214 nm. Better precision was obtained with a low injection temperature. The method was also satisfactorily applied to the analysis of NSAIDs spiked into a urine sample.

  2. Effects of non-steroidal anti-inflammatory drugs on proliferation, differentiation and migration in equine mesenchymal stem cells.

    PubMed

    Müller, Maike; Raabe, Oksana; Addicks, Klaus; Wenisch, Sabine; Arnhold, Stefan

    2011-03-01

    In equine medicine, stem cell therapies for orthopaedic diseases are routinely accompanied by application of NSAIDs (non-steroidal anti-inflammatory drugs). Thus, it has to be analysed how NSAIDs actually affect the growth and differentiation potential of MSCs (mesenchymal stem cells) in vitro in order to predict the influence of NSAIDs such as phenylbutazone, meloxicam, celecoxib and flunixin on MSCs after grafting in vivo. The effects of NSAIDs were evaluated regarding cell viability and proliferation. Additionally, the multilineage differentiation capacity and cell migration was analysed. NSAIDs at lower concentrations (0.1-1 μM for celecoxib and meloxicam and 10-50 μM for flunixin) exert a positive effect on cell proliferation and migration, while at higher concentrations (10-200 μM for celecoxib and meloxicam and 100-1000 μM for flunixin and phenylbutazone), there is rather a negative influence. While there is hardly any influence on the adipogenic as well as on the chondrogenic MSC differentiation, the osteogenic differentiation potential, as demonstrated with the von Kossa staining, is significantly disturbed. Thus, it can be concluded that the effects of NSAIDs on MSCs are largely dependent on the concentrations used. Additionally, for some differentiation lineages, also the choice of NSAID is critical.

  3. Non-steroidal anti-inflammatory drug, nabumetone, prevents indometacin-induced gastric damage via inhibition of neutrophil functions.

    PubMed

    Ishiwata, Yoshiro; Okamoto, Masayuki; Yokochi, Shoji; Hashimoto, Hiroyuki; Nakamura, Takashi; Miyachi, Atsushi; Naito, Yuji; Yoshikawa, Toshikazu

    2003-02-01

    Nabumetone is a non-steroidal anti-inflammatory drug (NSAID). It works as a prodrug and is extensively metabolized to an active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). It is well known that neutrophil infiltration and activation are critical in the pathogenesis of NSAID-induced gastric injury, and nabumetone shows less incidence of gastrointestinal irritancy. We examined the effects of nabumetone on neutrophil activation and on indometacin-induced gastric damage. In the indometacin-induced gastric mucosal injury, rats were treated with indometacin and then nabumetone or 6MNA was orally administered. Nabumetone prevented gastric damage accompanied by the reduction of neutrophil infiltration into gastric mucosa, but such an effect was not observed with 6MNA. Nabumetone reduced the formyl methionyl leucyl phenylalanine (fMLP)-induced respiratory burst of human neutrophils to 30% of the control level in-vitro, but 6MNA did not. In addition, nabumetone prevented the fMLP-induced migration of neutrophils. Nabumetone did not inhibit O2- generation in the xanthine-xanthine oxidase system. These results suggest that nabumetone prevents gastric damage induced by the active metabolite, 6MNA, via the suppression of neutrophil activation in gastric mucosa.

  4. The Prescription Pattern of Acetaminophen and Non-Steroidal Anti-Inflammatory Drugs in Patients with Liver Cirrhosis.

    PubMed

    Hong, Young Mi; Yoon, Ki Tae; Heo, Jeong; Woo, Hyun Young; Lim, Won; An, Dae Seong; Han, Jun Hee; Cho, Mong

    2016-10-01

    Analgesics, known to be hepatotoxic drugs, are frequently prescribed to patients with liver cirrhosis who are prone to drug-induced liver injury. No guidelines are available regarding the prescription of analgesics in these patients. Therefore, we aimed to evaluate the prescription pattern of most frequently used analgesics in patients with cirrhosis. We assessed the prescription pattern of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) in patients with liver cirrhosis registered in Health Insurance Review Assessment Service database between January 1, 2012 and December 31, 2012. A total of 125,505 patients with liver cirrhosis were registered from January 1, 2012 to December 31, 2012. Of that group, 50,798 (40.5%) patients claimed reimbursement for at least one prescription for acetaminophen or NSAIDs during the one year follow-up period. Overall, NSAIDs (82.7%) were more prescribed than acetaminophen (64.5%). NSAIDs were more prescribed than acetaminophen even in decompensated cirrhosis compared with compensated cirrhosis (71.5% vs. 68.8%, P value < 0.001). There was a marked difference in prescription preference between acetaminophen and NSAIDs among physicians. Internists more frequently prescribed acetaminophen than NSAIDs compared to other physicians (50.9% vs. 76.2%, P < 0.001). Gastroenterologists more frequently prescribed acetaminophen over NSAIDs compared to other internists (80.9% vs. 51.2%, P < 0.001). Analgesics were prescribed in 40.5% of patients with cirrhosis. NSAIDs were more frequently prescribed although they should be avoided. The prescription pattern of analgesics were different significantly among physicians in patients with liver cirrhosis. The harmful effects of NSAIDs in patients with cirrhosis should be reminded to all physicians prescribing analgesics.

  5. The Prescription Pattern of Acetaminophen and Non-Steroidal Anti-Inflammatory Drugs in Patients with Liver Cirrhosis

    PubMed Central

    2016-01-01

    Analgesics, known to be hepatotoxic drugs, are frequently prescribed to patients with liver cirrhosis who are prone to drug-induced liver injury. No guidelines are available regarding the prescription of analgesics in these patients. Therefore, we aimed to evaluate the prescription pattern of most frequently used analgesics in patients with cirrhosis. We assessed the prescription pattern of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) in patients with liver cirrhosis registered in Health Insurance Review Assessment Service database between January 1, 2012 and December 31, 2012. A total of 125,505 patients with liver cirrhosis were registered from January 1, 2012 to December 31, 2012. Of that group, 50,798 (40.5%) patients claimed reimbursement for at least one prescription for acetaminophen or NSAIDs during the one year follow-up period. Overall, NSAIDs (82.7%) were more prescribed than acetaminophen (64.5%). NSAIDs were more prescribed than acetaminophen even in decompensated cirrhosis compared with compensated cirrhosis (71.5% vs. 68.8%, P value < 0.001). There was a marked difference in prescription preference between acetaminophen and NSAIDs among physicians. Internists more frequently prescribed acetaminophen than NSAIDs compared to other physicians (50.9% vs. 76.2%, P < 0.001). Gastroenterologists more frequently prescribed acetaminophen over NSAIDs compared to other internists (80.9% vs. 51.2%, P < 0.001). Analgesics were prescribed in 40.5% of patients with cirrhosis. NSAIDs were more frequently prescribed although they should be avoided. The prescription pattern of analgesics were different significantly among physicians in patients with liver cirrhosis. The harmful effects of NSAIDs in patients with cirrhosis should be reminded to all physicians prescribing analgesics. PMID:27550489

  6. The Diamine Oxidase Gene Is Associated with Hypersensitivity Response to Non-Steroidal Anti-Inflammatory Drugs

    PubMed Central

    Agúndez, José A. G.; Ayuso, Pedro; Cornejo-García, José A.; Blanca, Miguel; Torres, María J.; Doña, Inmaculada; Salas, María; Blanca-López, Natalia; Canto, Gabriela; Rondon, Carmen; Campo, Paloma; Laguna, José J.; Fernández, Javier; Martínez, Carmen; García-Martín, Elena

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR  = 1.7 (95% CI  = 1.3–2.1; Pc  = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc  = 0.008 and Pc  = 0.004, respectively). Conclusions and implications The DAO polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response. PMID:23152756

  7. Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn.

    PubMed

    Antonucci, Roberto; Zaffanello, Marco; Puxeddu, Elisabetta; Porcella, Annalisa; Cuzzolin, Laura; Pilloni, Maria Dolores; Fanos, Vassilios

    2012-05-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed in pregnancy to treat fever, pain and inflammation. Indications for chronic use of these agents during pregnancy are inflammatory bowel or chronic rheumatic diseases. Since the seventies, NSAIDs have been used as effective tocolytic agents: indomethacin has been the reference drug, delaying delivery for at least 48 hours and up to 7-10 days. Additionally, self-medication with NSAIDs is practiced by pregnant women. NSAIDs given to pregnant women cross the placenta and may cause embryo-fetal and neonatal adverse effects, depending on the type of agent, the dose and duration of therapy, the period of gestation, and the time elapsed between maternal NSAID administration and delivery. These effects derive from the action mechanisms of NSAIDs (mainly inhibition of prostanoid activity) and from the physiological changes in drug pharmacokinetics occurring during pregnancy. Increased risks of miscarriage and malformations are associated with NSAID use in early pregnancy. Conversely, exposure to NSAIDs after 30 weeks' gestation is associated with an increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios. Fetal and neonatal adverse effects affecting the brain, kidney, lung, skeleton, gastrointestinal tract and cardiovascular system have also been reported after prenatal exposure to NSAIDs. NSAIDs should be given in pregnancy only if the maternal benefits outweigh the potential fetal risks, at the lowest effective dose and for the shortest duration possible. This article discusses in detail the placental transfer and metabolism of NSAIDs, and the adverse impact of prenatal NSAID exposure on the offspring.

  8. Microextraction of non-steroidal anti-inflammatory drugs from waste water samples by rotating-disk sorptive extraction.

    PubMed

    Manzo, Valentina; Honda, Luis; Navarro, Orielle; Ascar, Loreto; Richter, Pablo

    2014-10-01

    In this study, six non-steroidal anti-inflammatory drugs (NSAIDs) were extracted from water samples using the rotating-disk sorptive extraction (RDSE) technique. The extraction disk device contains a central cavity that allows for the incorporation of a powdered sorbent phase (Oasis™ HLB). The analytes were extracted from water and pre-concentrated on the sorbent to reach the extraction equilibrium, and then they were desorbed with solvent, derivatized and determined by gas chromatography-mass spectrometry (GC-MS). The variables for the extraction were studied using high performance liquid chromatography with a diode array detector (HPLC-DAD) to avoid the derivatization step, and the optimum values were as follows: 60 mg of Oasis™ HLB, a rotation velocity of 3,000 rpm, a pH of 2, a sample volume of 50 mL, and an extraction time of approximately 90-100 min. The recoveries ranged from 71 to 104%, with relative standard deviations (RSD) between 2 and 8%. The detection limits ranged from 0.001 to 0.033 µg L(-1). The described method was applied to the analysis of influents and effluents from wastewater treatment plants (WWTP) in Santiago, Chile. The concentrations of the detected drugs ranged from 1.5 to 13.4 µg L(-1) and from 1.0 to 3.2 µg L(-1) in the influents and effluents, respectively. The samples were extracted by solid phase extraction (SPE). No significant differences were observed in the determined concentrations for most of the NSAIDs, indicating that RDSE is an alternative method for the preparation of water samples.

  9. [Non-steroidal anti-inflammatory drugs and tramadol in the treatment of osteoarthrosis deformans in patients with arterial hypertension].

    PubMed

    Lazebnik, L B; Kotsiubinskaia, O B; Konev, Iu V; Drozdov, V N

    2004-01-01

    The prohypertensive effect of non-steroidal anti-inflammatory drugs (NSAIDs) can be manifested by the decreased efficiency of antihypertensive therapy. The tactics of their differential use in relation to the its effect on blood pressure (BP) in patients with osteoarthrosis (OA) and arterial hypertension (AH) has not been developed for the most effective and safe therapy. In this connection, it is extremely urgent to study the comparative safety of used NSAIDs as to their prohypertensive effect and to work out the management of patients with AH and OA. Ninety-eight patients with second-third degree OA of the knee and hip joints concurrent with the pain syndrome and first-second grade AH were followed up. Diclofenac, ketoprofen, arthrotec, nimesulide, and meloxicam were used. In a control group, the analgesic tramadol was supplemented to the therapy. AH was controlled by enalapril monotherapy. In groups of patients receiving diclofenac, arthrotec, meloxicam, and ketoprofen, there was a trend for the number of cases of an adequate nocturnal BP lowering (Dipper) to reduce and for those of an inadequate nocturnal BP decrease (Non-dipper), which may be accounted for by the prohypertensive effect of these drugs; this trend was most pronounced in the diclofenac and arthrotec groups. Despite its marked prohypertensive effect, nimesulide did not impair circadian BP variations. The central-acting analgesic tramadol exerted no prohypertensive effect and it did not increase BP values. The prohypertensive effect of the tested NSAIDs and tramadol increases in the following order: tramadol, ketoprofen, meloxicam, nimesulide, arthrotec, diclofenac.

  10. Non-Steroidal Anti-Inflammatory Drugs and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic Pericarditis

    PubMed Central

    Schwier, Nicholas; Tran, Nicole

    2016-01-01

    Aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay of therapy for the treatment of idiopathic pericarditis (IP). A comprehensive review consisting of pertinent clinical literature, pharmacokinetic, and pharmacodynamic considerations, has not been released in recent years. This review will facilitate the clinician’s understanding of pharmacotherapeutic considerations for using ASA/NSAIDs to treat IP. Data were compiled using clinical literature consisting of case reports, cohort data, retrospective and prospective studies, and manufacturer package inserts. ASA, ibuprofen, indometacin, and ketorolac relatively have the most evidence in the treatment of IP, provide symptomatic relief of IP, and should be tapered accordingly. ASA is the drug of choice in patients with coronary artery disease (CAD), heart failure (HF), or renal disease, but should be avoided in patients with asthma and nasal polyps, who are naïve to ASA therapy. Ibuprofen is an inexpensive and relatively accessible option in patients who do not have concomitant CAD, HF, or renal disease. Indometacin is not available over-the-counter in the USA, and has a relatively higher incidence of central nervous system (CNS) adverse effects. Ketorolac is an intravenous option; however, clinicians must be mindful of the maximum dose that can be administered. While ASA/NSAIDs do not ameliorate the disease process of IP, they are part of first-line therapy (along with colchicine), for preventing recurrence of IP. ASA/NSAID choice should be dictated by comorbid conditions, tolerability, and adverse effects. Additionally, the clinician should be mindful of considerations such as tapering, high-sensitivity CRP monitoring, bleeding risk, and contraindications to ASA/NSAID therapy. PMID:27023565

  11. Non-steroidal anti-inflammatory drugs and renal response to exercise: a comparison of indomethacin and nabumetone.

    PubMed

    Olsen, N V; Jensen, N G; Hansen, J M; Christensen, N J; Fogh-Andersen, N; Kanstrup, I L

    1999-10-01

    Nabumetone, a newer non-steroidal anti-inflammatory drug (NSAID) which preferentially blocks cyclo-oxygenase-2 activity, may be less nephrotoxic than indomethacin. This study tested whether nabumetone has effects different from those of indomethacin on exercise-induced changes in renal function and the renin-aldosterone system. In a randomized fashion, ten subjects were studied after indomethacin (100 mg), nabumetone (1 g) or no medication (control) administered orally at 22.00 hours on the day before each study day, and again at 8.00 hours upon arrival at the laboratory. Renal function was studied at baseline, during graded 20-min exercise sessions at 25%, 50% and 75% of the maximal oxygen uptake rate, and subsequently during two 1-h recovery periods. Heart rate, arterial blood pressure, cardiac output and plasma catecholamines at rest and during exercise were not altered by indomethacin or nabumetone. Indomethacin decreased urinary rates of excretion of 6-oxo-prostaglandin F(1alpha) (6-oxo-PGF(1alpha)) and thromboxane B(2) in all study periods. Nabumetone decreased 6-oxo-PGF(1alpha) excretion during and after exercise. Excretion rates for PGE(2) did not change. Neither indomethacin nor nabumetone changed baseline values or exercise-induced decreases in renal plasma flow or glomerular filtration rate. Indomethacin, but not nabumetone, decreased sodium excretion, urine flow rate and free water clearance. The renal response to exercise, however, remained unchanged. In contrast with nabumatone, indomethacin decreased the plasma renin concentration. Thus, during exercise, nabumetone may decrease the excretion of 6-oxo-PGF(1alpha) by inhibition of cyclo-oxygenase-1 or by inhibition of specific exercise-induced activation of cyclo-oxygenase-2, or both. None of the drugs changed the renal response to exercise. Inhibition by indomethacin of angiotensin II and thromboxane A(2) synthesis may, during exercise, counterbalance renal vasoconstriction caused by blockade of

  12. Evidence based educational outreach visits: effects on prescriptions of non-steroidal anti-inflammatory drugs

    PubMed Central

    Bernal-Delgado, E; Galeote-Mayor, M; Pradas-Arnal, F; Peiro-Moreno, S

    2002-01-01

    Design: Randomised controlled simple blind trial, with randomisation into three groups: experimental (evidence based educational outreach visit), placebo (conventional education session), and control (without intervention). Setting: The 24 primary care centres of the National Institute of Healthcare Network in a rural province of Aragon, Spain. Participants: The 24 primary health care teams of the network, with 158 general practitioners (GPs). The teams were randomised into the groups, experimental (8 teams, 48 GPs), placebo (8 teams, 54 GPs), and control (8 teams, 56 GPs). Intervention: Experimental group: one group educational outreach visit, conveying data based on a systematic review of the literature that was reinforced with printed material; placebo group: one non-structured educational session; control group: no intervention. Both educational sessions emphasised that there are no differences in the effectiveness of the NSAIDs reviewed (diclofenac, piroxicam, and tenoxicam); a recommendation was made to prescribe diclofenac over tenoxicam because of price differences. Main outcome measures: Changes in the number of packages prescribed for each of the drugs and changes in the cost per package of NSAIDs prescribed during the six months before, and after the intervention. Results: There were no differences in the basal characteristics of the three groups, except for the number of prescriptions during the six months before the intervention. Prescriptions for NSAIDs decreased homogeneously in the three groups. For tenoxicam, the experimental group reduced prescriptions by 22.5% (95%CI: 34.42 to -10.76), compared with a reduction of 9.78% (95%CI: -17.70 to -1.86) in the placebo group and an increase of 14.44% (95%CI: 5.22 to 23.66) in the control group. The average cost per prescription decreased by 1.91% (95%CI: -0.33% to -3.49%) in the experimental group, 0.16% (95%CI: -0.27% to -2.93%) in the placebo group, and rose by 1.76% (95%CI: 0.35% to 3.17%) in the

  13. Manganese(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid: structure and biological perspectives.

    PubMed

    Zampakou, Marianthi; Rizeq, Natalia; Tangoulis, Vassilis; Papadopoulos, Athanasios N; Perdih, Franc; Turel, Iztok; Psomas, George

    2014-02-17

    Manganese(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid (Htolf) with the nitrogen-donor heterocyclic ligands 1,10-phenanthroline (phen), pyridine (py), or 2,2'-bipyridylamine (bipyam) and/or the oxygen-donor ligands H2O or N,N-dimethylformamide (DMF) have been synthesized and characterized. The crystal structures of complexes [Mn(tolf-O)(tolf-O,O')(phen)(H2O)], [Mn2(μ2-tolf-O,O')2(tolf-O,O')2(bipyam)2], [Mn2(μ2-H2O)(μ2-tolf-O,O')2(tolf-O)2(py)4]·1.5MeOH·py, and [Mn(μ2-tolf-O,O')2(DMF)2]n have been determined by X-ray crystallography. The interaction of the complexes with serum albumin proteins was investigated, and relative high binding constant values were calculated. The ability of the compounds to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), and hydroxyl radicals was evaluated, and [Mn(tolf)2(phen)(H2O)] was the most active scavenger among the compounds. The compounds have also exhibited noteworthy in vitro inhibitory activity against soybean lipoxygenase. UV titration studies of the interaction of the complexes with calf-thymus (CT) DNA have proved the binding to CT DNA with [Mn(μ2-tolf)2(DMF)2]n exhibiting the highest DNA-binding constant (Kb = 5.21 (±0.35) × 10(5) M(-1)). The complexes bind to CT DNA probably via intercalation as suggested by DNA-viscosity measurements and competitive studies with ethidium bromide (EB), which revealed the ability of the complexes to displace the DNA-bound EB.

  14. Toxicity of non-steroidal anti-inflammatory drugs to Gyps vultures: a new threat from ketoprofen.

    PubMed

    Naidoo, Vinny; Wolter, Kerri; Cromarty, Duncan; Diekmann, Maria; Duncan, Neil; Meharg, Andrew A; Taggart, Mark A; Venter, Leon; Cuthbert, Richard

    2010-06-23

    Three Gyps vulture species are on the brink of extinction in South Asia owing to the veterinary non-steroidal anti-inflammatory drug (NSAID) diclofenac. Carcasses of domesticated ungulates are the main food source for Asia's vultures and birds die from kidney failure after consuming diclofenac-contaminated tissues. Here, we report on the safety testing of the NSAID ketoprofen, which was not reported to cause mortality in clinical treatment of scavenging birds and is rapidly eliminated from livestock tissues. Safety testing was undertaken using captive non-releasable Cape griffon vultures (Gyps coprotheres) and wild-caught African white-backed vultures (G. africanus), both previously identified as susceptible to diclofenac and suitable surrogates. Ketoprofen doses ranged from 0.5 to 5 mg kg(-1) vulture body weight, based upon recommended veterinary guidelines and maximum levels of exposure for wild vultures (estimated as 1.54 mg kg(-1)). Doses were administered by oral gavage or through feeding tissues from cattle dosed with ketoprofen at 6 mg kg(-1) cattle body weight, before slaughter. Mortalities occurred at dose levels of 1.5 and 5 mg kg(-1) vulture body weight (within the range recommended for clinical treatment) with the same clinical signs as observed for diclofenac. Surveys of livestock carcasses in India indicate that toxic levels of residual ketoprofen are already present in vulture food supplies. Consequently, we strongly recommend that ketoprofen is not used for veterinary treatment of livestock in Asia and in other regions of the world where vultures access livestock carcasses. The only alternative to diclofenac that should be promoted as safe for vultures is the NSAID meloxicam.

  15. Photocatalytic degradation of non-steroidal anti-inflammatory drugs with TiO2 and simulated solar irradiation.

    PubMed

    Méndez-Arriaga, Fabiola; Esplugas, Santiago; Giménez, Jaime

    2008-02-01

    The aim of this work is to evaluate and compare the degradation achieved for three non-steroidal anti-inflammatory drugs (NSAIDs) by heterogeneous TiO2 photocatalytic means in aqueous solution at laboratory scale. The selected pharmaceutical compounds were diclofenac (DCF), naproxen (NPX) and ibuprofen (IBP). These compounds were used in their sodium salt chemical form. Previous experiments (adsorption, photolysis and thermodegradation) were developed to evaluate non-catalytic degradation for each NSAID. Photocatalytic experiments were carried out in a Xe-lamp reactor in order to study the influences of different operational conditions (catalyst load, temperature and dissolved oxygen concentration). These results showed that the optimum amount of TiO2, to achieve maximum degradation, of IBP was 1g/L. In contrast, the maximum degradation for DCF or NPX was observed at a TiO2 loading of 0.1g/L. Temperature had a significant effect only for NPX degradation, achieving almost 99% phototransformation. No significant differences were observed for DCF and IBP at 20, 30 and 40 degrees C. Dissolved oxygen concentration was an important parameter to increase the degradation for NPX and IBP. However, it was observed that its rate of mineralization did not increase. Intermediate metabolites were detected in all cases. Hydroxyl metabolites were the most important residual compounds after the photocatalytic treatment of IBP. The inhibition percentage of bioluminescence from Vibro fischeri--as a toxicity parameter--increased during the irradiation time due to the residual concentration of the hydroxyl metabolites generated. However, after 120 min, in experiments with 40 mg/L of dissolved oxygen, a decrease of the % inhibition was observed. Only photocatalytic treatment of IBP drives to a satisfactory biodegradability index BOD5/COD (between 0.16 and 0.42) and, only in this case, a post-biological treatment could be suggested.

  16. Non-Steroidal Anti-Inflammatory Drugs, Acetaminophen, and Risk of Skin Cancer in the Nurses’ Health Study

    PubMed Central

    Jeter, JM; Han, J; Martinez, ME; Alberts, DS; Qureshi, AA; Feskanich, D

    2012-01-01

    Purpose Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with lower risk of certain cancers, but data on the effect on skin cancer risk have been limited and contradictory. We prospectively examined whether use of NSAIDS or acetaminophen was associated with a lower risk of skin cancer in women. Methods The 92,125 Caucasian women in the Nurses’ Health Study provided information on aspirin use in 1980. Other NSAIDs and acetaminophen were added in 1990. Medication use, frequency, and quantity were reassessed on biennial questionnaires. Through 2008, we confirmed 658 melanoma cases, 1337 squamous cell carcinoma (SCC) cases, and had 15,079 self-reports of basal cell carcinoma (BCC). We used COX proportional hazards models to compute relative risks (RR) adjusted for known skin cancer risk factors. Results Neither aspirin nor non-aspirin NSAID use was associated with a lower risk of melanoma, SCC or BCC, even for women with high quantity, frequency, or duration of use. Instead, we observed an increased risk of melanoma among current aspirin users (RR=1.32, 95% CI 1.03–1.70), though an increase of similar magnitude among past users and lack of a dose-response effect did not support a pharmacologic mechanism. We observed a mild reduction in SCC risk in current acetaminophen users (RR=0.88, 95% CI 0.75–1.02), with a linear decrease in risk with greater frequency of use (p=0.04). Conclusions Aspirin and other NSAIDs were not associated with a lower risk of melanoma, SCC or BCC in women. Our large, prospective study does not support a chemoprotective effect of NSAIDs against skin cancers. PMID:22763500

  17. Monitoring of the non-steroid anti-inflammatory drug indomethacin: development of immunochemical methods for its purification and detection.

    PubMed

    Skalka, Nir; Krol, Alex; Schlesinger, Haim; Altstein, Miriam

    2011-07-01

    The present research focused on the development of an immunoassay and an immunochemical sol-gel-based immunoaffinity purification (IAP) method for purification and detection of the non-steroid anti-inflammatory drug (NSAID) indomethacin (IMT). A polyclonal antibody (Ab) for IMT was generated, and two sensitive microplate assays for the detection of IMT were developed (termed OV and HRP formats), based on the enzyme-linked immunosorbent assay (ELISA) method. The limits of detection of the assays were 15 ± 1.25 ng mL(-1) (n = 50) and 12 ± 0.17 ng mL(-1) (n = 4) for the OVA and HRP formats, respectively. The Abs exhibited slight cross-reactivity with other NSAIDs. The Abs were also used to develop a sol-gel-based IAP method for clean-up and concentration of IMT. Several sol-gel formats with various amounts of antibodies were examined; the best and most reproducible format was at a TMOS:HCl molar ratio of 1:6 in which 120 μL of IMT Abs was entrapped. The binding capacity under these conditions was ca. 100 to 250 ng of IMT with very low non-specific binding (less than 5% of the applied amount). The sol-gel IAP method, combined with solid-phase extraction, successfully eliminated serum interference to a degree that enabled analysis of spiked serum samples by ELISA. The method was also found to be fully compatible with subsequent chemical analytical methods, such as liquid chromatography followed by mass spectrometry. The approaches developed in this study form a basis for analysis of IMT in biological samples in order to monitor their pharmacokinetic properties, and may be further used to study population exposure to IMT, and to monitor the occurrence of IMT contamination in water samples.

  18. Thermal nociception as a measure of non-steroidal anti-inflammatory drug effectiveness in broiler chickens with articular pain.

    PubMed

    Caplen, Gina; Baker, Laurence; Hothersall, Becky; McKeegan, Dorothy E F; Sandilands, Victoria; Sparks, Nick H C; Waterman-Pearson, Avril E; Murrell, Joanna C

    2013-12-01

    Pain associated with poultry lameness is poorly understood. The anti-nociceptive properties of two non-steroidal anti-inflammatory drugs (NSAIDs) were evaluated using threshold testing in combination with an acute inflammatory arthropathy model. Broilers were tested in six groups (n=8 per group). Each group underwent a treatment (saline, meloxicam (3 or 5mg/kg) or carprofen (15 or 25mg/kg)) and a procedure (Induced (arthropathy-induction) or sham (sham-handling)) prior to testing. Induced groups had Freund's complete adjuvant injected intra-articularly into the left intertarsal joint (hock). A ramped thermal stimulus (1°C/s) was applied to the skin of the left metatarsal. Data were analysed using random-intercept multi-level models. Saline-induced birds had a significantly higher skin temperature (± SD) than saline-sham birds (37.6 ± 0.8°C vs. 36.5 ± 0.5°C; Z=-3.47, P<0.001), consistent with an inflammatory response. Saline was associated with significantly lower thermal thresholds (TT) than analgesic treatment (meloxicam: Z=2.72, P=0.007; carprofen: Z=2.58, P=0.010) in induced birds. Saline-induced birds also had significantly lower TT than saline-sham birds (Z=-2.17, P=0.030). This study found direct evidence of an association between inflammatory arthropathies and thermal hyperalgesia, and showed that NSAID treatment maintained baseline thermal sensitivity (via anti-nociception). Quantification of nociceptive responsiveness in a predictable broiler pain model identified thermal anti-hyperalgesic properties of two NSAIDs, which suggested that therapeutically effective treatment was provided at the doses administered. Such validation of analgesic strategies will increase the understanding of pain associated with specific natural broiler lameness types.

  19. Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone.

    PubMed

    Roy, H K; Karolski, W J; Ratashak, A

    2001-05-15

    Use of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention of colon cancer has been hindered by their potential gastro-intestinal toxicity. Nabumetone, which is approximately 10 to 36 times safer than conventional NSAIDs, was evaluated in 2 models of experimental colon carcinogenesis. In azoxymethane (AOM)-treated Fisher 344 rats, nabumetone caused dose-dependent inhibition of aberrant crypt foci (ACF), with 750 and 1,500 ppm resulting in 15% and 37% reductions, respectively (p < 0.05). Moreover, complex ACF were reduced by 48% in the latter group. MIN mice studies confirmed the chemopreventive efficacy of nabumetone, with 900 ppm suppressing approximately half of the intestinal tumors. Interestingly, inhibition of intermediate biomarkers in both models was markedly greater in the distal than the proximal bowel. To mechanistically evaluate this regional selectivity, we assessed cyclo-oxygenase-2 (COX-2) expression in the uninvolved mucosa and demonstrated a 3- to 4-fold excess in the distal relative to the proximal bowel in both MIN mice and AOM-treated rats. We then investigated another putative NSAID target, peroxisome proliferator-activated receptor-delta (PPAR-delta) and demonstrated up-regulation during AOM-induced colonic tumorigenesis. Furthermore, in pre-neoplastic mucosa, there was a 3-fold excess of PPAR-delta in the distal colon. We demonstrate that nabumetone is an effective protective agent in both experimental models of colon carcinogenesis. The striking distal predilection of nabumetone may be, at least partially, explained by distal bowel over-expression of COX-2 and PPAR-delta.

  20. Variable Effects of Non-steroidal Anti-inflammatory Drugs (NSAIDs) on Selected Biochemical Processes Mediated by Soil Microorganisms

    PubMed Central

    Cycoń, Mariusz; Borymski, Sławomir; Żołnierczyk, Bartłomiej; Piotrowska-Seget, Zofia

    2016-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used group of pharmaceuticals. The high consumption and the uncontrolled disposal of unused drugs into municipal waste or their deposit in landfills can result in an increased concentration of these compounds in soils. Moreover, these drugs can affect the microbial activity. However, there is a lack of knowledge about these effects or it is very limited. Therefore, the objective of this study was to compare the impact of selected commercially available NSAIDs, i.e., diclofenac (DCF), naproxen (NPX), ibuprofen (IBF) and ketoprofen (KTP), applied at concentrations of 1 and 10 mg/kg soil, on the activity of soil microorganisms during the 90-day experiment. To ascertain this impact, substrate-induced respiration (SIR), soil enzyme activities, i.e., dehydrogenase (DHA), acid and alkaline phosphatases (PHOS-H and PHOS-OH) and urease (URE) as well as changes in the rates of nitrification and ammonification processes were determined. In addition, the number of culturable bacteria and fungi were enumerated. In general, the obtained data showed a significant stimulatory effect of NSAIDs on the microbial activity. Higher concentrations of NSAIDs caused a greater effect, which was observed for SIR, PHOS-H, PHOS-OH, URE, N-NO3- and N-NH4+, even during the whole incubation period. Moreover, the number of heterotrophic bacteria and fungi increased significantly during the experiment, which was probably a consequence of the evolution of specific microorganisms that were capable of degrading NSAIDs and used them as an additional source of carbon and energy. However, an inhibitory effect of NPX, IBF or KTP for SIR, DHA, on both phosphatases and culturable bacteria and fungi was observed at the beginning of the experiment. At lower concentrations of NSAIDs, in turn, the effects were negligible or transient. In conclusion, the application of NSAIDs altered the biochemical and microbial activity of soil what may

  1. Efficacy of non-steroidal anti-inflammatory drugs for low back pain: a systematic review of randomised clinical trials

    PubMed Central

    Koes, B.; Scholten, R.; Mens, J.; Bouter, L.

    1997-01-01

    PURPOSE—To assess the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) for low back pain.
DATA SOURCES—Computer aided search of published randomised clinical trials and assessment of the methods of the studies.
STUDY SELECTION—26 randomised clinical trials evaluating NSAIDs for low back pain were identified.
DATA EXTRACTION—Score for quality (maximum = 100 points) of the methods based on four categories: study population; interventions; effect measurement; data presentation and analysis. Determination of success rate per study group and evaluation of different contrasts. Statistical pooling of placebo controlled trials in similar patient groups and using similar outcome measures.
RESULTS—The methods scores of the trials ranged from 27 to 83 points. NSAIDs were compared with placebo treatment in 10 studies. The pooled odds ratio in four trials comparing NSAIDs with placebo after one week was 0.53 (95% confidence intervals 0.32 to 0.89) using the fixed effect model, indicating a significant effect in favour of NSAIDs compared with placebo. In nine studies NSAIDs were compared with other (drug) therapies. Of these, only two studies reported better results of NSAIDs compared with paracetamol with and without dextropropoxyphene. In the other trials NSAIDs were not better than the reference treatment. In 11 studies different NSAIDs were compared, of which seven studies reported no differences in effect.
CONCLUSIONS—There are flaws in the design of most studies. The pooled odds ratio must be interpreted with caution because the trials at issue, including the high quality trials, did not use identical outcome measures. The results of the 26 randomised trials that have been carried out to date, suggest that NSAIDs might be effective for short-term symptomatic relief in patients with uncomplicated low back pain, but are less effective or ineffective in patients with low back pain with sciatica and patients with sciatica with nerve

  2. Non-Steroidal Anti-Inflammatory Drugs and Cardiovascular Outcomes in Women: Results from the Women’s Health Initiative

    PubMed Central

    Bavry, Anthony A.; Thomas, Fridtjof; Allison, Matthew; Johnson, Karen C.; Howard, Barbara V.; Hlatky, Mark; Manson, JoAnn E.; Limacher, Marian C.

    2014-01-01

    Background Conclusive data regarding cardiovascular (CV) toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for CV events in post-menopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 compared with cox-1 inhibition. Methods and Results Post-menopausal women enrolled in the Women’s Health Initiative (WHI) were classified as regular users or non-users of non-aspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total CV disease defined as CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (e.g., celecoxib), non-selective agents with cox-2>cox-1 inhibition (e.g., naproxen), and non-selective agents with cox-1>cox-2 inhibition (e.g., ibuprofen) with the primary outcome. Overall, 160,801 participants were available for analysis (mean follow-up 11.2 years). Regular NSAID use at some point in time was reported by 53,142 participants. Regular NSAID use was associated with an increased hazard for CV events versus no NSAID use (HR=1.10[95% CI 1.06–1.15], Pitalic>0.001). Selective cox-2 inhibitors were associated with a modest increased hazard for CV events (HR=1.13[1.04–1.23], P=0.004; celecoxib only HR=1.13[1.01–1.27], P=0.031). Among aspirin users, concomitant selective cox-2 inhibitor use was no longer associated with increased hazard for CV events. There was an increased risk for agents with cox-2>cox-1 inhibition (HR=1.17[1.10–1.24], Pbold>0.001; naproxen only HR=1.22[1.12–1.34], P<0.001). This harmful association remained among concomitant aspirin users. We did not observe a risk elevation for agents with cox-1>cox-2 inhibition (HR=1.01[0.95–1.07], P=0.884; ibuprofen only HR=1.00[0.93–1.07], P=0.996). Conclusions Regular use of selective cox-2 inhibitors and non

  3. [Effect of protracted therapy with chondroprotectors and non-steroidal anti-inflammatory drugs on the quality of life in patients with osteoarthrosis].

    PubMed

    Maĭko, O Iu; Bagirova, G G

    2009-01-01

    Dynamics of clinical parameters and quality of life (QL) was evaluated in 281 patients with knee and hip osteoarthrosis (OA) during long-term treatment of different duration. The group was dominated by women (71%) aged 41-65 yr with grade I-III OA according to Kellgren. Patients of groups I and II received only non-steroidal anti-inflammatory drugs (diclofenac, nize), those of groups III-IV the same drugs in combination with structum, chondrolon, and zeel T respectively. Clinical parameters were assessed based on VAS at rest and in motion, Leken's indices, and WOMAC, QL from SF-36 questionnaire. Variable clinical course was recorded in patients treated with non-steroidal drugs alone that caused rapid improvement after the very first treatment sessions followed by deterioration of the patients' condition. Addition of structum resulted in marked optimization of clinical and QL parameters within 3 months after the onset of combined therapy. Similar effect was obtained using chondrolon and zeel T, but 2-3 clinical parameters and 3 QL parameters were not significantly different from the initial ones after 12 and 24 months of therapy. It is concluded that structum produced the best therapeutic effect followed by chondrolon and zeel T. Non-steroidal anti-inflammatory drugs had no beneficial action whatever in patients with OA.

  4. Drug interactions between antihypertensive drugs and non-steroidal anti-inflammatory agents: a descriptive study using the French Pharmacovigilance database.

    PubMed

    Fournier, Jean-Pascal; Sommet, Agnès; Durrieu, Geneviève; Poutrain, Jean-Christophe; Lapeyre-Mestre, Maryse; Montastruc, Jean-Louis

    2014-04-01

    Drug-drug interactions (DDIs) between antihypertensive drugs and non-steroidal anti-inflammatory drugs (NSAIDs) can lead to adverse drug reactions (ADRs). Guidelines are available to help prescribers deal with these drug associations, but their implementation is not well evaluated. The aims of this study were to assess the prevalence of NSAIDs exposure in patients treated with antihypertensive drugs, using the French Pharmacovigilance database, and explore the ADRs related to DDIs between antihypertensive drugs and NSAIDs. Over the 11, 442 notifications of ADRs recorded in this database in patients treated with oral antihypertensive drugs between 2008 and 2010, 517 (4.5 and 95% CI: 4.1-4.9) also included exposure to NSAIDs. These subjects were more frequently women, took more drugs in general, and were younger and less frequently treated with antiplatelet drugs. In 24.2% of them (125 patients), a DDI between NSAIDs and antihypertensive drugs was potentially the cause of the reported ADR. Acute renal failure caused by DDIs between NSAIDs and angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or diuretics was the most frequently reported ADR (20.7%). Finally, in the French Pharmacovigilance database, around one-fourth of associations NSAIDs  +  antihypertensive drugs are associated with a 'serious' ADR (mainly acute renal failure), suggesting that this well-known DDI is not enough taken into account by prescribers.

  5. [U.S. Food and Drug Administration (FDA) strengthens warning that non-aspirin non steroidal anti-inflammatory drugs (NSAIDs) can cause myocardial infarctions or strokes: the dentist's perspective].

    PubMed

    Rosen, E; Tsesis, I; Vered, M

    2015-10-01

    This short communication is aimed to update dental practitioners regarding the recently published warning of the U.S. Food and Drug Administration (FDA) regarding the risk for severe cardiovascular complications such as myocardial infarction or stroke following the use of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs).

  6. The effect of non-steroidal anti-inflammatory drugs on the metabolism of /sup 14/C-arachidonic acid by human gingival tissue in vitro

    SciTech Connect

    Elattar, T.M.; Lin, H.S.; Tira, D.E.

    1983-09-01

    We investigated the effect of non-steroidal anti-inflammatory drugs on prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid (12-HETE) formation by inflamed human gingival tissues. Gingival tissue homogenates were incubated with /sup 14/C-arachidonic acid in the presence of indomethacin, piroxicam, or ibuprofen, and the organic solvent extracts were chromatographed on silica gel plates with standards for radiometric assay. There was a significant negative trend between the doses (10(-7)-10(-3) M) of each of indomethacin, piroxicam, and ibuprofen, and the amounts of PGF2 alpha, PGE2, PGD2, and 15-keto-PGE2 produced. All three drugs have a significant inhibitory effect on PGs and 12-HETE production at 10(-3) M when compared with the control. The rank order effectiveness of the drugs, at 10(-3) M, on PG inhibition was indomethacin greater than piroxicam greater than ibuprofen, and on 12-HETE inhibition was indomethacin greater than ibuprofen greater than piroxicam.

  7. Effects of non-steroidal anti-inflammatory drugs on the hyperalgesia to noxious mechanical stimulation induced by the application of a tourniquet to a forelimb of sheep.

    PubMed

    Welsh, E M; Nolan, A M

    1994-11-01

    A tourniquet was used in conjunction with a mechanical threshold testing device to investigate the suitability of the technique for the investigation of analgesic drugs in sheep. The changes to the mechanical thresholds to noxious stimulation during and after the inflation of a pneumatic tourniquet on a limb were recorded, and the influence of pre-treatment with two non-steroidal anti-inflammatory drugs was studied. Fentanyl, an opioid agonist with known analgesic properties in sheep, was used as a positive control. The tourniquet significantly reduced the mechanical thresholds on the ipsi- but not the contralateral limb. Pretreatment with either flunixin meglumine or carprofen attenuated the development of mechanical hyperalgesia, and fentanyl initially caused a significant anti-nociceptive effect. The time to aversion was not significantly different between the treatments. These results suggest that hyperalgesia induced by a tourniquet may be a useful technique for the investigation of the anti-nociceptive effects of analgesic drugs in sheep.

  8. The Role of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in the Treatment of Patients With Hepatic Disease: A Review Article

    PubMed Central

    Soleimanpour, Maryam; Imani, Farnad; Safari, Saeid; Sanaie, Sarvin; Soleimanpour, Hassan; Ameli, Hoorolnesa; Alavian, Seyed Moayed

    2016-01-01

    Context Patients with hepatic dysfunction suffer from many problems and associated complications in organs other than the liver. Therefore, it is very important to investigate the effects of different drugs in the treatment of these patients. Due to the high consumption of non-steroidal anti-inflammatory drugs (NSAIDs), studying the effects of these drugs in patients with hepatic dysfunction is particularly important. Evidence Acquisition Research studies published from 1958 to 2014 were investigated in the present study. The literature search was conducted based on the following keywords: non-steroidal anti-inflammatory drugs (NSAIDs), liver dysfunction, cirrhosis, pharmaceutical complications, drug-induced liver injury (DILI), and similar words from reliable resources. In total, 63 articles and two books (out of 179 initially identified resources) were included in the study. Results In addition to significant hemostatic disorders and cardiovascular disorders, disorders of the renal, respiratory, and gastrointestinal systems, as well as disorders of the central nervous system, occur in patients with hepatic dysfunction. The various NSAIDs have different effects on different bodily systems. Therefore, the appropriate drug should be chosen based on both the condition of the disease and the severity of the dysfunction. Conclusions Due to the potential adverse effects of NSAIDs in patients with hepatic disease, their impact on all bodily systems should be emphasized when determining whether their use is necessary. Further, the appropriate medication should be selected after a careful assessment of the severity of the disease and any associated complications. It is logical that medicines should only be prescribed by a qualified physician. PMID:27843779

  9. Meta-analysis of short term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis

    PubMed Central

    Gøtzsche, Peter C; Johansen, Helle Krogh

    1998-01-01

    Objective: To determine whether short term, oral low dose prednisolone (⩽15 mg daily) is superior to placebo and non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis. Design: Meta-analysis of randomised trials of oral corticosteroids compared with placebo or a non-steroidal anti-inflammatory drug. Setting: Trials conducted anywhere in the world. Subjects: Patients with rheumatoid arthritis. Main outcome measures: Joint tenderness, pain, and grip strength. Outcomes measured on different scales were combined by using the standardised effect size (difference in effect divided by SD of the measurements). Results: Ten studies were included in the meta-analysis. Prednisolone had a marked effect over placebo on joint tenderness (standardised effect size 1.31; 95% confidence interval 0.78 to 1.83), pain (1.75; 0.87 to 2.64), and grip strength (0.41; 0.13 to 0.69). Measured in the original units the differences were 12 (6 to 18) tender joints and 22 mm Hg (5 mm Hg to 40 mm Hg) for grip strength. Prednisolone also had a greater effect than non-steroidal anti-inflammatory drugs on joint tenderness (0.63; 0.11 to 1.16) and pain (1.25; 0.26 to 2.24), whereas the difference in grip strength was not significant (0.31; −0.02 to 0.64). Measured in the original units the differences were 9 (5 to 12) tender joints and 12 mm Hg (−6 mm Hg to 31 mm Hg). The risk of adverse effects during moderate and long term use seemed acceptable. Conclusion: Prednisolone in low doses (⩽15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means. Key messages Prednisolone in low doses—that is, no more than 15 mg daily—is highly effective in patients with rheumatoid arthritis The risk of adverse effects is acceptable in short, moderate, or long term use Oral low dose prednisolone may be used intermittently in patients with rheumatoid arthritis, particularly if

  10. Effects of non-steroidal anti-inflammatory drugs on cyanobacteria and algae in laboratory strains and in natural algal assemblages.

    PubMed

    Bácsi, István; B-Béres, Viktória; Kókai, Zsuzsanna; Gonda, Sándor; Novák, Zoltán; Nagy, Sándor Alex; Vasas, Gábor

    2016-05-01

    In recent years measurable concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) have been shown in the aquatic environment as a result of increasing human consumption. Effects of five frequently used non-steroidal anti-inflammatory drugs (diclofenac, diflunisal, ibuprofen, mefenamic acid and piroxicam in 0.1 mg ml(-1) concentration) in batch cultures of cyanobacteria (Synechococcus elongatus, Microcystis aeruginosa, Cylindrospermopsis raciborskii), and eukaryotic algae (Desmodesmus communis, Haematococcus pluvialis, Cryptomonas ovata) were studied. Furthermore, the effects of the same concentrations of NSAIDs were investigated in natural algal assemblages in microcosms. According to the changes of chlorophyll-a content, unicellular cyanobacteria seemed to be more tolerant to NSAIDs than eukaryotic algae in laboratory experiments. Growth of eukaryotic algae was reduced by all drugs, the cryptomonad C. ovata was the most sensitive to NSAIDs, while the flagellated green alga H. pluvialis was more sensitive than the non-motile green alga D. communis. NSAID treatments had weaker impact in the natural assemblages dominated by cyanobacteria than in the ones dominated by eukaryotic algae, confirming the results of laboratory experiments. Diversity and number of functional groups did not change notably in cyanobacteria dominated assemblages, while they decreased significantly in eukaryotic algae dominated ones compared to controls. The results highlight that cyanobacteria (especially unicellular ones) are less sensitive to the studied, mostly hardly degradable NSAIDs, which suggest that their accumulation in water bodies may contribute to the expansion of cyanobacterial mass productions in appropriate environmental circumstances by pushing back eukaryotic algae. Thus, these contaminants require special attention during wastewater treatment and monitoring of surface waters.

  11. A sensitive enzyme-linked immunosorbent assay amplified by biotin-streptavidin system for detecting non-steroidal anti-inflammatory drug ketoprofen.

    PubMed

    Bu, Dan; Zhuang, Hui S; Yang, Guang X

    2014-01-01

    A sensitive biotin-streptavidin-amplified enzyme-linked immunosorbent assay (BA-ELISA) method was developed for detecting non-steroidal anti-inflammatory drug ketoprofen. Compared with traditional ELISA method, the sensitivity of proposed immunoassay was enhanced by the biotin-streptavidin system. Under the optimal condition, the median inhibitory concentration (IC50) was 0.25 ng mL(-1), with minor cross-reactivity to a number of structural analogs. This developed assay was successfully applied to detect the ketoprofen residues in different fish samples, and good recoveries (72.6-105.5%) were obtained. The results indicated that this immunoassay method could specifically detect trace ketoprofen residues and could be widely used for routine monitoring of food samples.

  12. Two non-steroidal anti-inflammatory drugs, niflumic acid and diclofenac, inhibit the human glutamate transporter EAAT1 through different mechanisms.

    PubMed

    Takahashi, Kanako; Ishii-Nozawa, Reiko; Takeuchi, Kouichi; Nakazawa, Ken; Sato, Kaoru

    2010-01-01

    We investigated the effects of non-steroidal anti-inflammatory drugs on substrate-induced currents of L-glutamate (L-Glu) transporter EAAT1 expressed in Xenopus laevis oocytes. Niflumic acid (NFA) and diclofenac inhibited L-Glu-induced current through EAAT1 in a non-competitive manner. NFA produced a leftward shift in reversal potential (E(rev)) of L-Glu-induced current and increased current amplitude at the potentials more negative than -100 mV. Diclofenac had no effects on E(rev) and inhibited the current amplitude to the same extent at all negative potentials. These results indicate that NFA and diclofenac inhibit the L-Glu-induced EAAT1 current via different mechanisms.

  13. [Safe prescription recommendations for non steroidal anti-inflammatory drugs: Consensus document ellaborated by nominated experts of three scientific associations (SER-SEC-AEG)].

    PubMed

    Lanas, Angel; Benito, Pere; Alonso, Joaquín; Hernández-Cruz, Blanca; Barón-Esquivias, Gonzalo; Perez-Aísa, Angeles; Calvet, Xavier; García-Llorente, José Francisco; Gobbo, Milena; Gonzalez-Juanatey, José R

    2014-03-01

    This article outlines key recommendations for the appropriate prescription of non steroidal anti-inflammatory drugs to patients with different musculoskeletal problems. These recommendations are based on current scientific evidence, and takes into consideration gastrointestinal and cardiovascular safety issues. The recommendations have been agreed on by experts from three scientific societies (Spanish Society of Rheumatology [SER], Spanish Association of Gastroenterology [AEG] and Spanish Society of Cardiology [SEC]), following a two-round Delphi methodology. Areas that have been taken into account encompass: efficiency, cardiovascular risk, gastrointestinal risk, liver risk, renal risk, inflammatory bowel disease, anemia, post-operative pain, and prevention strategies. We propose a patient management algorithm that summarizes the main aspects of the recommendations.

  14. Pollution-induced community tolerance to non-steroidal anti-inflammatory drugs (NSAIDs) in fluvial biofilm communities affected by WWTP effluents.

    PubMed

    Corcoll, Natàlia; Acuña, Vicenç; Barceló, Damià; Casellas, Maria; Guasch, Helena; Huerta, Belinda; Petrovic, Mira; Ponsatí, Lidia; Rodríguez-Mozaz, Sara; Sabater, Sergi

    2014-10-01

    We assessed the tolerance acquired by stream biofilms to two non-steroidal anti-inflammatory-drugs (NSAIDs), ibuprofen and diclofenac. Biofilms came from a stream system receiving the effluent of a wastewater treatment plant (WWTP). The response of biofilms from a non-polluted site (upstream the WWTP) was compared to that of others downstream with relevant and decreasing levels of NSAIDs. Experiments performed in the laboratory following the pollution-induced community tolerance (PICT) approach determined that both algae and microbial communities from biofilms of the sites exposed at the highest concentrations of ibuprofen and diclofenac acquired tolerance to the mixture of these NSAIDs occurring at the sites. It was also observed that the chronic pollution by the WWTP effluent affected the microbial metabolic profile, as well as the structure of the algal community. The low (at ng L(-1) level) but chronic inputs of pharmaceuticals to the river ecosystem result in tolerant communities of lower diversity and altered microbial metabolism.

  15. Concentration of Non-Steroidal Anti-Inflammatory Drugs in the Pelvic Floor Muscles: An Experimental Comparative Rat Model

    PubMed Central

    Chin, Hung-Yen; Changchien, Eileen; Lin, Mei-Fung; Chiang, Chi-Hsin

    2014-01-01

    Purpose The aim of this study is to explore non-steroid anti-inflammation drugs (NSAIDs) potency for pelvic floor muscle pain by measuring local concentration in a rat model. Materials and Methods We used nine NSAIDs, including nabumetone, naproxen, ibuprofen, meloxicam, piroxicam, diclofenac potassium, etodolac, indomethacin, and sulindac, and 9 groups of female Wister rats. Each group of rats was fed with one kind of NSAID (2 mg/mL) for three consecutive days. Thereafter, one mL of blood and one gram of pelvic floor muscle were taken to measure drug pharmacokinetics, including partition coefficient, lipophilicity, elimination of half-life (T1/2) and muscle/plasma converting ratio (Css, muscle/Css, plasma). Results Diclofenac potassium had the lowest T1/2 and the highest mean Css, muscle/Css, plasma (1.9 hours and 0.85±0.53, respectively). The mean Css, muscle/Css, plasma of sulindac, naproxen and ibuprofen were lower than other experimental NSAIDs. Conclusion Diclofenac potassium had the highest disposition in pelvic floor muscle in a rat model. The finding implies that diclofenac potassium might be the choice for pain relief in pelvic muscle. PMID:24954342

  16. Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac.

    PubMed

    Rattner, Barnett A; Whitehead, Maria A; Gasper, Grace; Meteyer, Carol U; Link, William A; Taggart, Mark A; Meharg, Andrew A; Pattee, Oliver H; Pain, Deborah J

    2008-11-01

    The nonsteroidal anti-inflammatory drug diclofenac is extremely toxic to Old World Gyps vultures (median lethal dose -0.1-0.2 mg/kg), evoking visceral gout, renal necrosis, and mortality within a few days of exposure. Unintentional secondary poisoning of vultures that fed upon carcasses of diclofenac-treated livestock decimated populations in the Indian subcontinent. Because of the widespread use of diclofenac and other cyclooxygenase-2 inhibiting drugs, a toxicological study was undertaken in turkey vultures (Cathartes aura) as an initial step in examining sensitivity of New World scavenging birds. Two trials were conducted entailing oral gavage of diclofenac at doses ranging from 0.08 to 25 mg/kg body weight. Birds were observed for 7 d, blood samples were collected for plasma chemistry (predose and 12, 24, and 48 h and 7 d postdose), and select individuals were necropsied. Diclofenac failed to evoke overt signs of toxicity, visceral gout, renal necrosis, or elevate plasma uric acid at concentrations greater than 100 times the estimated median lethal dose reported for Gyps vultures. For turkey vultures receiving 8 or 25 mg/kg, the plasma half-life of diclofenac was estimated to be 6 h, and it was apparently cleared after several days as no residues were detectable in liver or kidney at necropsy. Differential sensitivity among avian species is a hallmark of cyclooxygenase-2 inhibitors, and despite the tolerance of turkey vultures to diclofenac, additional studies in related scavenging species seem warranted.

  17. Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac

    USGS Publications Warehouse

    Rattner, B.A.; Whitehead, M.A.; Gasper, G.; Meteyer, C.U.; Link, W.A.; Taggart, M.A.; Meharg, A.A.; Pattee, O.H.; Pain, D.J.

    2008-01-01

    The nonsteroidal anti-inflammatory drug diclofenac is extremely toxic to Old World Gyps vultures (median lethal dose 0.1?0.2 mg/kg), evoking visceral gout, renal necrosis, and mortality within a few days of exposure. Unintentional secondary poisoning of vultures that fed upon carcasses of diclofenac-treated livestock decimated populations in the Indian subcontinent. Because of the widespread use of diclofenac and other cyclooxygenase-2 inhibiting drugs, a toxicological study was undertaken in turkey vultures (Cathartes aura) as an initial step in examining sensitivity of New World scavenging birds. Two trials were conducted entailing oral gavage of diclofenac at doses ranging from 0.08 to 25 mg/kg body weight. Birds were observed for 7 d, blood samples were collected for plasma chemistry (predose and 12, 24, and 48 h and 7 d postdose), and select individuals were necropsied. Diclofenac failed to evoke overt signs of toxicity, visceral gout, renal necrosis, or elevate plasma uric acid at concentrations greater than 100 times the estimated median lethal dose reported for Gyps vultures. For turkey vultures receiving 8 or 25 mg/kg, the plasma half-life of diclofenac was estimated to be 6 h, and it was apparently cleared after several days as no residues were detectable in liver or kidney at necropsy. Differential sensitivity among avian species is a hallmark of cyclooxygenase-2 inhibitors, and despite the tolerance of turkey vultures to diclofenac, additional studies in related scavenging species seem warranted.

  18. The histopathology of non-steroidal anti-inflammatory drug induced gastroduodenal damage: correlation with Helicobacter pylori, ulcers, and haemorrhagic events

    PubMed Central

    Frezza, M; Gorji, N; Melato, M

    2001-01-01

    Aims—The spectrum of microscopic lesions resulting from the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), known as chemical gastritis, remains unclear, and the variable prevalence reported in different studies makes this issue a matter of lively debate. The aim of this study was to evaluate the prevalence and importance of chemical gastritis in patients regularly taking NSAIDs. Owing to the high prevalence of Helicobacter pylori infection, particularly in subjects over 60 years of age, and in view of a possible association with damage, the presence of H pylori infection in the same tissue sample was also determined in all patients. Methods—One hundred and ninety seven subjects were enrolled, 118 of whom were receiving chronic treatment with NSAIDs and 79 of whom were controls, pair matched for age, sex, and clinical symptoms (ulcer-like dyspepsia or upper digestive tract haemorrhage). Antral biopsies taken during upper gastroduodenal endoscopy were assessed for chemical gastritis according to a modified version of Dixon's score, and for helicobacter correlated chronic active gastritis, according to the updated Sydney system. Results—Chemical gastritis was identified in 11 patients taking NSAIDs (9%) and in four controls (5%) (p < 0.05). Helicobacter pylori was detected in 53 patients taking NSAIDs (45%) and in 34 controls (43%). Patients taking NSAIDs had a significantly higher number of erosions and ulcers and worse endoscores than controls. The presence of H pylori did not appear to increase histological damage, ulcer prevalence, or haemorrhagic events. Conclusions—Chemical gastritis is present in a limited number of patients regularly taking NSAIDs, and is not strongly correlated with NSAID induced damage. In many cases of peptic ulcer or upper gastrointestinal bleeding in patients taking NSAIDs, the presence of chemical gastritis or H pylori infection cannot solely account for the development of mucosal damage. Key Words: chemical

  19. Physicochemical profile and in vitro permeation behavior of a new class of non-steroidal anti-inflammatory drug candidates.

    PubMed

    Rolando, Barbara; Lazzarato, Loretta; Di Stilo, Antonella; Fruttero, Roberta; Carrupt, Pierre-Alain; Martel, Sophie; Gasco, Alberto

    2010-06-14

    Recently a new series of nitrooxy-acyl derivatives of salicylic acid (SA) was described presenting similar anti-inflammatory activities but reduced or no gastrotoxicity compared to aspirin. In this work, lipophilicity and permeability profiles of SA derivatives were performed to evaluate their ADME properties related to oral or transdermic delivery. All tested compounds showed potential good passive permeation through gastrointestinal track and also through percutaneous barrier which could be a way to avoid the first hepatic pass.

  20. Impact and mechanism of non-steroidal anti-inflammatory drugs combined with chemotherapeutic drugs on human lung cancer-nude mouse transplanted tumors

    PubMed Central

    SUN, WEIYI; CHEN, GANG

    2016-01-01

    The present study aimed to investigate the impact of indomethacin treatment combined with oxaliplatin treatment on the expression of cluster of differentiation 44 variant 6 (CD44v6), matrix metalloproteinase-2 (MMP-2) and survivin in human lung cancer-nude mouse transplanted tumors. The human lung adenocarcinoma (A549)-nude mouse transplanted tumor model was established, and the mice were divided into a control group, an indomethacin treatment group, an oxaliplatin treatment group and an indomethacin-oxaliplatin combination treatment group. The tumor inhibition rate was calculated following sacrificing of the mice. Immunohistochemical staining and fluorescence reverse transcription-quantitative polymerase chain reaction were utilized to detect the protein and messenger (m)RNA expression of CD44v6, MMP-2 and survivin. The tumor inhibition rates of the indomethacin group, the oxaliplatin group and the combination group were 26.67, 47.70 and 68.88%, respectively. The protein and mRNA expression levels of CD44v6, MMP-2 and survivin in the transplanted tumors of each treatment group were reduced compared with the control group (P<0.05), and those of the combination group were lower compared with the single-drug treatment groups (P<0.05). Survivin and MMP-2, MMP-2 and CD44v6, and MMP-2 and CD44v6 all exhibited linear positive correlation. The present study provides evidence that the administration of indomethacin alone, or in combination with oxaliplatin, may significantly inhibit the growth of lung cancer-nude mouse transplanted tumors and the expression of CD44v6, MMP-2 and survivin inside the tumor. The combination of non-steroidal anti-inflammatory drugs with chemotherapeutic drugs may improve the antitumor effects. PMID:27313765

  1. Cardiovascular Risk Comparisons of Non-Steroidal Anti-Inflammatory Agents in the TRICARE Population

    DTIC Science & Technology

    2005-09-01

    February of 2005, the Food and Drug Administration (FDA) examined the entire class of COX-2 inhibitors and recommended that Valdecoxib also be......and stroke. This prompted an extensive review of all non-steroidal anti-inflammatory agents by the Food and Drug Administration (FDA), with a

  2. In Vitro Interactions between Non-Steroidal Anti-Inflammatory Drugs and Antifungal Agents against Planktonic and Biofilm Forms of Trichosporon asahii

    PubMed Central

    Cong, Lin; Lu, Xuelian

    2016-01-01

    Increasing drug resistance has brought enormous challenges to the management of Trichosporon spp. infections. The in vitro antifungal activities of non-steroidal anti-inflammatory drugs (NSAIDs) against Candida spp. and Cryptococcus spp. were recently discovered. In the present study, the in vitro interactions between three NSAIDs (aspirin, ibuprofen and diclofenac sodium) and commonly used antifungal agents (fluconazole, itraconazole, voriconazole, caspofungin and amphotericin B) against planktonic and biofilm cells of T. asahii were evaluated using the checkerboard microdilution method. The spectrophotometric method and the XTT reduction assay were used to generate data on biofilm cells. The fractional inhibitory concentration index (FICI) and the ΔE model were compared to interpret drug interactions. Using the FICI, the highest percentages of synergistic effects against planktonic cells (86.67%) and biofilm cells (73.33%) were found for amphotericin B/ibuprofen, and caspofungin/ibuprofen showed appreciable percentages (73.33% for planktonic form and 60.00% for biofilm) as well. We did not observe antagonism. The ΔE model gave consistent results with FICI (86.67%). Our findings suggest that amphotericin B/ibuprofen and caspofungin/ibuprofen combinations have potential effects against T. asahii. Further in vivo and animal studies to investigate associated mechanisms need to be conducted. PMID:27275608

  3. Effect of non-steroidal anti-inflammatory drugs on biological properties of Acanthamoeba castellanii belonging to the T4 genotype.

    PubMed

    Siddiqui, Ruqaiyyah; Lakhundi, Sahreena; Iqbal, Junaid; Khan, Naveed Ahmed

    2016-09-01

    Non-steroidal anti-inflammatory drug, Diclofenac, targeting COX have shown promise in the treatment of Acanthamoeba keratitis, but the underlying mechanisms remain unknown. Using various NSAIDs, Diclofenac sodium, Indomethacin, and Acetaminophen, here we determined the effects of NSAIDs on the biological properties of Acanthamoeba castellanii belonging to the T4 genotype. Using amoebicidal assays, the results revealed that Diclofenac sodium, and Indomethacin affected growth of A. castellanii. In contrast, none of the compounds tested had any effect on the viability of A. castellanii. Importantly, all NSAIDs tested abolished A. castellanii encystation. This is a significant finding as the ability of amoebae to transform into the dormant cyst form presents a significant challenge in the successful treatment of infection. The NSAIDs inhibit production of cyclo-oxegenase, which regulates the synthesis of prostaglandins suggesting that cyclooxygenases (COX-1 and COX-2) and prostaglandins play significant role(s) in Acanthamoeba biology. As NSAIDs are routinely used in the clinical practice, these findings may help design improved preventative strategies and/or of therapeutic value to improve prognosis, when used in combination with other anti-amoebic drugs.

  4. Non-steroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease.

    PubMed Central

    Evans, J M; McMahon, A D; Murray, F E; McDevitt, D G; MacDonald, T M

    1997-01-01

    BACKGROUND: To evaluate the relation between non-steroidal anti-inflammatory drugs (NSAIDs) and colitis due to inflammatory bowel disease. METHODS: A case-control study was conducted using a prospectively constructed, record linkage database containing hospital event and dispensed drug data (1989-93). The study population consisted of 319,465 people resident in Tayside in January 1989, and still resident (or dead) in October 1994. RESULTS: Of the 785 patients admitted to hospital as emergencies with colitis between July 1989 and June 1993, 200 fulfilled the case criterion of colitis due to inflammatory bowel disease. A further 1198 persons were used as community controls. Odds ratios were calculated for three exposure periods (current, recent, and past exposure). The overall odds ratios (with 95% confidence intervals) for current and recent exposure to NSAIDs were 1.77 (1.01 to 3.10) and 1.93 (1.20 to 3.09) respectively. Current and recent exposure to NSAIDs was also associated for incident cases, with odds ratios of 2.96 (1.32 to 6.64) and 2.51 (1.13 to 5.55). There was a trend for recent exposure among non-incident cases. CONCLUSION: The use of NSAIDs may be associated with an increased risk of emergency admission to hospital for colitis due to inflammatory bowel disease, particularly among patients with no previous history. PMID:9203940

  5. Determination of fourteen non-steroidal anti-inflammatory drugs in animal serum and plasma by liquid chromatography/mass spectrometry.

    PubMed

    Vinci, Floriana; Fabbrocino, Serena; Fiori, Maurizio; Serpe, Luigi; Gallo, Pasquale

    2006-01-01

    The European Union has regulated the use of non-steroidal anti-inflammatory drugs (NSAIDs) in animal production and requires its member states to detect their residues in different matrices. In this work, a detailed MS and MS/MS study by ion-trap mass spectrometry of fourteen NSAIDs is described. Two multi-residue reversed-phase LC/ESI-MS/MS methods were developed, one for the determination of salicylic acid, naproxen, carprofen, flurbiprofen, ibuprofen, niflumic acid and meclofenamic acid in the negative ion mode, and the other for the determination of ketoprofen, suxibutazone, diclofenac, mefenamic acid, tolfenamic acid, phenylbutazone and its metabolite oxyphenbutazone in the positive ion mode. It was thus possible to confirm up to 14 different NSAID residues in serum and plasma samples of farmed animals, after chromatographic separation by a linear gradient. These substances were chosen as representative of different chemical subclasses of NSAIDs. The two methods were also validated in-house at three contamination levels, evaluating specificity and calculating mean recoveries, repeatability and within-laboratory reproducibility. The MS/MS product ion spectra were successfully used for the qualitative identification of all the drugs tested. All the NSAIDs, apart from salicylic acid, were recovered in high amounts, ranging between 71.6% and 100.9%.

  6. Knowledge and Use of, and Attitudes toward, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Practice: A Survey of Ontario Physiotherapists.

    PubMed

    Green, Maggie; Norman, Kathleen E

    2016-01-01

    Purpose: To investigate Ontario physiotherapists' knowledge and use of, and attitudes toward, non-steroidal anti-inflammatory drugs (NSAIDs) to identify whether there is a need for physiotherapists to receive education specific to NSAIDs. Method: An existing survey instrument was modified and tested by five Ontario physiotherapists. The final version was distributed electronically to approximately 4,400 Ontario Physiotherapy Association members as a self-administered online questionnaire. Results: A total of 294 physiotherapists responded to the survey (response rate=6.7%). Respondents demonstrated variability in their knowledge of NSAID contraindications, side effects, and drug interactions. Most respondents (62.6%) were incorrect or unsure about where and how to obtain most NSAIDs, and most demonstrated incorrect or uncertain knowledge of the relevant legislation. Despite this lack of knowledge, 50% of respondents recommend NSAIDs to their patients. Conclusions: Many Ontario physiotherapists who participated in this survey recommend NSAIDs to their patients despite having a variable understanding of the legislation and medication-related factors. A lack of thorough knowledge of risks and contraindications has implications for patient safety. Physiotherapists who incorporate medications into their practice should access comprehensive information on appropriate NSAID use and should inform themselves about legislative restrictions to ensure that associated treatment is provided in a manner that is evidence based, safe, and in keeping with regulatory boundaries.

  7. Prenatal exposure to a non-steroidal anti-inflammatory drug or saline solution impairs sciatic nerve morphology: a stereological and histological study.

    PubMed

    Canan, Sinan; Aktaş, Abit; Ulkay, M Basak; Colakoglu, Serdar; Ragbetli, Murat Cetin; Ayyildiz, Mustafa; Geuna, Stefano; Kaplan, Suleyman

    2008-11-01

    The toxic effect of non-steroidal anti-inflammatory drugs (NSAIDs) during development has been widely investigated. While it has been shown that these drugs impair central nervous development and compromise the neural activity, the effects of these substances on the development of peripheral nerves are still not clarified. In the present study, sciatic nerves withdrawn from three experimental groups of 4-week-old rats, prenatally exposed to either saline solution, or diclofenac sodium, and controls not exposed to any substance, were evaluated in terms of axon number, cross-sectional area of axon and myelin sheet thickness as well as of the ultrastructure of nerve fibers. Comparisons of stereological estimations among these three groups showed that axon number and mean axon cross-sectional area, but not average myelin sheet thickness, were significantly decreased in rats that were exposed to both diclofenac sodium and also to the saline solution, in comparison of the control group. Electron microscope analysis revealed, in both treated groups, deterioration of myelin sheaths that was more pronounced in rats that were exposed to diclofenac sodium. Altogether, these findings show that the prenatal administration of both diclofenac sodium and saline solution impairs peripheral nervous system development, thus suggesting that this potential teratogenic effect should be also taken into consideration in the clinical use of these substances in pregnant patients.

  8. Use of aspirin, non-steroidal anti-inflammatory drugs, and acetaminophen (paracetamol), and risk of psoriasis and psoriatic arthritis: a cohort study.

    PubMed

    Wu, Shaowei; Han, Jiali; Qureshi, Abrar A

    2015-02-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to induce or exacerbate psoriasis. We aimed to evaluate the association between several widely used analgesics, including aspirin, non-aspirin NSAIDs, and acetaminophen (paracetamol), and risk of psoriasis and psoriatic arthritis (PsA) in a large cohort of US women, the Nurses' Health Study II (1991-2005). Information on regular use of aspirin, NSAIDs, and acetaminophen was collected for 95,540 participants during the follow-up. During 1,321,280 person-years of follow-up, we documented 646 incident psoriasis cases and 165 concomitant PsA cases. Compared to women who reported no use, regular acetaminophen and NSAIDs users with more than 10 years of use had multivariate hazard ratios of 3.60 [95% confidence interval (CI): 2.02-6.41] and 2.10 (95% CI: 1.11-3.96) for PsA, respectively. There was no clear association between aspirin and risk of psoriasis or PsA. In conclusion, long-term acetaminophen and NSAIDs use may be associated with an increased risk of PsA. Special attention on psoriasis and PsA screening may be needed for those who are prescribed for acetaminophen and NSAIDs for long-term periods.

  9. Lame broiler chickens respond to non-steroidal anti-inflammatory drugs with objective changes in gait function: a controlled clinical trial.

    PubMed

    Caplen, G; Colborne, G R; Hothersall, B; Nicol, C J; Waterman-Pearson, A E; Weeks, C A; Murrell, J C

    2013-06-01

    Leg health of intensively reared broiler chickens is a significant problem, yet little is known regarding the nature of lameness-associated pain. Kinematic changes in gait have been reported in naturally lame broilers following subcutaneous non-steroidal anti-inflammatory drug (NSAID) administration, compared to a placebo group. In the current study, an extensive range of gait parameters were defined using a commercial motion-capturing system to record three-dimensional temporospatial information from walking broilers pre- and post-treatment. Data analysis, performed using multi-level models, revealed gait modifications in broilers receiving NSAID, but not in those receiving saline. The effect of walking velocity was accounted for retrospectively. An increase in velocity following NSAID treatment (carprofen: P<0.001; meloxicam: P=0.044) indicated improved walking ability. For several measures, the polarity of the treatment effect depended upon walking speed. At slow speeds certain parameters become more like those of non-lame broilers, which may have been indicative of improved stability: stride length and duration (both NSAIDs), transverse back displacement (meloxicam), and vertical leg displacement (carprofen). However, these same parameters also revealed that NSAID treatment caused imbalance at faster speeds, which may have signified an excessive dosage. Although doses employed were not conclusively effective, evidence was provided that factors besides body conformation influenced mobility in the test cohort. The study showed that the model would be useful in future studies to increase our understanding of pain associated with specific lameness types in broiler chickens.

  10. Metal-organic frameworks@graphene hybrid aerogels for solid-phase extraction of non-steroidal anti-inflammatory drugs and selective enrichment of proteins.

    PubMed

    Zhang, Xiaoqiong; Liang, Qionglin; Han, Qiang; Wan, Wei; Ding, Mingyu

    2016-06-20

    Graphene aerogel (GA)-supported metal-organic framework (MOF) particles with a three-dimensional (3D) architecture were fabricated for the first time via a facile template-free "sol-cryo" method. The prepared MOFs@graphene hybrid aerogels exhibit a 3D interconnected macroporous framework of graphene sheets with uniform dispersion of MOF particles. We also report the first attempt at using the hybrid aerogels as adsorbents for the solid-phase extraction (SPE) of non-steroidal anti-inflammatory drugs (NSAIDs) and the selective enrichment of proteins. The macroporous skeletons of GA provide both low backpressure and rapid mass transfer in SPE application, thus overcoming the obstacle of high backpressure caused by directly packing submicron or micron sized MOF particles into SPE cartridges. Excellent performances including satisfactory recoveries, high sensitivity and good reproducibility were achieved in the extraction of five NSAIDs. The hybrid aerogels also showed an interesting ability for selective enrichment of ribonuclease A (RNase A) and simultaneous exclusion of cytochrome C (Cyt C) and lysozyme (Lyz), which could be attributed to the electrostatic interactions between proteins and the positively charged coordinatively unsaturated metal sites (CUS) in MIL-101. We believe that this work will promote the application of MOFs in adsorption and separation, and our synthetic strategy could be further extended to develop other graphene-based hybrid aerogels.

  11. Prevalence of Helicobacter Pylori-Negative, Non-Steroidal Anti-Inflammatory Drug Related Peptic Ulcer Disease in Patients Referred to Afzalipour Hospital.

    PubMed

    Seyed Mirzaei, Seyed Mahdi; Zahedi, Mohammad Javad; Shafiei Pour, Sara

    2015-10-01

    BACKGROUND Although Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs) are the main causes of peptic ulcers disease (PUD), recently the prevalence of idiopathic peptic ulcer (IPU) is increasing in most parts of the world. The aim of this study was to assess the prevalence of IPU in Kerman, the center of largest province in south-east Iran. METHODS We included 215 patients with peptic ulcer in our study. Combined methods rapid urease test (RUT), histology, and real time polymerase chain reaction (PCR) was performed on endoscopic samples of peptic ulcers. NSAID use was determined by medical history. SPSS software version 16 was used for data analysis. p value<0.05 was considered as statistically significant. RESULTS Of 215 consecutive patients with peptic ulcer, four (1.8%) had H.pylorinegative and NSAID-negative PUD. There were not significant differences between patients with IPU and patients with peptic ulcer associated with H.pylori or NSAIDs regarding the sex, age, cigarette smoking, and opioid abuse. CONCLUSION Our study showed that in contrast to other reports from western and some Asian countries, the prevalence of IPU is low in Kerman and H.pylori infection is still the major cause of PUD. We recommend a large and multi-central study to determine the prevalence of IPU in Iran.

  12. Structural Mechanism of the Interaction of Alzheimer Disease Aβ Fibrils with the Non-steroidal Anti-inflammatory Drug (NSAID) Sulindac Sulfide.

    PubMed

    Prade, Elke; Bittner, Heiko J; Sarkar, Riddhiman; Lopez Del Amo, Juan Miguel; Althoff-Ospelt, Gerhard; Multhaup, Gerd; Hildebrand, Peter W; Reif, Bernd

    2015-11-27

    Alzheimer disease is the most severe neurodegenerative disease worldwide. In the past years, a plethora of small molecules interfering with amyloid-β (Aβ) aggregation has been reported. However, their mode of interaction with amyloid fibers is not understood. Non-steroidal anti-inflammatory drugs (NSAIDs) are known γ-secretase modulators; they influence Aβ populations. It has been suggested that NSAIDs are pleiotrophic and can interact with more than one pathomechanism. Here we present a magic angle spinning solid-state NMR study demonstrating that the NSAID sulindac sulfide interacts specifically with Alzheimer disease Aβ fibrils. We find that sulindac sulfide does not induce drastic architectural changes in the fibrillar structure but intercalates between the two β-strands of the amyloid fibril and binds to hydrophobic cavities, which are found consistently in all analyzed structures. The characteristic Asp(23)-Lys(28) salt bridge is not affected upon interacting with sulindac sulfide. The primary binding site is located in the vicinity of residue Gly(33), a residue involved in Met(35) oxidation. The results presented here will assist the search for pharmacologically active molecules that can potentially be employed as lead structures to guide the design of small molecules for the treatment of Alzheimer disease.

  13. Practical experience with the treatment of recipient mares with a non-steroidal anti-inflammatory drug in an equine embryo transfer programme.

    PubMed

    Koblischke, P; Budik, S; Müller, J; Aurich, C

    2010-12-01

    As part of a commercial embryo transfer programme, 20 embryos were transferred to spontaneously synchronous or synchronized recipient mares. In 14 cases, embryo recipients were treated with non-steroidal anti-inflammatory drugs (NSAID), receiving flunixin meglumine i.v. at the time of transfer and vedaprofen orally twice a day on the 3 days after embryo transfer, while six embryos were transferred to untreated mares that served as controls. Out of the 14 recipient mares treated with NSAID, 11 (79%) were pregnant at 6-8 days after transfer and in 10 mares, the pregnancy was continued. From the six untreated recipients, only one became pregnant but underwent early embryonic death between day 14 and 35 after ovulation. In conclusion, pregnancy rate in NSAID-treated recipients is higher than that in untreated recipients and above reported average values, indicating that treatment of recipient mares with NSAID helps to increase pregnancy rates after transcervical transfer and can be recommended for equine embryo transfer.

  14. Development of high-throughput multi-residue method for non-steroidal anti-inflammatory drugs monitoring in swine muscle by LC-MS/MS.

    PubMed

    Castilhos, Tamara S; Barreto, Fabiano; Meneghini, Leonardo; Bergold, Ana Maria

    2016-07-01

    A reliable and simple method for the detection and quantification of residues of 14 non-steroidal anti-inflammatory drugs and a metamizole metabolite in swine muscle was developed using liquid chromatography-electrospray ionisation-tandem mass spectrometry (LC-ESI-MS/MS). The samples were extracted with acetonitrile (ACN) in solid-liquid extraction followed by a low-temperature partitioning (LLE-LTP) process at -20 ± 2°C. After evaporation to dryness, the residue was reconstituted with hexane and a mixture of water:acetonitrile (1:1). LC separation was achieved on a reversed-phase (RP18) column with gradient elution using water (phase A) and ACN (phase B) both containing 1 mmol l(-)(1) ammonium acetate (NH4COO) with 0.025% acetic acid. Analysis was carried out on a triple-quadrupole tandem mass spectrometer (LC-MS/MS) in multiple reaction monitoring mode using an electrospray interface in negative and positive mode in a single run. Method validation was performed according to the criteria of Commission Decision No. 2002/657/EC. The matrix effect and linearity were evaluated. Decision limit (CCα), detection capability (CCβ), accuracy and repeatability of the method are also reported. The proposed method proved to be simple, easy and adequate for high-throughput analysis and was applied to routine analysis by the Brazilian Ministry of Agriculture, Livestock and Food Supply.

  15. Molecular modelling of the differential interaction between several non-steroidal anti-inflammatory drugs and human prostaglandin endoperoxide H synthase-2 (h-PGHS-2).

    PubMed

    Pouplana, R; Lozano, J J; Ruiz, J

    2002-01-01

    The prostaglandin endoperoxide H synthase-1 (PGHS-1) and prostaglandin endoperoxide H synthase-2 (PGHS-2) are the targets of non-steroidal anti-inflammatory drugs (NSAIDs). The high degree of selectivity for inhibition of PGHS-2 shown by certain compounds appears to stem from two mechanisms (time-dependent, time-independent inhibition) by which they interact with each isoform. Molecular models of the complexes between indomethacin, fenamates, 2-phenylpropionic acids and the selective cyclooxygenase-2 (COX-2) inhibitors, with the cyclooxygenase active site of human PGHS-2 have been built by combining homology modelling, conformational searching and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations combined with extended linear response calculations. The results allow us to identify regions of biological significance consistent with both X-ray crystallographic and kinetic results. The selective PGHS-2 inhibitors exploit the extra space of a side-pocket in the active site of PGHS-2 that is not found in PGHS-1. The results obtained point out a marked relationship between the experimental affinity and the electrostatic interaction energy alone for a series of NSAIDs. Analysis of the structural and the energetic data provides evidence supporting that network of hydrogen bonds between Tyr355, Glu524, Arg120 and Arg513 might be involved in mediating the binding of the time-dependent inhibitors of PGHS-2.

  16. Ecotoxicological potential of non-steroidal anti-inflammatory drugs (NSAIDs) in marine organisms: Bioavailability, biomarkers and natural occurrence in Mytilus galloprovincialis.

    PubMed

    Mezzelani, M; Gorbi, S; Da Ros, Z; Fattorini, D; d'Errico, G; Milan, M; Bargelloni, L; Regoli, F

    2016-10-01

    Pharmaceuticals represent a major environmental concern since the knowledge on their occurrence, distribution and ecotoxicological potential is still limited particularly in coastal areas. In this study, bioaccumulation and cellular effects of various non steroidal anti-inflammatory drugs (NSAIDs) were investigated in mussels Mytilus galloprovincialis to reveal whether common molecules belonging to the same therapeutic class might cause different effects on non target organisms. Organisms exposed to environmental concentrations of acetaminophen (AMP), diclofenac (DIC), ibuprofen (IBU), ketoprofen (KET) and nimesulide (NIM) revealed a significant accumulation of DIC, IBU and NIM, while AMP and KET were always below detection limit. Nonetheless, for all tested NSAIDs, measurement of a large panel of ecotoxicological biomarkers highlighted impairment of immunological parameters, onset of genotoxicity and modulation of lipid metabolism, oxidative and neurotoxic effects. Laboratory results were integrated with a field study which provided the first evidence on the occurrence of DIC, IBU and NIM in tissues of wild mussels sampled during summer months from an unpolluted, touristic area of Central Adriatic Sea. Overall results demonstrated M. galloprovincialis as a good sentinel species for monitoring presence and ecotoxicological hazard of pharmaceuticals in the Mediterranean.

  17. Synthesis, crystal structure and spectroscopy of bioactive Cd(II) polymeric complex of the non-steroidal anti-inflammatory drug diclofenac sodium: Antiproliferative and biological activity

    NASA Astrophysics Data System (ADS)

    Tabrizi, Leila; Chiniforoshan, Hossein; McArdle, Patrick

    2015-02-01

    The interaction of Cd(II) with the non-steroidal anti-inflammatory drug diclofenac sodium (Dic) leads to the formation of the complex [Cd2(L)41.5(MeOH)2(H2O)]n(L = Dic), 1, which has been isolated and structurally characterized by X-ray crystallography. Diclofenac sodium and its metal complex 1 have also been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines, MCF-7 (breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma), and a mouse fibroblast L-929 cell line. The results of cytotoxic activity in vitro expressed as IC50 values indicated the diclofenac sodium and cadmium chloride are non active or less active than the metal complex of diclofenac (1). Complex 1 was also found to be a more potent cytotoxic agent against T-24 and MCF-7 cancer cell lines than the prevalent benchmark metallodrug, cisplatin, under the same experimental conditions. The superoxide dismutase activity was measured by Fridovich test which showed that complex 1 shows a low value in comparison with Cu complexes. The binding properties of this complex to biomolecules, bovine or human serum albumin, are presented and evaluated. Antibacterial and growth inhibitory activity is also higher than that of the parent ligand compound.

  18. Genetic variants in COX-2, non-steroidal anti-inflammatory drugs, and breast cancer risk: the Western New York Exposures and Breast Cancer (WEB) Study.

    PubMed

    Brasky, Theodore M; Bonner, Matthew R; Moysich, Kirsten B; Ochs-Balcom, Heather M; Marian, Catalin; Ambrosone, Christine B; Nie, Jing; Tao, Meng Hua; Edge, Stephen B; Trevisan, Maurizio; Shields, Peter G; Freudenheim, Jo L

    2011-02-01

    Chronic inflammation has been consistently associated with cancers of several sites, including the breast, and inhibition of inflammation through the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been inversely associated with risk. As NSAIDs bind with cyclooxygenase-2 (COX-2), genetic variation in COX-2 may influence breast cancer risk by affecting inflammatory response and response to NSAID use. We identified eight single nucleotide polymorphisms (SNPs) for COX-2 and examined their association with risk of breast cancer in a population-based case-control study in Western New York. Cases had incident, first primary, histologically confirmed breast cancer (n = 1077). Controls (n = 1910) were randomly selected from NY Department of Motor Vehicles records (< 65) or Medicare rolls (≥ 65). Participants were queried on adult lifetime use of aspirin and recent use of ibuprofen. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). One SNP, rs2745559, was associated with an increased risk of breast cancer (OR 1.23, 95% CI 1.03-1.46). Associations with other variants were not evident. Significant interaction (P interaction = 0.04) between recent aspirin use and rs4648261 was also observed. Variation in COX-2 was modestly associated with breast cancer risk, indicating that COX-2 may play a role in breast carcinogenesis. Better understanding of the role of COX-2 genetic variation and interaction with NSAID use in breast carcinogenesis has potential to inform prevention strategies.

  19. Role of carbonyl reducing enzymes in the phase I biotransformation of the non-steroidal anti-inflammatory drug nabumetone in vitro.

    PubMed

    Skarydova, Lucie; Nobilis, Milan; Wsól, Vladimir

    2013-04-01

    1. Nabumetone is a clinically used non-steroidal anti-inflammatory drug, its biotransformation includes major active metabolite 6-methoxy-2-naphtylacetic acid and another three phase I as well as corresponding phase II metabolites which are regarded as inactive. One important biotransformation pathway is carbonyl reduction, which leads to the phase I metabolite, reduced nabumetone. 2. The aim of this study is the determination of the role of a particular human liver subcellular fraction in the nabumetone reduction and the identification of participating carbonyl reducing enzymes along with their stereospecificities. 3. Both subcellular fractions take part in the carbonyl reduction of nabumetone and the reduction is at least in vitro the main biotransformation pathway. The activities of eight cytosolic carbonyl reducing enzymes--CBR1, CBR3, AKR1B1, AKR1B10, AKR1C1-4--toward nabumetone were tested. Except for CBR3, all tested reductases transform nabumetone to its reduced metabolite. AKR1C4 and AKR1C3 have the highest intrinsic clearances. 4. The stereospecificity of the majority of the tested enzymes is shifted to the production of an (+)-enantiomer of reduced nabumetone; only AKR1C1 and AKR1C4 produce predominantly an (-)-enantiomer. This project provides for the first time evidence that seven specific carbonyl reducing enzymes participate in nabumetone metabolism.

  20. Optimisation by response surface methodology of microextraction by packed sorbent of non steroidal anti-inflammatory drugs and ultra-high performance liquid chromatography analysis of dialyzed samples.

    PubMed

    D'Archivio, Angelo Antonio; Maggi, Maria Anna; Ruggieri, Fabrizio; Carlucci, Maura; Ferrone, Vincenzo; Carlucci, Giuseppe

    2016-06-05

    A procedure based on microextraction by packed sorbent (MEPS) followed by ultra-high performance liquid chromatography (UHPLC) with photodiode array (PDA) detection has been developed for the analysis of seven selected non steroidal anti-inflammatory drugs (NSAIDs) in human dialysates. The influence on MEPS efficiency of pH of the sample, pH of the washing solvent and methanol content in the hydro-alcoholic elution mixture has been investigated by response surface methodology based on a Box-Behnken design of experiments. Among the above factors, pH of sample is the variable that mostly influences MEPS recovery. UHPLC separation of the NSAIDs was completed within less than 4min under isocratic elution conditions on a Fortis SpeedCore C18 column (150×4.6mm I.D., 2.6μm) using acetonitrile-phosphate buffer as the mobile phase. Calibration curves of the NSAIDs were linear over the concentration range 0.025-15μg/mL, with correlation coefficients≥0.998. Intra- and inter-assay relative standard deviations were <8% and recovery values ranged from 94% to 100% for the quality control samples. The results reveal that the developed MEPS/PDA-UHPLC method exhibits a good accuracy and precision and is well suited for the rapid analysis of human dialysate from patients treated with the selected NSAIDs.

  1. Severe water intoxication secondary to the concomitant intake of non-steroidal anti-inflammatory drugs and desmopressin: a case report and review of the literature.

    PubMed

    Verrua, Elisa; Mantovani, Giovanna; Ferrante, Emanuele; Noto, Andrea; Sala, Elisa; Malchiodi, Elena; Iapichino, Gaetano; Peccoz, Paolo Beck; Spada, Anna

    2013-01-01

    Most of the clinical data on the safety profile of desmopressin (DDAVP), which is an effective treatment for both polyuric conditions and bleeding disorders, originate from studies on the tailoring of drug treatment, whereas few reports exist describing severe side effects secondary to drug-drug interaction. We herein describe a case of severe hyponatremia complicated by seizure and coma due to the intake of non-steroidal anti-inflammatory drugs (NSAIDs) in a patient on DDAVP replacement therapy for central diabetes insipidus (DI). A 50-yr-old Caucasian man, with congenital central DI, developed an episode of generalized tonic-clonic seizure, resulting in coma immediately after being admitted to the Emergency Unit for weakness and emesis. Based on his medical history and clinical findings, water intoxication secondary to ketoprofen intake (200 mg/day for the last 3 days) concomitant with DDAVP replacement therapy (Minirin(®) 60 mcg 4 tablets a day) was hypothesized as being the cause of the severe euvolemic hypotonic hyponatremia (natremia 113 mEq/l, plasma osmolality 238 mOsm/Kg). After standard emergency procedures, appropriate gradual restoration of serum sodium levels to the normal range was achieved in 72 hours. Hydratation was maintained according to water excretion and desmopressin therapy was re-introduced. We discuss this case report in the context of the published literature. The present report first highlights the potentially life-threatening side effects associated with over-the-counter NSAIDs during DDAVP replacement therapy for central DI. Risks and benefits of co-treatment should be carefully considered and therapeutic alternatives to NSAIDs should be recommended to patients with central DI in order to improve DDAVP safety.

  2. Asthma and Rhinitis Induced by Selective Immediate Reactions to Paracetamol and Non-steroidal Anti-inflammatory Drugs in Aspirin Tolerant Subjects.

    PubMed

    Pérez-Alzate, Diana; Blanca-López, Natalia; Doña, Inmaculada; Agúndez, José A; García-Martín, Elena; Cornejo-García, José A; Perkins, James R; Blanca, Miguel; Canto, Gabriela

    2016-01-01

    In subjects with non-steroidal anti-inflammatory drugs (NSAIDs)- exacerbated respiratory disease (NERD) symptoms are triggered by acetyl salicylic acid (ASA) and other strong COX-1 inhibitors, and in some cases by weak COX-1 or by selective COX-2 inhibitors. The mechanism involved is related to prostaglandin pathway inhibition and leukotriene release. Subjects who react to a single NSAID and tolerate others are considered selective responders, and often present urticaria and/or angioedema and anaphylaxis (SNIUAA). An immunological mechanism is implicated in these reactions. However, anecdotal evidence suggests that selective responders who present respiratory airway symptoms may also exist. Our objective was to determine if subjects might develop selective responses to NSAIDs/paracetamol that manifest as upper/lower airways respiratory symptoms. For this purpose, we studied patients reporting asthma and/or rhinitis induced by paracetamol or a single NSAID that tolerated ASA. An allergological evaluation plus controlled challenge with ASA was carried out. If ASA tolerance was found, we proceeded with an oral challenge with the culprit drug. The appearance of symptoms was monitored by a clinical questionnaire and by measuring FEV1 and/or nasal airways volume changes pre and post challenge. From a total of 21 initial cases, we confirmed the appearance of nasal and/or bronchial manifestations in ten, characterized by a significant decrease in FEV1% and/or a decrease in nasal volume cavity after drug administration. All cases tolerated ASA. This shows that ASA tolerant subjects with asthma and/or rhinitis induced by paracetamol or a single NSAID without skin/systemic manifestations exist. Whether these patients represent a new clinical phenotype to be included within the current classification of hypersensitivity reactions to NSAIDs requires further investigation.

  3. Asthma and Rhinitis Induced by Selective Immediate Reactions to Paracetamol and Non-steroidal Anti-inflammatory Drugs in Aspirin Tolerant Subjects

    PubMed Central

    Pérez-Alzate, Diana; Blanca-López, Natalia; Doña, Inmaculada; Agúndez, José A.; García-Martín, Elena; Cornejo-García, José A.; Perkins, James R.; Blanca, Miguel; Canto, Gabriela

    2016-01-01

    In subjects with non-steroidal anti-inflammatory drugs (NSAIDs)- exacerbated respiratory disease (NERD) symptoms are triggered by acetyl salicylic acid (ASA) and other strong COX-1 inhibitors, and in some cases by weak COX-1 or by selective COX-2 inhibitors. The mechanism involved is related to prostaglandin pathway inhibition and leukotriene release. Subjects who react to a single NSAID and tolerate others are considered selective responders, and often present urticaria and/or angioedema and anaphylaxis (SNIUAA). An immunological mechanism is implicated in these reactions. However, anecdotal evidence suggests that selective responders who present respiratory airway symptoms may also exist. Our objective was to determine if subjects might develop selective responses to NSAIDs/paracetamol that manifest as upper/lower airways respiratory symptoms. For this purpose, we studied patients reporting asthma and/or rhinitis induced by paracetamol or a single NSAID that tolerated ASA. An allergological evaluation plus controlled challenge with ASA was carried out. If ASA tolerance was found, we proceeded with an oral challenge with the culprit drug. The appearance of symptoms was monitored by a clinical questionnaire and by measuring FEV1 and/or nasal airways volume changes pre and post challenge. From a total of 21 initial cases, we confirmed the appearance of nasal and/or bronchial manifestations in ten, characterized by a significant decrease in FEV1% and/or a decrease in nasal volume cavity after drug administration. All cases tolerated ASA. This shows that ASA tolerant subjects with asthma and/or rhinitis induced by paracetamol or a single NSAID without skin/systemic manifestations exist. Whether these patients represent a new clinical phenotype to be included within the current classification of hypersensitivity reactions to NSAIDs requires further investigation. PMID:27489545

  4. Chemiluminescence of the reaction system Ce(IV)-non-steroidal anti-inflammatory drugs containing europium(III) ions and its application to the determination of naproxen in pharmaceutical preparations and urine.

    PubMed

    Kaczmarek, Małgorzata

    2011-11-01

    The chemiluminescence (CL) of oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) by Ce(IV) ions, was recorded in the presence and absence europium(III) ions, in solution of pH ~ 4 of solution. Kinetic curves and CL emission spectra of the all studied systems were discussed. CL of measurable intensity was observed in the Ce(IV)-NP-Eu(III) reaction system only in acidic solutions. The CL spectrum rcegistered for this system shows emission bands, typical of Eu(III) ions, with maximum at λ ~ 600 nm. The chemiluminescent method, based on Eu(III) emission in reaction system of NP-Ce(IV)-Eu(III) in acid solution was therefore used for the determination of naproxen in mixture of non-steroidal anti-inflammatory drugs.

  5. Non-steroidal anti-inflammatory drugs, Cyclooxygenase-2 inhibitors and paracetamol use in Queensland and in the whole of Australia

    PubMed Central

    Barozzi, Nadia; Tett, Susan E

    2008-01-01

    Background Cross national drug utilization studies can provide information about different influences on physician prescribing. This is important for medicines with issues around safety and quality of use, like non selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors. To enable comparison of prescription medicine use across different jurisdictions with a range of population sizes, data first need to be compared within Australia to understand whether use in a smaller sub-population may be considered as representative of the total use within Australia. The aim of this study was to compare the utilization of non selective NSAID, COX-2 inhibitors and paracetamol between Queensland and Australia. Method Dispensing data were obtained for concession beneficiaries for Australia for ns-NSAIDs, COX-2 inhibitors and paracetamol subsidized by the PBS over the period 1997–2003. The same data were purchased for Queensland. Data were converted to Defined Daily Dose (DDD)/1000 beneficiaries/day (World Health Organization anatomical therapeutic chemical classification, 2005). Results Total NSAID and paracetamol consumption were similar in Australia and Queensland. Ns-NSAID use decreased sharply with the introduction of COX-2 inhibitors (from approximately 80 to 40 DDD/1000 beneficiaries/day). Paracetamol was constant (approximately 45 DDD/1000 beneficiaries/day). COX-2 inhibitors consumption was initially higher in Queensland than in the whole of Australia. Conclusion Despite initial divergence in celecoxib use between Queensland and Australia, the use of ns-NSAIDs, COX-2 inhibitors and paracetamol overall, in concession beneficiaries, was comparable in Australia and Queensland. PMID:18816393

  6. Variants of CEP68 gene are associated with acute urticaria/angioedema induced by multiple non-steroidal anti-inflammatory drugs.

    PubMed

    Cornejo-García, José Antonio; Flores, Carlos; Plaza-Serón, María C; Acosta-Herrera, Marialbert; Blanca-López, Natalia; Doña, Inmaculada; Torres, María J; Mayorga, Cristobalina; Guéant-Rodríguez, Rosa M; Ayuso, Pedro; Fernández, Javier; Laguna, José J; Agúndez, José A G; García-Martín, Elena; Guéant, Jean-Louis; Canto, Gabriela; Blanca, Miguel

    2014-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most consumed drugs worldwide because of their efficacy and utility in the treatment of pain and inflammatory diseases. However, they are also responsible for an important number of adverse effects including hypersensitivity reactions. The most important group of these reactions is triggered by non-immunological, pharmacological mechanisms catalogued under the denomination of cross-intolerance (CRI), with acute urticaria/angioedema induced by multiple NSAIDs (MNSAID-UA) the most frequently associated clinical entity. A recent genome-wide association study identified the gene encoding the centrosomal protein of 68 KDa (CEP68) as the major locus associated with aspirin intolerance susceptibility in asthmatics. In this study, we aimed to assess the role of this locus in susceptibility to CRI to NSAIDs by examining 53 common gene variants in a total of 635 patients that were classified as MNSAID-UA (n = 399), airway exacerbations (n = 110) or blended pattern (n = 126), and 425 controls. We found in the MNSAID-UA group a number of variants (17) associated (lowest p-value = 1.13 × 10(-6)), including the non-synonymous Gly74Ser variant (rs7572857) previously associated with aspirin intolerance susceptibility in asthmatics. Although not being significant in the context of multiple testing, eight of these variants were also associated with exacerbated respiratory disease or blended reactions. Our results suggest that CEP68 gene variants may play an important role in MNSAID-UA susceptibility and, despite the different regulatory mechanisms involved depending on the specific affected organ, in the development of hypersensitivity reactions to NSAIDs.

  7. Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study

    PubMed Central

    Ishida, Yuri; Takechi, Kenshi; Katayama, Hitoshi; Ito, Ryoji; Yakushijin, Yoshihiro; Moriguchi, Toshihide; Tanaka, Mamoru; Tanaka, Akihiro; Araki, Hiroaki

    2017-01-01

    Purpose As the major toxicity induced by pemetrexed plus carboplatin is severe hematologic toxicities, the aim of this study was to determine the risk factors for severe hematologic toxicities in lung cancer patients. Methods We retrospectively investigated data from lung cancer patients who had received pemetrexed plus carboplatin, with or without bevacizumab. This observational study was carried out at Ehime University Hospital using electronic medical records dating from July 2009 to March 2015. Severe hematologic toxicities were defined as grade 3 or 4, according to the Common Terminology Criteria for Adverse Events, version 4.0. Results Forty-two patients were included in the study. The incidence of grade 3 or 4 hematologic toxicities during the first cycle of chemotherapy and during all cycles was 19.0% and 16.1%, respectively. Multivariate time-depend generalized estimating equations logistic regression analysis revealed that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted odds ratio (OR): 8.32, 95% confidence interval (CI): 1.27–54.38; p = 0.03), whereas creatinine clearance of <45 mL/min was not significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted OR: 0.91, 95% CI: 0.25–3.34; p = 0.88). Conclusions The results suggest that severe hematologic toxicities in patients receiving carboplatin-based pemetrexed may be significantly induced by the inhibition of renal tubular pemetrexed secretion through drug–drug interactions between NSAIDs and pemetrexed rather than through glomerular filtration of pemetrexed, even with moderate to sufficient renal function. PMID:28158216

  8. Diets with no or low amounts of dietary fiber can reduce small intestinal ulcers induced by non-steroidal anti-inflammatory drugs in dogs.

    PubMed

    Satoh, H; Kondo, R; Shinoda, T; Idaka, S; Ishigami, K; Shiotani, S

    2016-08-01

    Recent progress in endoscopic techniques has revealed that non-steroidal anti-inflammatory drugs (NSAIDs) often cause ulcers in the small intestine in humans, but effective therapy is not available at present. In the present study, we investigated the effects of feeding condition and the amount of dietary fiber (DF) in the diet on the formation of gastrointestinal ulcers induced by NSAIDs in dogs. Several types of diets containing various percentages of DF were given to dogs. Indomethacin (1 or 3 mg/kg, p.o.), ketoprofen (2 mg/kg, s.c.), or fulnixin (1 mg/kg, s.c.) was administered once daily at 10 a.m. after a morning meal or without a morning meal (fasted condition) for 3 - 7 days. Gastrointestinal lesions were examined 24 h after the final dose of the drugs. When indomethacin (3 mg/kg) was administered after a morning meal (fed condition) for 7 days, it produced many lesions in the small intestine. However, when it was given in the fasted condition without the morning meal, the lesions were markedly decreased. All the NSAIDs given after feeding of regular dry food containing 6% DF once a day for 3 days produced many lesions in the small intestine. The lesions were decreased or increased in dogs given prescription diets containing low DF (1.1%) and high DF (15.4%), respectively. Furthermore, lesions were not observed in dogs given canned diet containing very low DF (< 0.1%), whereas lesions appeared again in dogs given canned diet supplemented with cellulose (3 or 10%) but not with pectin (10%). These results suggested that both feeding condition and insoluble DF, such as cellulose in the diet, play an important role in the formation of NSAID-induced small intestinal lesions, and that a diet with no or low amounts of DF may decrease gastrointestinal side-effects associated with the use of NSAIDs.

  9. Variants of CEP68 Gene Are Associated with Acute Urticaria/Angioedema Induced by Multiple Non-Steroidal Anti-Inflammatory Drugs

    PubMed Central

    Cornejo-García, José Antonio; Flores, Carlos; Plaza-Serón, María C.; Acosta-Herrera, Marialbert; Blanca-López, Natalia; Doña, Inmaculada; Torres, María J.; Mayorga, Cristobalina; Guéant-Rodríguez, Rosa M.; Ayuso, Pedro; Fernández, Javier; Laguna, José J.; Agúndez, José A. G.; García-Martín, Elena; Guéant, Jean-Louis; Canto, Gabriela; Blanca, Miguel

    2014-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most consumed drugs worldwide because of their efficacy and utility in the treatment of pain and inflammatory diseases. However, they are also responsible for an important number of adverse effects including hypersensitivity reactions. The most important group of these reactions is triggered by non-immunological, pharmacological mechanisms catalogued under the denomination of cross-intolerance (CRI), with acute urticaria/angioedema induced by multiple NSAIDs (MNSAID-UA) the most frequently associated clinical entity. A recent genome-wide association study identified the gene encoding the centrosomal protein of 68 KDa (CEP68) as the major locus associated with aspirin intolerance susceptibility in asthmatics. In this study, we aimed to assess the role of this locus in susceptibility to CRI to NSAIDs by examining 53 common gene variants in a total of 635 patients that were classified as MNSAID-UA (n = 399), airway exacerbations (n = 110) or blended pattern (n = 126), and 425 controls. We found in the MNSAID-UA group a number of variants (17) associated (lowest p-value = 1.13×10−6), including the non-synonymous Gly74Ser variant (rs7572857) previously associated with aspirin intolerance susceptibility in asthmatics. Although not being significant in the context of multiple testing, eight of these variants were also associated with exacerbated respiratory disease or blended reactions. Our results suggest that CEP68 gene variants may play an important role in MNSAID-UA susceptibility and, despite the different regulatory mechanisms involved depending on the specific affected organ, in the development of hypersensitivity reactions to NSAIDs. PMID:24618698

  10. Modulatory effects of non-steroidal anti-inflammatory drugs on the luminol and lucigenin amplified chemiluminescence of equine neutrophils.

    PubMed

    Benbarek, H; Ayad, A; Deby-Dupont, G; Boukraa, L; Serteyn, D

    2012-03-01

    The purpose of this study was to explore the potential modulation of equine neutrophil oxidative burst by a series of classical NSAIDs which was subsequently monitored by the luminol or lucigenin-enhanced chemiluminescence (CL) technique. A significant dose-dependent inhibition of the luminol CL was observed with the majority of investigated drugs. This inhibition was very significant for phenylbutazone and Indomethacin; while for aspirin, a higher concentration is required. The action of Ketoprofen was significant during the first 5 min and only when the concentration was above 1 mM. Indomethacin and acetylsalicylic acid result in an inhibition dose-dependent of luminol CL. On the other hand, the phenylbutazone showed an inhibiting effect when used either luminol or lucigenin though luminol is slightly better. When the ketoprofen is considered, an inhibiting effect of luminal CL was observed but less significant than the other NSAIDs investigated. The flunixin meglumine enhances strongly the CL.

  11. Biological evaluation of bismuth non-steroidal anti-inflammatory drugs (BiNSAIDs): stability, toxicity and uptake in HCT-8 colon cancer cells.

    PubMed

    Hawksworth, Emma L; Andrews, Philip C; Lie, Wilford; Lai, Barry; Dillon, Carolyn T

    2014-06-01

    Recent studies showed that the metal-coordinated non-steroidal anti-inflammatory drug (NSAID), copper indomethacin, reduced aberrant crypt formation in the rodent colon cancer model, while also exhibiting gastrointestinal sparing properties. In the present study, the stability and biological activity of three BiNSAIDs of the general formula [Bi(L)3]n, where L=diflunisal (difl), mefenamate (mef) or tolfenamate (tolf) were examined. NMR spectroscopy of high concentrations of BiNSAIDs (24h in cell medium, 37°C) indicated that their structural stability and interactions with cell medium components were NSAID specific. Assessment of cell viability using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium]bromide (MTT) assay showed that the toxicity ranking of the BiNSAIDs paralleled those of the respective free NSAIDs: diflH

  12. Fabrication of aluminum terephthalate metal-organic framework incorporated polymer monolith for the microextraction of non-steroidal anti-inflammatory drugs in water and urine samples.

    PubMed

    Lyu, Dan-Ya; Yang, Cheng-Xiong; Yan, Xiu-Ping

    2015-05-08

    Polymer monolith microextraction (PMME) based on capillary monolithic column is an effective and useful technique to preconcentrate trace analytes from environmental and biological samples. Here, we report the fabrication of a novel aluminum terephthalate metal-organic framework (MIL-53(Al)) incorporated capillary monolithic column via in situ polymerization for the PMME of non-steroidal anti-inflammatory drugs (NSAIDs) (ketoprofen, fenbufen and ibuprofen) in water and urine samples. The fabricated MIL-53(Al) incorporated monolith was characterized by X-ray powder diffractometry, scanning electron microscopy, Fourier transform infrared spectrometry, and nitrogen adsorption experiment. The MIL-53(Al) incorporated monolith gave larger surface area than the neat polymer monolith. A 2-cm long MIL-53(Al) incorporated capillary monolith was applied for PMME coupled with high-performance liquid chromatography for the determination of the NSAIDs. Potential factors affecting the PMME were studied in detail. Under the optimized conditions, the developed method gave the enhancement factors of 46-51, the linear range of 0.40-200μgL(-1), the detection limits (S/N=3) of 0.12-0.24μgL(-1), and the quantification limits (S/N=10) of 0.40-0.85μgL(-1). The recoveries for spiked NSAIDs (20μgL(-1)) in water and urine samples were in the range of 77.3-104%. Besides, the MIL-53(Al) incorporated monolith was stable enough for 120 extraction cycles without significant loss of extraction efficiency. The developed method was successfully applied to the determination of NSAIDs in water and urine samples.

  13. Occurrence and behavior of non-steroidal anti-inflammatory drugs and lipid regulators in wastewater and urban river water of the Pearl River Delta, South China.

    PubMed

    Huang, Qiuxin; Yu, Yiyi; Tang, Caiming; Zhang, Kun; Cui, Jianlan; Peng, Xianzhi

    2011-04-01

    Occurrence of five non-steroidal anti-inflammatory drugs (salicylic acid, ibuprofen, naproxen, indomethacin and diclofenac) and three lipid regulators (bezafibrate, clofibric acid and gemfibrozil) was investigated in wastewater, sewage sludge, and river water of the urban section of the Pearl River at Guangzhou in South China. Behavior and fate of the pharmaceuticals during treatment in two sewage treatment plants (STPs) were also studied in depth by determining concentrations in the influents and effluents at major treatment units and the sewage sludge. Concentrations of the pharmaceuticals in the raw wastewater were mostly at ng L(-1) levels except salicylic acid whose concentrations ranged from 9.6 to 23.3 μg L(-1). No significant amount of the pharmaceuticals was detected in the suspended particulate matter of wastewater and sewage sludge. Salicylic acid, indomethacin, and naproxen were almost completely removed (≥ 99%); gemfibrozil, ibuprofen and bezafibrate were significantly removed (>75%), whereas diclofenac and clofibric acid were removed by 60-70% during treatment in the STPs. Generally, biodegradation was the governing process for elimination of the investigated pharmaceuticals. Anaerobic biodegradation was responsible for most of the removal of diclofenac whereas aerobic biodegradation also played an important role in elimination of the other pharmaceuticals except SA, which was nearly completely removed after the anoxic process. In the Pearl River, the pharmaceuticals were widely detected. Both the concentrations and detection frequency were higher in March 2008 than those in the other seasons, which may be ascribed mainly to less dilution caused by lower precipitation. Besides the STPs, urban canals directly connected with the Pearl River may also be important contributors to the pharmaceutical contamination in the river.

  14. Molecular modeling and simulation studies of recombinant laccase from Yersinia enterocolitica suggests significant role in the biotransformation of non-steroidal anti-inflammatory drugs.

    PubMed

    Singh, Deepti; Rawat, Surender; Waseem, Mohd; Gupta, Sunita; Lynn, Andrew; Nitin, Mukesh; Ramchiary, Nirala; Sharma, Krishna Kant

    2016-01-08

    The YacK gene from Yersinia enterocolitica strain 7, cloned in pET28a vector and expressed in Escherichia coli BL21 (DE3), showed laccase activity when oxidized with 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and guaiacol. The recombinant laccase protein was purified and characterized biochemically with a molecular mass of ≈58 KDa on SDS-PAGE and showed positive zymogram with ABTS. The protein was highly robust with optimum pH 9.0 and stable at 70 °C upto 12 h with residual activity of 70%. Kinetic constants, Km values, for ABTS and guaiacol were 675 μM and 2070 μM, respectively, with corresponding Vmax values of 0.125 μmol/ml/min and 6500 μmol/ml/min. It also possess antioxidative property against BSA and Cu(2+)/H2O2 model system. Constant pH MD simulation studies at different protonation states of the system showed ABTS to be most stable at acidic pH, whereas, diclofenac at neutral pH. Interestingly, aspirin drifted out of the binding pocket at acidic and neutral pH, but showed stable binding at alkaline pH. The biotransformation of diclofenac and aspirin by laccase also corroborated the in silico results. This is the first report on biotransformation of non-steroidal anti-inflammatory drugs (NSAIDs) using recombinant laccase from gut bacteria, supported by in silico simulation studies.

  15. Poly(2-aminobenzothiazole)-coated graphene oxide/magnetite nanoparticles composite as an efficient sorbent for determination of non-steroidal anti-inflammatory drugs in urine sample.

    PubMed

    Asgharinezhad, Ali Akbar; Ebrahimzadeh, Homeira

    2016-02-26

    In this study, for the first time, 2-aminobenzothiazole monomer was polymerized on Fe3O4 NPs, graphene oxide/Fe3O4 (GO/Fe3O4) and graphene/Fe3O4 (G/Fe3O4) nanocomposites. The synthesized magnetic nanosorbents were characterized by various techniques. The extraction ability of these nanosorbents including Fe3O4, GO/Fe3O4, G/Fe3O4, Fe3O4@poly(2-aminobenzothiazole) (Fe3O4@PABT), GO/Fe3O4@PABT and G/Fe3O4@PABT were compared for dispersive-micro-solid phase extraction of three non-steroidal anti-inflammatory drugs. The results revealed that GO/Fe3O4@PABT nanocomposite demonstrates higher extraction efficiency for naproxen, diclofenac and ibuprofen as selected model analytes. Following the sorption and elution steps, the model analytes were quantified by high performance liquid chromatography-photo diode array detection. Afterwards, a central composite design methodology combined with desirability function approach was applied to find out the optimal experimental conditions. Under the optimized conditions, the limits of detection and linear dynamic ranges were achieved in the range of 0.07-0.3 μg L(-1) and 0.25-2000 μg L(-1), respectively. The percent of extraction recovery was 87.4, 85.5 and 90.5% for naproxen, diclofenac and ibuprofen, respectively. The obtained relative standard deviation (n=5) was 7.2, 5.4 and 6.4% for naproxen, diclofenac and ibuprofen, respectively. Ultimately, this method was employed for urinary monitoring of the target analytes and satisfactory results were obtained.

  16. Effects of conventional and hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs in rats with stress-induced and epinephrine-induced gastric damage.

    PubMed

    Fomenko, Iryna; Sklyarov, Alexander; Bondarchuk, Tetyana; Biletska, Lilya; Panasyuk, Natalia; Wallace, John L

    2014-12-01

    Mechanisms of gastric defence under conditions of combined influence of acute stress and non-steroidal anti-inflammatory drugs (NSAIDs) are still poorly studied. The aim of this study was to explore the effects of different types of NSAIDs (naproxen, celecoxib and ATB-346) in producing experimental gastric lesions (induced by water-restraint stress (WRS) or by epinephrine (EPN) injection) and to determine the role of lipid peroxidation and the nitric oxide (NO) system in the pathogenesis of the damage. Male rats were used (eight per group) in this work. The NSAIDs were all administered at a dose 10 mg kg(-1) 30 min prior to WRS or EPN injection. Administration of naproxen to the control rats caused development of gastric lesions, whereas administration of a hydrogen sulfide (H2S)-releasing NSAID (ATB-346) or a selective cyclooxygenase-2 inhibitor (celecoxib) did not cause gastric damage. In contrast, lipid peroxidation processes were enhanced in all groups as was the activity of NO synthase (NOS). Pretreatment with naproxen in the WRS model caused an increase in severity of damage and a decrease in NOS activity. ATB-346 displayed beneficial effects, manifested by a decrease in the area of gastric damage, but parameters of lipid peroxidation and the NOS system did not differ substantially from those in the group treated with naproxen. Administration of different NSAIDs under conditions of EPN-induced gastric damage resulted in the decrease in NOS activity and lipid peroxidation. None of the tested NSAIDs exacerbated EPN-induced gastric mucosal injury; indeed, they all reduced the extent of damage.

  17. Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?

    PubMed

    Strand, Vibeke

    2007-12-22

    Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.

  18. Fabric phase sorptive extraction: a new sorptive microextraction technique for the determination of non-steroidal anti-inflammatory drugs from environmental water samples.

    PubMed

    Racamonde, Inés; Rodil, Rosario; Quintana, José Benito; Sieira, Benigno José; Kabir, Abuzar; Furton, Kenneth G; Cela, Rafael

    2015-03-20

    Fabric phase sorptive extraction (FPSE) is a new, yet very promising member of the sorbent-based sorptive microextraction family. It has simultaneously improved both the extraction sensitivity and the speed of the extraction by incorporating high volume of sol-gel hybrid inorganic-organic sorbents into permeable fabric substrates. The advantages of FPSE have been investigated for the determination of four non-steroidal anti-inflammatory drugs, ibuprofen, naproxen, ketoprofen and diclofenac, in environmental water samples in combination with gas chromatography-mass spectrometry. Initially, the significance of several parameters affecting FPSE: sorbent chemistry, matrix pH and ionic strength were investigated using a mixed level factorial design (3(1)×2(2)). Then, other important parameters e.g., sample volume, extraction kinetics, desorption time and volume were also carefully studied and optimized. Due to the high sorbent loading on the FPSE substrate in the form of ultra-thin coating and the open geometry of the microextraction device, higher mass transfer of the target analytes occurs at a faster rate, leading to high enrichment factors in a relatively short period of time (equilibrium times: 45-100 min). Under optimal operational conditions, the limits of detection (S/N=3) were found to be in the range of 0.8 ng L(-1) to 5 ng L(-1). The enrichment factors ranged from 162 to 418 with absolute extraction efficiencies varied from 27 to 70%, and a good trueness (82-116% relative recoveries) indicating that the proposed method can be readily deployed to routine environmental pollution monitoring. The proposed method was successfully applied to the analysis of target analytes in two influent and effluent samples from a wastewater treatment plant and two river water samples in Spain.

  19. The non-steroidal anti-inflammatory drug diclofenac sodium attenuates lipopolysaccharide-induced alterations to reward behavior and corticosterone release.

    PubMed

    De La Garza, Richard; Fabrizio, Kevin R; Radoi, Gina Elena; Vlad, Tudor; Asnis, Gregory M

    2004-02-04

    Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to counteract stress hormone and pro-inflammatory cytokine activation. To extend these findings, we tested whether the NSAID diclofenac sodium would attenuate lipopolysaccharide (LPS)-induced reductions in reward behavior. In the first experiment, male, Wistar rats pressed a lever for food reward and subsequently received 10 days treatment of saline (1 ml/kg, s.c.) or diclofenac (2.5mg/kg, s.c.). On the subsequent test day, rats were given a final injection of saline or diclofenac 30 min prior to LPS (20 micrograms/kg, i.p.). LPS significantly reduced rate of food self-administration and total reinforcers obtained and increased corticosterone levels in saline-treated rats, while these effects were significantly attenuated in diclofenac-treated rats. In the second experiment, rats pressed a lever for sweetened milk. In contrast to food self-administration, acute LPS exposure did not reduce rate of responding or total reinforcers obtained in either saline- or diclofenac-treated rats. In the third experiment, rats trained to press a lever for sweetened milk were pre-exposed to a high dose of LPS (250 micrograms/kg, i.p.) 2 weeks prior to a challenge injection of LPS. In this case, LPS challenge significantly reduced rate of sweetened milk self-administration, but not total reinforcers obtained, in saline-treated rats. Rats treated with diclofenac did not exhibit reductions in rate of responding or total reinforcers obtained. Overall, the data indicate that the NSAID diclofenac sodium counteracts LPS-induced reductions in reward behavior and corticosterone release, and may therefore have therapeutic potential for specific components of endotoxin-induced sickness behavior, including anhedonia.

  20. Non-steroidal anti-inflammatory drugs and risk of cerebrovascular events in patients with osteoarthritis: a nested case-control study.

    PubMed

    Lapi, Francesco; Piccinni, Carlo; Simonetti, Monica; Levi, Miriam; Lora Aprile, Pierangelo; Cricelli, Iacopo; Cricelli, Claudio; Fanelli, Andrea

    2016-02-01

    Recent studies show that the risk of cardiovascular adverse events for certain traditional non-steroidal anti-inflammatory drugs (NSAIDs) is similar to that of rofecoxib. While these results are focused on ischemic cardiomyopathy, there is little evidence concerning the risk of ischemic stroke/transient ischemic attack and hemorrhagic stroke. Additionally, there is no information on nimesulide and ketoprofen, the most frequently prescribed NSAIDs in Italy, along with diclofenac. This study aims to determine whether the use of NSAIDs is associated with an increased risk of cerebrovascular events in Italy. We performed a case-control analysis nested in a cohort of patients with osteoarthritis between 2002 and 2011 who were newly treated with NSAIDs. The patients were followed until December 31, 2012. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI) of cerebrovascular events (index date) associated with current (until 30 days before the index date), recent (31-365 days) and past (>365 days) use of NSAIDs. Within a cohort of 29,722 patients, 1566 cases (1546 matched with controls) were identified (incidence rate = 11.0/1000 person-years). The overall rate of cerebrovascular event was not elevated with current NSAIDs overall when compared with past use. Among individual NSAIDs, diclofenac and ketoprofen were the molecules significantly associated with an increased rate of cerebrovascular events (OR = 1.53; 95% CI 1.04-2.24; OR = 1.62; 95% CI 1.02-2.58, respectively). The most frequent event was hemorrhagic stroke following the use of ketoprofen (OR = 2.09; 95% CI 1.05-4.15). Diclofenac and ketoprofen seemed to increase the risk of cerebrovascular events. These findings might influence the choice of NSAIDs according to patient characteristics.

  1. Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double blind placebo controlled study.

    PubMed

    Belch, J J; Ansell, D; Madhok, R; O'Dowd, A; Sturrock, R D

    1988-02-01

    In rheumatoid arthritis (RA) benefit from non-steroidal anti-inflammatory drugs (NSAIDs) is mediated through inhibition of the cyclo-oxygenase enzyme, thereby decreasing production of the 2 series prostaglandins (PGs). The lipoxygenase enzyme is intact, however, allowing leucotriene (LT) production, e.g., LTB4 (an inflammatory mediator). Treatment with evening primrose oil (EPO) which contains gamma-linolenic acid (GLA) leads to production of the 1 series PGs, e.g., PGE1, which has less inflammatory effects. Also LT production is inhibited. Eicosapentaenoic acid (EPA, fish oil) treatment provides a substrate for PGs and LTs, which are also less inflammatory. In this study 16 patients with RA were given 540 mg GLA/day (EPO), 15 patients 240 mg EPA and 450 mg GLA/day (EPO/fish oil), and 18 patients an inert oil (placebo). The aim of this study was to determine if EPO or EPO/fish oil could replace NSAID treatment in RA. The initial 12 month treatment period was followed by three months of placebo for all groups. Results at 12 months showed a significant subjective improvement for EPO and EPO/fish oil compared with placebo. In addition, by 12 months the patients receiving EPO and EPO/fish oil had significantly reduced their NSAIDs. After 3 months of placebo those receiving active treatment had relapsed. Despite the decrease in NSAIDs, measures of disease activity did not worsen. It is suggested that EPO and EPO/fish oil produce a subjective improvement and allow some patients to reduce or stop treatment with NSAIDs. There is, however, no evidence that they act as disease modifying agents.

  2. Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double blind placebo controlled study.

    PubMed Central

    Belch, J J; Ansell, D; Madhok, R; O'Dowd, A; Sturrock, R D

    1988-01-01

    In rheumatoid arthritis (RA) benefit from non-steroidal anti-inflammatory drugs (NSAIDs) is mediated through inhibition of the cyclo-oxygenase enzyme, thereby decreasing production of the 2 series prostaglandins (PGs). The lipoxygenase enzyme is intact, however, allowing leucotriene (LT) production, e.g., LTB4 (an inflammatory mediator). Treatment with evening primrose oil (EPO) which contains gamma-linolenic acid (GLA) leads to production of the 1 series PGs, e.g., PGE1, which has less inflammatory effects. Also LT production is inhibited. Eicosapentaenoic acid (EPA, fish oil) treatment provides a substrate for PGs and LTs, which are also less inflammatory. In this study 16 patients with RA were given 540 mg GLA/day (EPO), 15 patients 240 mg EPA and 450 mg GLA/day (EPO/fish oil), and 18 patients an inert oil (placebo). The aim of this study was to determine if EPO or EPO/fish oil could replace NSAID treatment in RA. The initial 12 month treatment period was followed by three months of placebo for all groups. Results at 12 months showed a significant subjective improvement for EPO and EPO/fish oil compared with placebo. In addition, by 12 months the patients receiving EPO and EPO/fish oil had significantly reduced their NSAIDs. After 3 months of placebo those receiving active treatment had relapsed. Despite the decrease in NSAIDs, measures of disease activity did not worsen. It is suggested that EPO and EPO/fish oil produce a subjective improvement and allow some patients to reduce or stop treatment with NSAIDs. There is, however, no evidence that they act as disease modifying agents. PMID:2833184

  3. Effects of acute exposure to the non-steroidal anti-inflammatory drug ibuprofen on the developing North American Bullfrog (Rana catesbeiana) tadpole.

    PubMed

    Veldhoen, Nik; Skirrow, Rachel C; Brown, Lorraine L Y; van Aggelen, Graham; Helbing, Caren C

    2014-09-02

    A variety of pharmaceutical chemicals can represent constituents of municipal effluent outflows that are dispersed into aquatic receiving environments worldwide. Increasingly, there is concern as to the potential of such bioactive substances to interact with wildlife species at sensitive life stages and affect their biology. Using a combination of DNA microarray, quantitative real-time polymerase chain reaction, and quantitative nuclease protection assays, we assessed the ability of sub-lethal and environmentally relevant concentrations of ibuprofen (IBF), a non-steroidal anti-inflammatory agent and prevalent environmental contaminant, to function as a disruptor of endocrine-mediated post-embryonic development of the frog. While the LC50 of IBF for pre-metamorphic Rana catesbeiana tadpoles is 41.5 mg/L (95% confidence interval: 32.3-53.5 mg/L), exposure to concentrations in the ppb range elicited molecular responses both in vivo and in organ culture. A nominal concentration of 15 μg/L IBF (actual = 13.7 μg/L) altered the abundance of 26 mRNA transcripts within the liver of exposed pre-metamorphic R. catesbeiana tadpoles within 6 d. IBF-treated animals demonstrated subsequent disruption of thyroid hormone-mediated reprogramming in the liver transcriptome affecting constituents of several metabolic, developmental, and signaling pathways. Cultured tadpole tail fin treated with IBF for 48 h also demonstrated altered mRNA levels at drug concentrations as low as 1.5 μg/L. These observations raise the possibility that IBF may alter the post-embryonic development of anuran species in freshwater environs, where IBF is a persistent or seasonal pollutant.

  4. The role of activated carbon and disinfection on the removal of endocrine disrupting chemicals and non-steroidal anti-inflammatory drugs from wastewater.

    PubMed

    Noutsopoulos, Constantinos; Mamais, Daniel; Mpouras, Thanasis; Kokkinidou, Despina; Samaras, Vasilios; Antoniou, Korina; Gioldasi, Marianna

    2014-01-01

    Endocrine disrupting chemicals and non-steroidal anti-inflammatory drugs are two important groups of emerging pollutants due to their toxicological and chemical characteristics and their persistent detection in the aquatic environment. Wastewater treatment plants are a significant pathway for their transfer to the water courses. It is well evidenced that these chemicals are only partially removed through biological treatment of wastewater and therefore being detected in secondary effluents. This work focuses on the evaluation of the efficiency of two well-established disinfection technologies (chlorination and UV irradiation) along with UV/H2O2 and powdered activated carbon (PAC) to remove these chemicals from biologically treated wastewater. Based on the results it is shown that appreciable removal efficiencies due to chlorination should be expected for most of the target compounds, whereas this was not the case for ibuprofen and ketoprofen. With the exemption of diclofenac and ketoprofen direct UV irradiation did not efficiently removed target compounds for UV doses usually applied for disinfection purposes. The application of advanced UV treatment through the addition of H2O2 although resulted in increased removal of the target compounds is not sufficient at moderate UV and H2O2 doses to achieve satisfactory removal efficiencies. PAC use resulted in sufficient removal of target compounds although high PAC doses were required for some chemicals. Comparison of Freundlich isotherms of this study with those of other studies, derived employing water samples, suggested that the water matrix along with the target compounds concentration range can significantly affect the outcome of the experiments.

  5. Crystal structure of a mixed-ligand silver(I) complex of the non-steroidal anti-inflammatory drug diclofenac and pyrimidine

    PubMed Central

    Hamamci Alisir, Sevim; Dege, Necmi

    2016-01-01

    In the title mixed-ligand silver(I) coordination polymeric complex with the non-steroidal anti-inflammatory drug diclofenac (C14H11Cl2NO2) (diclH) and pyrimidine (pym), namely poly[{μ2-2-[2-(2,6-di­chloro­anilino)phen­yl]acetato-κ2 O:O′}(μ2-pyrimidine-κ2 N 1:N 3)silver(I)], [Ag(C14H10Cl2NO2)(C4H4N2)]n or [Ag(μ-dicl)(μ-pym)]n, the very distorted tetra­hedral AgN2O2 coordination centres comprise two N-atom donors from bridging pym ligands [Ag—N = 2.381 (3) and 2.412 (3) Å] and two carboxyl­ate O-atom donors from dicl ligands [Ag—O = 2.279 (2) and 2.280 (2) Å], which bridge Ag atoms, giving a centrosymmetric dinuclear units with a short Ag⋯Ag separation [2.8931 (5) Å]. Within the units are short intra­ligand C—Cl⋯π(pym) inter­actions [3.6409 (15) Å]. The units are linked through the bridging N atoms of the pym ligand into a two-dimensional sheet–polymer structure lying parallel to (100) and stabilized by inter-ring π–π inter­actions between the pym ligands [Cg⋯Cg = 3.4199 (17) Å]. Additional inter-unit C—H⋯O and C—H⋯Cg hydrogen-bonding inter­actions between the sheets give an overall three-dimensional structure. PMID:27746945

  6. A naturalistic study of the determinants of health related quality of life improvement in osteoarthritic patients treated with non-specific non-steroidal anti-inflammatory drugs

    PubMed Central

    Rabenda, V; Burlet, N; Ethgen, O; Raeman, F; Belaiche, J; Reginster, J

    2005-01-01

    Objectives: To capture changes in the quality of life (QoL) occurring in patients with osteoarthritis (OA) during treatment with non-specific non-steroidal anti-inflammatory drugs (NSAIDs) and to identify factors that predict such changes. Methods: A naturalistic, prospective follow up of 783 patients with OA in whom primary care physicians decided to start treatment with non-selective NSAIDs. Short Form-36 (SF-36) and the Western Ontario and McMaster Universities OA index (WOMAC) were assessed at baseline and after 3 months. Baseline results were compared with QoL values in 4800 subjects randomly selected from the general population. Multiple regression analysis was performed to identify determinants of QoL at baseline and measures influencing changes in SF-36 or WOMAC during follow up. Results: All QoL dimensions were significantly (p<0.01) decreased in patients with OA compared with controls. Significant improvement (p<0.05) in four dimensions of the SF-36 (vitality, role emotional, role physical, bodily pain) and in all components of the WOMAC was seen between baseline and month 3. Older age, female sex, longer duration of OA, and a higher number of comorbidities were the major determinants of a poor QoL at baseline. Maximal benefit from non-specific NSAIDs was seen in patients with the most severe impairment in QoL and the shortest duration of OA. Conclusion: OA negatively impacts all dimensions of the QoL. Non-specific NSAIDs improve the QoL in patients with OA treated in a "real life setting". The profile of patients receiving maximal benefit from such treatment may be of interest for health providers, enabling them to decide who should preferentially be given cytoprotective treatments or coxibs. PMID:15528282

  7. Non-steroidal anti-inflammatory drug use, hormone receptor status, and breast cancer-specific mortality in the Carolina Breast Cancer Study.

    PubMed

    Allott, E H; Tse, C-K; Olshan, A F; Carey, L A; Moorman, P G; Troester, M A

    2014-09-01

    Epidemiologic studies report a protective association between non-steroidal anti-inflammatory drug (NSAID) use and hormone receptor-positive breast cancer risk, a finding consistent with NSAID-mediated suppression of aromatase-driven estrogen biosynthesis. However, the association between NSAID use and breast cancer-specific mortality is uncertain and it is unknown whether this relationship differs by hormone receptor status. This study comprised 935 invasive breast cancer cases, of which 490 were estrogen receptor (ER)-positive, enrolled between 1996 and 2001 in the Carolina Breast Cancer Study. Self-reported NSAID use in the decade prior to diagnosis was categorized by duration and regularity of use. Differences in tumor size, stage, node, and receptor status by NSAID use were examined using Chi-square tests. Associations between NSAID use and breast cancer-specific mortality were examined using age- and race-adjusted Cox proportional hazards analysis. Tumor characteristics did not differ by NSAID use. Increased duration and regularity of NSAID use was associated with reduced breast cancer-specific mortality in women with ER-positive tumors (long-term regular use (≥8 days/month for ≥ 3 years) versus no use; hazard ratio (HR) 0.48; 95 % confidence interval (CI) 0.23-0.98), with a statistically significant trend with increasing duration and regularity (p-trend = 0.036). There was no association for ER-negative cases (HR 1.19; 95 %CI 0.50-2.81; p-trend = 0.891). Long-term, regular NSAID use in the decade prior to breast cancer diagnosis was associated with reduced breast cancer-specific mortality in ER-positive cases. If confirmed, these findings support the hypothesis that potential chemopreventive properties of NSAIDs are mediated, at least in part, through suppression of estrogen biosynthesis.

  8. Prescription of and Adherence to Non-Steroidal Anti-Inflammatory Drugs and Gastroprotective Agents in At-Risk Gastrointestinal Patients

    PubMed Central

    Lanas, Angel; Polo-Tomás, Mónica; Roncales, Pilar; Gonzalez, Miguel A; Zapardiel, Javier

    2012-01-01

    OBJECTIVES: Patients with gastrointestinal (GI) risk factors who take non-steroidal anti-inflammatory drugs (NSAIDs) should also take gastroprotective agents (GPAs). No studies have evaluated adherence and reasons for non-adherence to GPA and NSAID therapies. METHODS: This was a prospective, multicenter, observational, longitudinal study. Patients attending rheumatology/orthopedic clinics who were co-prescribed NSAID plus GPA for at least 15 days and had risk factors for GI complications were followed up by telephone call. Optimal adherence was defined as taking the drug for ≥80% of prescribed days. Multivariate logistic regression analysis was used to determine factors associated with non-adherence. RESULTS: Of 1,232 patients interviewed, 192 were excluded because of inaccurate data. Of the remaining 1,040 patients, 74% were prescribed low-dose NSAIDs and 99.8% were prescribed a standard or high-dose GPA. In all, 70% of NSAIDs and 63.1% of GPA prescriptions were short term (<30 days). The majority of patients who were prescribed either an NSAID (92.5%) or GPA (85.9%) started therapy. Optimal adherence to GPA or NSAIDs was reported by 79.7% (95% confidence interval (CI): 76.9−82.2%) and 84.1% (95% CI: 81.7−86.3%) of patients, respectively. More adverse events occurred among patients who reported non-optimal adherence than among patients with optimal adherence to GPA (22.1 vs. 1.9%, P<0.0001). As reasons for non-adherence, patients most frequently cited infrequent/low-intensity rheumatic pain (NSAIDs) or forgetfulness (GPAs). Adverse events and short-term treatment were independent factors associated with poor adherence for both NSAIDs and GPAs. History of uncomplicated peptic ulcer and frequent dosing were additional factors associated with non-adherence to NSAIDs. CONCLUSIONS: Most frequent reasons for non-adherence are infrequent/low-intensity rheumatic pain (NSAIDs) or forgetfulness (GPAs). Short-term treatment and adverse events were associated with poor

  9. Comparison of three inhaled non-steroidal anti-inflammatory drugs on the airway response to sodium metabisulphite and adenosine 5'-monophosphate challenge in asthma.

    PubMed Central

    Wang, M.; Wisniewski, A.; Pavord, I.; Knox, A.; Tattersfield, A.

    1996-01-01

    BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used to assess the role of prostaglandins in asthma but their effects on bronchoconstrictor challenges have been inconsistent. The effects of three nebulised nonsteroidal anti-inflammatory drugs on the airway response to inhaled sodium metabisulphite (MBS) and adenosine 5'-monophosphate (AMP) were compared in the same asthmatic subjects to see whether contractile prostaglandins were involved in MBS or AMP induced bronchoconstriction. A possible protective effect of the osmolarity or pH of the inhaled solutions was also assessed. METHODS: Two double blind placebo controlled studies were carried out. In study 1, 15 non-aspirin sensitive patients with mild asthma attended on four occasions and inhaled 5 ml of lysine aspirin (L-aspirin) 900 mg, indomethacin 50 mg, sodium salicylate 800 mg, or saline 20 minutes before an inhaled MBS challenge. On four further occasions 14 of the patients inhaled the same solutions followed by an inhaled AMP challenge. In study 2, 10 of the patients attended on four additional occasions and inhaled 5 ml of 0.9%, 3%, 10%, or 9.5% saline with indomethacin 50 mg 20 minutes before an inhaled MBS challenge. RESULTS: In study 1 inhaled lysine aspirin had a similar effect on MBS and AMP induced bronchoconstriction, increasing the provocative dose causing a 20% fall in FEV1 (PD20) by 1.29 (95% CI 0.54 to 2.03) and 1.23 (95% CI 0.53 to 1.93) doubling doses, respectively. Indomethacin increased the MBS PD20 and AMP PD20 by 0.64 (95% CI -0.1 to 1.38) and 0.99 (95% CI 0.29 to 1.69) doubling doses, respectively. Sodium salicylate had no significant effect on either challenge. The two solutions causing most inhibition were the most acidic and the most alkaline. In study 2 inhaled 9.5% saline with indomethacin (osmolarity 3005 mOsm/kg) increased the MBS PD20 by 1.1 doubling doses (95% CI 0.2 to 2.0) compared with only 0.09 (95% CI -0.83 to 1.0) and 0.04 (95% CI -0.88 to 0.95) doubling doses

  10. Detection of the non-steroidal anti-inflammatory drug niflumic acid in humans: a combined 19F-MRS in vivo and in vitro study.

    PubMed

    Bilecen, Deniz; Schulte, Anja-Carina; Kaspar, Armin; Küstermann, Eckerhardt; Seelig, Joachim; Elverfeldt, Dominik; Scheffler, Klaus

    2003-05-01

    This study describes for the first time results of a (19)F-MRS study on humans exposed to the fluorinated non-steroidal anti-inflammatory drug niflumic acid. The accumulation and elimination of this commercially available selective prostaglandin synthase inhibitor is studied after an oral bolus in the human liver, in blood plasma and in urine samples. The in vivo spectra of the liver display two resonances with a similar increase in signal intensity during the investigation period of 240 min. One resonance refers to the parent compound niflumic acid (P), whereas the second resonance corresponds to a metabolite (M1) formed by the biotransformation by liver enzymes. The spectroscopic comparison with model compounds suggests 4'-hydroxyniflumic acid as the metabolite. During the entire experiment the concentration ratios of these resonances (P/M1) ranged between 0.7 and 0.9, indicating a high metabolite concentration most probably due to an efficient first pass metabolism. Both resonances (P, M1) were observed in the in vitro study of the blood plasma samples after plasma protein denaturation. However, in comparison to the liver spectra, the amount of the metabolite M1 is very small with a P/M1-ratio of 36.6 after 90 min and 16.1 after the end of measurement. This finding suggests an efficient biliary excretion of the metabolite M1, which bypasses the blood circulation system. Both resonances are also identified in the native urine samples. The signal intensity of the parent compound dominates the spectra of all urine samples, whereas the signal intensity of M1 increases slowly reaching a similar value to the parent compound P at the end of the measurement. This observation demonstrates an effective renal elimination of niflumic acid and suggests the existence of an enterohepatic circuit with a re-entry mechanism for the biliary excreted metabolite M1. In the urine spectra, an additional metabolite M2 is found. This resonance exhibits a low but constant signal

  11. The efficacy of duloxetine, non-steroidal anti-inflammatory drugs, and opioids in osteoarthritis: a systematic literature review and meta-analysis

    PubMed Central

    2014-01-01

    Background This meta-analysis assessed the efficacy of duloxetine versus other oral treatments used after failure of acetaminophen for management of patients with osteoarthritis. Methods A systematic literature review of English language articles was performed in PUBMED, EMBASE, MedLine In-Process, Cochrane Library, and ClinicalTrials.gov between January 1985 and March 2013. Randomized controlled trials of duloxetine and all oral non-steroidal anti-inflammatory drugs and opioids were included if treatment was ≥12 weeks and the Western Ontario and McMaster Universities Index (WOMAC) total score was available. Studies were assessed for quality using the assessment tool from the National Institute for Health and Clinical Excellence guidelines for single technology appraisal submissions. WOMAC baseline and change from baseline total scores were extracted and standardized. A frequentist meta-analysis, meta-regression, and indirect comparison were performed using the DerSimonian-Laird and Bucher methods. Bayesian analyses with and without adjustment for study-level covariates were performed using noninformative priors. Results Thirty-two publications reported 34 trials (2 publications each reported 2 trials) that met inclusion criteria. The analyses found all treatments except oxycodone (frequentist) and hydromorphone (frequentist and Bayesian) to be more effective than placebo. Indirect comparisons to duloxetine found no significant differences for most of the compounds. Some analyses showed evidence of a difference with duloxetine for etoricoxib (better), tramadol and oxycodone (worse), but without consistent results between analyses. Forest plots revealed positive trends in overall efficacy improvement with baseline scores. Adjusting for baseline, the probability duloxetine is superior to other treatments ranges between 15% to 100%. Limitations of this study include the low number of studies included in the analyses, the inclusion of only English language

  12. Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis

    PubMed Central

    2014-01-01

    Background It has been postulated that non-steroidal anti-inflammatory drugs (NSAIDs) use leads to decreased prostate cancer (PCa) risk. In recent years, NSAIDs’ role in PCa development has been extensively studied; however, there is not yet a definitive answer. Moreover, the epidemiological results for NSAIDs’ effect on PCa-specific mortality have been inconsistent. Therefore, we performed a meta-analysis to examine the controversy. Methods We performed a literature database search and included all published studies conducted in the general population exposed to any NSAID, extracting an odds ratio (OR) or a hazard ratio (HR) with 95% confidence intervals (95% CIs) that compared the incidence of PCa or PCa-specific mortality with non-exposure. We derived a pooled OR or HR using random or fixed effects models, as appropriate. Subgroup analyses were also performed. Results Thirty-nine studies (20 case–control and 19 cohort studies) were included in this analysis. Thirty-one studies were available concerning NSAID use and PCa incidence and eight studies on PCa-specific mortality. Compared to non-use, aspirin use was statistically significantly associated with PCa incidence risk, and the association was slightly stronger for advanced PCa than for total PCa (OR = 0.92, 95% CI = 0.87 to 0.97 for total PCa; OR = 0.81, 95% CI = 0.73 to 0.89 for advanced PCa). Aspirin use seems also to be associated with a modest reduction in PCa-specific mortality (HR = 0.86, 95% CI = 0.78 to 0.96 for total PCa; OR = 0.81, 95% CI = 0.71 to 0.92 for advanced PCa). Generally, the pooled effects for any NSAIDs, NA-NSAIDs and cyclooxygenase-2 inhibitors demonstrated no adverse or beneficial effects on PCa development or PCa-specific mortality, but the results were not consistent. The effect estimates did not vary markedly when stratified by study design and study quality but varied by geographic region. Furthermore, long-term aspirin use (≥4 years) was also significantly associated

  13. A healthy lifestyle index is associated with reduced risk of colorectal adenomatous polyps among non-users of non-steroidal anti-inflammatory drugs.

    PubMed

    Tabung, Fred K; Steck, Susan E; Burch, James B; Chen, Chin-Fu; Zhang, Hongmei; Hurley, Thomas G; Cavicchia, Philip; Alexander, Melannie; Shivappa, Nitin; Creek, Kim E; Lloyd, Stephen C; Hebert, James R

    2015-02-01

    In a Columbia, South Carolina-based case-control study, we developed a healthy lifestyle index from five modifiable lifestyle factors (smoking, alcohol intake, physical activity, diet, and body mass index), and examined the association between this lifestyle index and the risk of colorectal adenomatous polyps (adenoma). Participants were recruited from a local endoscopy center and completed questionnaires related to lifestyle behaviors prior to colonoscopy. We scored responses on each of five lifestyle factors as unhealthy (0 point) or healthy (1 point) based on current evidence and recommendations. We added the five scores to produce a combined lifestyle index for each participant ranging from 0 (least healthy) to 5 (healthiest), which was dichotomized into unhealthy (0-2) and healthy (3-5) lifestyle scores. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for adenoma with adjustment for multiple covariates. We identified 47 adenoma cases and 91 controls. In the main analyses, there was a statistically nonsignificant inverse association between the dichotomous (OR 0.54; 95% CI 0.22, 1.29) and continuous (OR 0.75; 95% CI 0.51, 1.10) lifestyle index and adenoma. Odds of adenoma were significantly modified by the use of non-steroidal anti-inflammatory drugs (NSAIDs) (p(interaction) = 0.04). For participants who reported no use of NSAIDs, those in the healthy lifestyle category had a 72% lower odds of adenoma as compared to those in the unhealthy category (OR 0.28; 95% CI 0.08, 0.98), whereas a one-unit increase in the index significantly reduced odds of adenoma by 53% (OR 0.47; 95% CI 0.26, 0.88). Although these findings should be interpreted cautiously given our small sample size, our results suggest that higher scores from this index are associated with reduced odds of adenomas, especially in non-users of NSAIDs. Lifestyle interventions are required to test this approach as a strategy to prevent colorectal adenomatous

  14. Quinolones and non-steroidal anti-inflammatory drugs interacting with copper(II), nickel(II), cobalt(II) and zinc(II): structural features, biological evaluation and perspectives.

    PubMed

    Psomas, George; Kessissoglou, Dimitris P

    2013-05-14

    The structural features of copper(II), nickel(II), cobalt(II) and zinc(II) complexes with the antimicrobial drugs quinolones and non-steroidal anti-inflammatory drugs (NSAIDs) as ligands are discussed. The binding properties of these complexes to biomolecules (calf-thymus DNA, bovine or human serum albumin) are presented and evaluated. The biological activity (antimicrobial, antioxidant and antiproliferative) of selected complexes is investigated. Further perspectives concerning the synthesis and the biological activity of novel complexes with quinolones or NSAIDs attractive to synthetic chemists, biochemists and/or biologists are presented.

  15. Steroidal and non-steroidal cyclooxygenase-2 inhibitor anti-inflammatory drugs as pre-emptive medication in patients undergoing periodontal surgery.

    PubMed

    Peres, Maria Fernanda Santos; Ribeiro, Fernanda Vieira; Ruiz, Karina Gonzalez Silvério; Nociti-Jr, Francisco Humberto; Sallum, Enilson Antônio; Casati, Márcio Zaffalon

    2012-01-01

    The aim of the present study was to compare the pre-emptive use of a cyclooxygenase-2 (COX-2) inhibitor with a well established steroidal anti-inflammatory drug for pain and edema relief following periodontal surgery for crown lengthening. Thirty patients requiring periodontal surgery were randomly assigned to receive one of the following medications: selective COX-2 inhibitor or steroidal anti-inflammatory drug, 60 min before the surgical procedure. To examine patient anxiety, a Corah's dental anxiety scale was applied before surgery. Using a visual analog scale, the extent of pain/discomfort during the trans-operative period and immediately after the surgery was measured. Additionally, intensity of pain/discomfort and edema were examined 4, 8, 12 and 24 h postoperatively. With regard to anxiety, no statistical differences between the groups were observed (p>0.05). With respect to the extent of pain/discomfort during the trans-operative, immediate and late postoperative period, data demonstrated no significant differences (p>0.05) between the COX-2 inhibitor and steroidal groups. With regard to edema, intragroup analysis did not reveal any statistically significant difference (p>0.05) during the 24 h following surgery in either group. In conclusion, both anti-inflammatory drugs presented a similar potential for pain and edema relief following periodontal surgery.

  16. Association of aspirin and non-steroidal anti-inflammatory drug use with risk of colorectal cancer according to genetic variants

    PubMed Central

    Nan, Hongmei; Hutter, Carolyn M.; Lin, Yi; Jacobs, Eric J.; Ulrich, Cornelia M.; White, Emily; Baron, John A.; Berndt, Sonja I.; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Chanock, Stephen J.; Cotterchio, Michelle; Duggan, David; Figueiredo, Jane C.; Fuchs, Charles S.; Giovannucci, Edward L.; Gong, Jian; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Jiao, Shuo; Lindor, Noralane M.; Lemire, Mathieu; Le Marchand, Loic; Newcomb, Polly A.; Ogino, Shuji; Pflugeisen, Bethann M.; Potter, John D.; Qu, Conghui; Rosse, Stephanie A.; Rudolph, Anja; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Thibodeau, Stephen N.; Thomas, Fridtjof; Thornquist, Mark; Warnick, Greg S.; Zanke, Brent W.; Gauderman, W. James; Peters, Ulrike; Hsu, Li; Chan, Andrew T.

    2015-01-01

    Importance Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. Prior studies examining a potential differential relationship of aspirin and NSAIDs with colorectal cancer risk according to genetic factors have been limited to analyses of candidate genes or pathways. Objective To comprehensively identify common genetic markers that characterize individuals who may obtain differential benefit from aspirin and/or NSAID chemoprevention, we tested gene by environment (G X E) interactions between regular use of aspirin and/or NSAIDs and single nucleotide polymorphisms (SNPs) across the genome in relation to risk of colorectal cancer. Design Case-control study using the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) that enrolled cases of colorectal cancer ascertained between 1976 and 2011 and matched controls. Odds ratios (ORs) of colorectal cancer and 95% confidence intervals (95% CIs) were estimated using conventional logistic regression analysis and case-only interaction analysis, after adjusting for age, sex, center, the first three principal components to account for population structure, and known colorectal cancer risk factors. For all genome-wide analyses, a two-sided p-value<5.0×10-8, which yields a genome-wide significance level of 0.05, was considered statistically significant. Setting 10 observational studies (5 case-control and 5 cohort studies) that were initiated between 1976 and 2003 across the U.S., Canada, Australia and Germany. Participants 8,634 colorectal cancer cases and 8,553 controls of European descent. Exposures Genome-wide SNP data generated from genome-wide association scans and imputation to HapMap II, as well as information on regular use of aspirin and/or NSAIDs and other colorectal cancer risk factors collected using in-person interviews and/or structured questionnaires. Main Outcomes and Measures

  17. In vitro evaluation of the effects of anti-fungals, benzodiazepines and non-steroidal anti-inflammatory drugs on the glucuronidation of 19-norandrosterone: implications on doping control analysis.

    PubMed

    Palermo, Amelia; Alessi, Beatrice; Botrè, Francesco; de la Torre, Xavier; Fiacco, Ilaria; Mazzarino, Monica

    2016-09-01

    We have studied whether the phase II metabolism of 19-norandrosterone, the most representative metabolite of 19-nortestosterone (nandrolone), can be altered in the presence of other drugs that are not presently included on the Prohibited List of the World Anti-Doping Agency. In detail, we have evaluated the effect of non-prohibited drugs belonging to the classes of anti-fungals, benzodiazepines, and non-steroidal anti-inflammatory drugs on the glucuronidation of 19-norandrosterone. In vitro assays based on the use of either pooled human liver microsomes or specific recombinant isoforms of uridine diphosphoglucuronosyl-transferase were designed and performed to monitor the formation of 19-norandrosterone glucuronide from 19-norandrosterone. Determination of 19-norandrosterone (free and conjugated fraction) was performed by gas chromatography - mass spectrometry after sample pretreatment consisting of an enzymatic hydrolysis (performed only for the conjugated fraction), liquid/liquid extraction with tert-butylmethyl ether, and derivatization to form the trimethylsilyl derivative. In parallel, a method based on reversed-phase liquid chromatography coupled to tandem mass spectrometry in positive electrospray ionization with acquisition in selected reaction monitoring mode was also developed to identify the non-prohibited drugs considered in this study. Incubation experiments have preliminarily shown that the glucuronidation of 19-norandrosterone is principally carried out by UGT2B7 (39%) and UGT2B17 (31%). Inhibition studies have shown that the yield of the glucuronidation reaction is reduced in the presence of the anti-fungals itraconazole, ketoconazole, and miconazole, of the benzodiazepine triazolam and of the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen, while no alteration was recorded in the presence of all other compounds considered in this study. Copyright © 2015 John Wiley & Sons, Ltd.

  18. Helicobacter pylori does not play a part in the dyspeptic complaints of rheumatology patients receiving long term treatment with non-steroidal anti-inflammatory drugs

    PubMed Central

    Calvet, X; Gratacos, J; Font, J; Larrosa, M; Sanfeliu, I; Roque, M

    2002-01-01

    Objective: To determine the variables related to dyspepsia in rheumatology patients requiring NSAID treatment, assessing in particular the role of Helicobacter pylori infection. Methods: One hundred and eighty six consecutive patients with a rheumatological disorder requiring NSAID treatment (68 male, 118 female; mean (SD) age 55 (15) years) were included in a cross sectional study; dyspeptic symptoms were measured by a previously validated scale. Helicobacter pylori infection was determined by serology. Variables related to the severity of symptoms and the need for antisecretory drugs were determined by multivariate analysis. Results: No relation was found between Helicobacter pylori infection and dyspepsia or any of its surrogate markers (antisecretory drug use or NSAID intolerance). Female sex and treatment with antisecretory drugs were found to be independent predictors for the appearance and severity of dyspeptic symptoms. The only independent predictive variables of the requirement for antisecretory drugs were age, previous ulcer disease, taking NSAIDs with a medium or high anti-inflammatory potential, and the symptoms score. Conclusion: Helicobacter pylori infection does not seem to play any part in the gastric symptoms of patients treated long term with NSAIDs. PMID:12079909

  19. High-performance liquid chromatography - mass spectrometry analysis of the parent drugs and their metabolites in extracts from cress (Lepidium sativum) grown hydroponically in water containing four non-steroidal anti-inflammatory drugs.

    PubMed

    Emhofer, Lisa; Himmelsbach, Markus; Buchberger, Wolfgang; Klampfl, Christian W

    2017-03-31

    In this paper the metabolism of four non-steroidal anti-inflammatory drugs, (ketoprofen, mefenamic acid, naproxen, and diclofenac) by cress (Lepidium sativum) is described. Cress was cultivated hydroponically in water spiked with the parent drugs at levels ranging from 0.01mgL(-1) to 1mgL(-1). Employing an approach based on the analysis of the plant extracts by HPLC coupled either with quadrupole-time-of-flight mass spectrometry, or Orbitrap MS or triple quadrupole (QqQ) MS allowed the identification of twenty substances (sixteen metabolites and four parent drugs). Metabolites were formed from the parent drug by hydroxylation or conjugation with polar molecules such as glucose, small organic acids or amino acids. Introducing a pre-concentration step employing solid-phase extraction and using HPLC-QqQ/MS in the multiple reaction monitoring mode enabled the positive detection of 11 of the proposed metabolites next to the four parent components even in plants grown in a 0.01mgL(-1) solution of the tested drugs, which is close to the conditions in real reclaimed waters.

  20. Selection of background electrolyte for CZE analysis by a chemometric approach. Part I. Separation of a mixture of acidic non-steroidal anti-inflammatory drugs.

    PubMed

    Furlanetto, Sandra; Lanteri, Silvia; Orlandini, Serena; Gotti, Roberto; Giannini, Iacopo; Pinzauti, Sergio

    2007-03-12

    This paper is the first part of the presentation of a chemometric approach for the rapid selection of a suitable background electrolyte (BGE) in CZE analysis of small drug molecules. The strategy is based on principal component analysis and experimental design. In this first section, the approach is applied to the analysis of a mixture of six arylpropionic anti-inflammatory drugs. Initially, 222 possible aqueous background electrolytes (objects) were characterized using as descriptors pH, conductivity, ionic strength and relative viscosity. In order to allow the dissociation of the acidic analytes, this original data set was reduced to 154 background electrolytes with pH values higher than or equal to 5. Principal component analysis made it possible to graphically represent the new set of objects, described by the four variables, in a two-dimensional space. Among these electrolytes, Kennard-Stone algorithm selected ten objects to be tested by CZE, covering homogeneously principal component space. CZE analyses were carried out with the selected electrolytes, and 0.1 M borax was identified as the most suitable one for the specified application. Finally, the characteristics of the analysis were finely tuned by means of a response surface study, which allowed the best conditions to be determined: borax concentration, 0.09 M; methanol, 6% (v/v); temperature, 24 degrees C, voltage, 20 kV. Applying these conditions, a baseline resolution among the six compounds was obtained in less than 10 min.

  1. More on the "Triple Whammy": antihypertensive drugs, non-steroidal anti-inflammatory agents and acute kidney injury - a case/non-case study in the French pharmacovigilance database.

    PubMed

    Fournier, Jean-Pascal; Sommet, Agnès; Durrieu, Geneviève; Poutrain, Jean-Christophe; Lapeyre-Mestre, Maryse; Montastruc, Jean-Louis

    2014-08-01

    It has been suggested that the risk of acute kidney injury (AKI) increases with the number of drugs associated between non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEis) [or angiotensin receptor blockers (ARBs)] and diuretics. We aimed to investigate whether the number of drugs associated between NSAIDs, ACEis, ARBs and diuretics was associated to disproportionate reporting of AKI in the French Pharmacovigilance Database. In reports of Adverse Drug Reactions (ADRs) recorded between 01 January 2008 and 31 December 2010, we selected patients whose medications included at least one oral antihypertensive drug. We used a case/non-case methodology. Cases were AKI and non-cases were all the remaining reports. Among the 11,442 ADR reports in patients under antihypertensive drug recorded in the French Pharmacovigilance Database, 837 ADRs were AKI (7.3%, 95% CI 6.8-7.8). AKI and the number of drugs associated were disproportionately reported (one drug alone: adjusted ROR 2.19, 95% CI: 1.65-2.89, two drugs: adjusted ROR 5.27, 95% CI: 4.00-6.94, three and more: adjusted ROR 16.46, 95% CI: 11.38-23.80). There was no significant association between NSAIDs' half-lives and reporting of AKI (adjusted ROR=0.54, 95% CI: 0.25-1.15). Given the widespread use of these hazardous drugs in general population, caution is needed when they are associated.

  2. Safety of selective cyclooxygenase-2 inhibitors and a basic non-steroidal anti-inflammatory drug (NSAID) in Japanese patients with NSAID-induced urticaria and/or angioedema: Comparison of meloxicam, etodolac and tiaramide.

    PubMed

    Inomata, Naoko; Osuna, Hiroyuki; Yamaguchi, Junko; Onoda, Masahito; Takeshita, Yoshihiro; Chiba, Yoshiyuki; Kambara, Takeshi; Ikezawa, Zenro

    2007-03-01

    The identification of a safe and reliable alternative for patients with non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema is a frequent problem for dermatologists and other practitioners. Cyclooxygenase-2 (COX-2) inhibitors have been reported to be safe for NSAID-intolerant patients from the US and Europe but not all of them have yet been approved for use in Japan. It was our objective to investigate the clinical manifestations of oral NSAID challenges in Japanese patients with histories of urticaria and/or angioedema after the intake of NSAIDs and to find safe alternative drugs, including COX-2 inhibitors and a basic anti-inflammatory drug. Twenty subjects suspected NSAID-induced urticaria/angioedema from histories were included in a double-blind or single-blind, placebo-controlled oral challenge protocol using NSAIDs. Skin prick tests using NSAIDs, which were dissolved in saline, were conducted. The mean age of the patients was 37.3 years; 14 patients were female. The results of other challenge tests showed that the most frequently intolerated drugs was loxoprofen (100%), followed by acetyl salicylic (94.4%), etodolac (53.3%), dicrofenac (50%), acetaminophen (38.5%), meloxicam (33%), and tiaramide (21.4%). Urticaria and angioedema were induced after aspirin intake in 83.3% and 22.2% of patients, respectively, whereas an asthmatic response was seen in 5.6%. Skin prick tests with NSAIDs were 100% negative. This study showed that among the NSAIDs that are available in Japan and that were investigated in this study, tiaramide, which does not inhibit COX, is the relatively safe alternative drug for Japanese patients with NSAID-induced urtiacaria and/or angioedema. Furthermore, meloxicam seems to be better tolerated than etodolac between two selective COX-2 inhibitors.

  3. Molecular interactions between some non-steroidal anti-inflammatory drugs (NSAID's) and bovine (BSA) or human (HSA) serum albumin estimated by means of isothermal titration calorimetry (ITC) and frontal analysis capillary electrophoresis (FA/CE).

    PubMed

    Ràfols, Clara; Zarza, Sílvia; Bosch, Elisabeth

    2014-12-01

    The interactions between some non-steroidal anti-inflammatory drugs, NSAIDs, (naproxen, ibuprofen and flurbiprofen) and bovine (BSA) or human (HSA) serum albumin have been examined by means of two complementary techniques, isothermal titration calorimetry (ITC) and frontal analysis/capillary electrophoresis (FA/CE). It can be concluded that ITC is able to measure with high precision the strongest drug-albumin interactions but the higher order interactions can be better determined by means of FA/CE. Then, the combination of both techniques leads to a complete evaluation of the binding profiles between the selected NSAIDs and both kind of albumin proteins. When BSA is the binding protein, the NSAIDs show a strong primary interaction (binding constants: 1.5 × 10(7), 8 × 10(5) and 2 × 10(6) M(-1) for naproxen, ibuprofen and flurbiprofen, respectively), and also lower affinity interactions of the same order for the three anti-inflammatories (about 1.7 × 10(4) M(-1)). By contrast, when HSA is the binding protein two consecutive interactions can be observed by ITC for naproxen (9 × 10(5) and 7 × 10(4) M(-1)) and flurbiprofen (5 × 10(6) and 6 × 10(4) M(-1)) whereas only one is shown for ibuprofen (9 × 10(5) M(-1)). Measurements by FA/CE show a single interaction for each drug being the ones of naproxen and flurbiprofen the same that those evaluated by ITC as the second interaction events. Then, the ability of both techniques as suitable complementary tools to establish the whole interaction NSAIDs-albumin profile is experimentally demonstrated and allows foreseeing suitable strategies to establish the complete drug-protein binding profile. In addition, for the interactions analyzed by means of ITC, the thermodynamic signature is established and the relative contributions of the enthalpic and entropic terms discussed.

  4. Screening procedure for detection of non-steroidal anti-inflammatory drugs and their metabolites in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons by gas chromatography-mass spectrometry after extractive methylation.

    PubMed

    Maurer, H H; Tauvel, F X; Kraemer, T

    2001-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic and anti-rheumatic drugs, and they are often misused. A gas chromatographic-mass spectrometric (GC-MS) screening procedure was developed for their detection in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons after extractive methylation. The compounds were separated by capillary GC and identified by computerized MS in the full-scan mode. Using mass chromatography with the ions m/z 119, 135, 139, 152, 165, 229, 244, 266, 272, and 326, the possible presence of NSAIDs and their metabolites could be indicated. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with the reference spectra recorded during this study. This method allowed the detection of therapeutic concentrations of acemetacin, acetaminophen (paracetamol), acetylsalicylic acid, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, indometacin, kebuzone, ketoprofen, lonazolac, meclofenamic acid, mefenamic acid, mofebutazone, naproxen, niflumic acid, phenylbutazone, suxibuzone, tiaprofenic acid, tolfenamic acid, and tolmetin in urine samples. The overall recoveries of the different NSAIDs ranged between 50 and 80% with coefficients of variation of less than 15% (n = 5), and the limits of detection of the different NSAIDs were between 10 and 50 ng/mL (S/N = 3) in the full-scan mode. Extractive methylation has proved to be a versatile method for STA of various acidic drugs, poisons, and their metabolites in urine. It has also successfully been used for plasma analysis.

  5. Species difference in the inhibitory potentials of non-steroidal anti-inflammatory drugs on the hepatic sulfation and glucuronidation of bioactive flavonoids: differential observations among common inhibition parameters.

    PubMed

    Fong, Sophia Yui Kau; Zuo, Zhong

    2014-05-01

    1. This study elucidated the species differences between rats and humans in the inhibitory potential of drugs against sulfation and glucuronidation, and whether such differences depend on the inhibition parameter adopted. 2. With 14 non-steroidal anti-inflammatory drugs (NSAIDs) as model inhibitors and three flavanoids baicalein, wogonin and oroxylin A as model substrates, three common inhibition parameters percentage of control, IC50 and Ki were determined in rat liver cytosols (RLCs), human liver cytosols (HLCs), rat liver microsomes (RLMs) and human liver microsomes (HLMs). The closeness of the inhibition parameters from rat liver preparations to that from human liver preparations was analyzed by geometric mean fold error (GMFE) and statistical comparisons. 3. The percentage of control in RLC/RLM was not significantly different from that in HLC/HLM, with a GMFE of 0.85 (RLC-HLC) and 1.03 (RLM-HLM); whereas the IC50 and Ki in RLC/RLM were significantly different from that in HLC/HLM. The trend of difference was consistent between IC50 and Ki, where these parameters in RLC and RLM underestimated (GMFE <0.5) and overestimated (GMFE >2) that in HLC and HLM, respectively. 4. In conclusion, the inhibitory potentials of NSAIDs against sulfation and glucuronidation in rats and humans were different and depended on the adopted inhibition parameters.

  6. Use of Fixed Dose Combination (FDC) Drugs in India: Central Regulatory Approval and Sales of FDCs Containing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Metformin, or Psychotropic Drugs

    PubMed Central

    McGettigan, Patricia; Roderick, Peter; Mahajan, Rushikesh; Kadam, Abhay; Pollock, Allyson M.

    2015-01-01

    Background In 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states’ powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics). Methods and Findings This was an ecologic study with a time-trend analysis of FDC sales volumes (2007–2012) and a cross-sectional examination of 2011–2012 data to establish the numbers of formulations on the market with and without a record of CDSCO approval (“approved” and “unapproved”), their branded products, and sales volumes. Data from the CDSCO on approved FDC formulations were compared with sales data from PharmaTrac, a database of national drug sales. We determined the proportions of FDC sales volumes (2011–2012) arising from centrally approved and unapproved formulations and from formulations including drugs banned/restricted internationally. We also determined the proportions of centrally approved and unapproved formulations marketed before and after 1 May 2002, when amendments were made to the drug rules. FDC approvals in India, the United Kingdom (UK), and United States of America (US) were compared. For NSAID FDCs, 124 formulations were marketed, of which 34 (27%) were centrally approved and 90 (73%) were unapproved; metformin: 25 formulations, 20 (80%) approved, five (20%) unapproved; anti-depressants/benzodiazepines: 16 formulations, three (19%) approved, 13 (81%) unapproved

  7. In situ aqueous derivatization and determination of non-steroidal anti-inflammatory drugs by salting-out-assisted liquid-liquid extraction and gas chromatography-mass spectrometry.

    PubMed

    Noche, Gloria Grueiro; Laespada, María Esther Fernández; Pavón, José Luis Pérez; Cordero, Bernardo Moreno; Lorenzo, Soledad Muniategui

    2011-09-16

    A new analytical method for the determination of trace levels of five non-steroidal anti-inflammatory drugs (NSAIDs: clofibric acid, ibuprofen, naproxen, diclofenac and ketoprofen) in water samples is described. The analytical procedure involves in situ aqueous derivatization with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and 2,2,2-trifluoroethylamine hydrochloride (TFEA) and salting-out liquid-liquid extraction (SALLE), followed by gas chromatography-programmed temperature vaporizer-mass spectrometry (GC-PTV-MS). The influence of several parameters on the efficiency of the derivatization (stirring time, reaction time, reagent concentration and pH), and the extraction (solvent, volume, salts and stirring time) and injection steps (liner, injection volume, liner temperature, injection time, venting time and venting flow) was investigated. The detection limits of the method in water varied from 0.042 μg/L for ibuprofen to 1.2 μg/L for ketoprofen. The relative standard deviations (RSD) values were found to be relatively low (<10% for all compounds). The methodology developed was applied to the determination of NSAIDs in several environmental matrices including tap, river, sea and influent and effluent waste water samples. The results obtained show the presence of ibuprofen and naproxen in the influent waste water sample.

  8. In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDP-glucuronosyltransferase 1A9--potent inhibition by niflumic acid.

    PubMed

    Mano, Yuji; Usui, Takashi; Kamimura, Hidetaka

    2006-01-01

    The inhibitory potencies of non-steroidal anti-inflammatory drugs (NSAIDs) on UDP-glucuronosyltransferase (UGT) 1A9 activity were investigated in recombinant human UGT1A9 using 4-methylumbelliferone (4-MU) as a substrate for glucuronidation. 4-MU glucuronidation (4-MUG) showed Michaelis-Menten kinetics with a Km value of 6.7 microM. The inhibitory effects of the following seven NSAIDs were investigated: acetaminophen, diclofenac, diflunisal, indomethacin, ketoprofen, naproxen and niflumic acid. Niflumic acid had the most potent inhibitory effect on 4-MUG with an IC50 value of 0.0341 microM. The IC50 values of diflunisal, diclofenac and indomethacin were 1.31, 24.2, and 34.1 microM, respectively, while acetaminophen, ketoprofen and naproxen showed less potent inhibition. Niflumic acid, diflunisal, diclofenac and indomethacin inhibited 4-MUG competitively with Ki values of 0.0275, 0.710, 53.3 and 69.9 microM, respectively, being similar to each IC50 value. In conclusion, of the seven NSAIDs investigated, niflumic acid was the most potent inhibitor of recombinant UGT1A9 via 4-MUG in a competitive manner.

  9. Analysis of non-steroidal anti-inflammatory drugs in milk using QuEChERS and liquid chromatography coupled to mass spectrometry: triple quadrupole versus Q-Orbitrap mass analyzers.

    PubMed

    Rúbies, Antoni; Guo, Lili; Centrich, Francesc; Granados, Mercè

    2016-08-01

    We developed a Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method for the high throughput determination of 10 non-steroidal anti-inflammatory drugs (NSAIDs) in milk samples using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) with a triple quadrupole (QqQ) instrument and an electrospray ionization (ESI) source. The new extraction procedure is highly efficient, and we obtained absolute recoveries in the range 78.1-97.1 % for the extraction and clean-up steps. Chromatographic separation is performed in the gradient mode with a biphenyl column and acidic mobile phases consisting of water and acetonitrile containing formic acid. The chromatographic run time was about 12 min, and NSAID peaks showed a good symmetry factor. For MS/MS detection, we used multiple reaction monitoring (MRM) mode, using ESI in both positive and negative modes. Our method has been validated in compliance with the European Commission Decision 657/2002/EC, and we obtained very satisfactory results in inter-laboratory testing. Furthermore, we explored the use of a hybrid high resolution mass spectrometer, combining a quadrupole and an Orbitrap mass analyzer, for high resolution (HR) MS/MS detection of NSAIDs. We achieved lower NSAID quantification limits with Q-Orbitrap high resolution mass spectrometry (HRMS/MS) detection than those achieved with the QqQ instrument; however, its main feature is its very high selectivity, which makes HRMS/MS particularly suitable for confirmatory analysis.

  10. Gastric cytoprotection of the non-steroidal anti-inflammatory sesquiterpene, beta-caryophyllene.

    PubMed

    Tambe, Y; Tsujiuchi, H; Honda, G; Ikeshiro, Y; Tanaka, S

    1996-10-01

    The gastric cytoprotective effect of beta-caryophyllene, an anti-inflammatory sesquiterpene, was investigated in rats. The oral administration of beta-caryophyllene to rats significantly inhibited gastric mucosal injuries induced by necrotizing agents such as absolute ethanol and 0.6 N HCl, although it failed to prevent water immersion stress- and indomethacin-induced gastric lesions. In addition, this compound hardly affected the secretion of gastric acid and pepsin. Thus, beta-caryophyllene elicited anti-inflammatory effects without any indication of gastric mucosal damage typical of non-steroidal anti-inflammatory agents. Furthermore, this compound manifested cytoprotective effects, rendering the two-dimensional efficacious beta-caryophyllene to be a clinically safe and potentially useful agent.

  11. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis

    PubMed Central

    Roubille, Camille; Richer, Vincent; Starnino, Tara; McCourt, Collette; McFarlane, Alexandra; Fleming, Patrick; Siu, Stephanie; Kraft, John; Lynde, Charles; Pope, Janet; Gulliver, Wayne; Keeling, Stephanie; Dutz, Jan; Bessette, Louis; Bissonnette, Robert; Haraoui, Boulos

    2015-01-01

    The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010–2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk. PMID:25561362

  12. Design and Concept of Polyzwitterionic Copolymer Microgel Drug Delivery Systems In Situ Loaded with Non-steroidal Anti-inflammatory Ibuprofen.

    PubMed

    Kostova, Bistra; Kamenska, Elena; Georgieva, Dilyana; Balashev, Konstantin; Rachev, Dimitar; Georgiev, George

    2017-01-01

    Nowadays, the modern pharmaceutical investigations are directed toward obtaining of new polymer micro- and nano-sized drug delivery carriers. In this respect, the use of hydrogel carriers based on polyzwitterions (PZIs) is an opportunity in the preparation of polymer drug delivery systems with desired characteristics. This paper describes the synthesis and characterization of micro-structured p(VA-co-DMAPS) systems with different compositions in situ loaded with Ibuprofen by emulsifier-free emulsion copolymerization (EEC) in water. The mean size of the prepared microparticles was measured by SEM and particles have been visualized by AFM. The inclusion of Ibuprofen in the polyzwitterionic copolymer microgel systems was established by using DSC. In vitro drug release experiments were carried out in order to estimate the ability of the obtained microgels to modify the release of water-insoluble Ibuprofen.

  13. Chemoprevention of 1,2-dimethylhydrazine-induced colon carcinogenesis by a non-steroidal anti-inflammatory drug, etoricoxib, in rats: inhibition of nuclear factor kappaB.

    PubMed

    Tanwar, Lalita; Vaish, Vivek; Sanyal, S N

    2009-01-01

    Etoricoxib, a highly selective cyclooxygenase- 2 (COX-2) inhibitor (a non steroidal anti-inflammatory drug) used for the treatment of rheumatoid arthritis and osteoarthritis, has been newly marketed and studied for the chemopreventive response in the 1,2-dimethylhydrazine dihydrochloride (DMH) induced rat colon cancer model. Male Sprague-Dawley rats were divided into four groups. Group I served as the Control and received the vehicle treatment, while Groups 2 and 3 were administered freshly prepared DMH (30 mg/kg body weight, subcutaneously) in 1mM EDTA-saline (pH 7.0). Groups 3 and 4 received Etoricoxib (0.64 mg/kg body weight, orally) daily prepared in 0.5% carboxymethyl cellulose. After a 6 week treatment period, animals were sacrificed and the colons were subjected to macroscopic and histopathological studies. Well characterized pre-neoplastic features such as multiple plaque lesions (MPLs), aberrant crypts (ACs) and aberrant crypt foci (ACF) were found in the DMH group. The number was reduced in DMH + Etoricoxib group, while very few MPLs and ACFs were recorded in the Etoricoxib only group. Also, histologically well characterized dysplasia and hyperplasia were observed in DMH treated group. The simultaneous administration of DMH and Etoricoxib reduced these features. To study apoptosis, colonocytes were isolated by metal chelation from colonic sacs and studied by fluorescent staining. The DMH treated animals produced much less apoptotic nuclei as compared to the Control. The number of apoptotic nuclei was also found higher in the DMH + Etoricoxib group as well as in Etoricoxib only group. Studies of a nuclear transcription factor (NF-kB) and COX-2 by Western blot analysis and immunohistochemistry demonstrated expression of both to be elevated in the DMH treated group but reduced in the DMH + Etoricoxib group. Expression was also low in the Etoricoxib only group. It may be concluded that the drug, Etoricoxib, has the potential to reduce DMH induced colon cancer

  14. Non-steroidal anti-inflammatory drugs activate NADPH oxidase in adipocytes and raise the H2O2 pool to prevent cAMP-stimulated protein kinase a activation and inhibit lipolysis

    PubMed Central

    2013-01-01

    Background Non-steroidal anti-inflammatory drugs (NSAIDs) —aspirin, naproxen, nimesulide, and piroxicam— lowered activation of type II cAMP-dependent protein kinase A (PKA-II) in isolated rat adipocytes, decreasing adrenaline- and dibutyryl cAMP (Bt2cAMP)-stimulated lipolysis. The molecular bases of insulin-like actions of NSAID were studied. Results Based on the reported inhibition of lipolysis by H2O2, catalase was successfully used to block NSAID inhibitory action on Bt2cAMP-stimulated lipolysis. NSAID, at (sub)micromolar range, induced an H2O2 burst in rat adipocyte plasma membranes and in whole adipocytes. NSAID-mediated rise of H2O2 was abrogated in adipocyte plasma membranes by: diphenyleneiodonium, an inhibitor of NADPH oxidase (NOX); the NOX4 antibody; and cytochrome c, trapping the NOX-formed superoxide. These three compounds prevented the inhibition of Bt2cAMP-stimulated lipolysis by NSAIDs. Inhibition of aquaporin-mediated H2O2 transport with AgNO3 in adipocytes allowed NOX activation but prevented the lipolysis inhibition promoted by NSAID: i.e., once synthesized, H2O2 must reach the lipolytic machinery. Since insulin inhibits adrenaline-stimulated lipolysis, the effect of aspirin on isoproterenol-stimulated lipolysis in rat adipocytes was studied. As expected, isoproterenol-mediated lipolysis was blunted by both insulin and aspirin. Conclusions NSAIDs activate NOX4 in adipocytes to produce H2O2, which impairs cAMP-dependent PKA-II activation, thus preventing isoproterenol-activated lipolysis. H2O2 signaling in adipocytes is a novel and important cyclooxygenase-independent effect of NSAID. PMID:23718778

  15. Removal of endocrine disruptors and non-steroidal anti-inflammatory drugs through wastewater chlorination: the effect of pH, total suspended solids and humic acids and identification of degradation by-products.

    PubMed

    Noutsopoulos, Constantinos; Koumaki, Elena; Mamais, Daniel; Nika, Maria-Christina; Bletsou, Anna A; Thomaidis, Nikolaos S

    2015-01-01

    Endocrine disrupting chemicals (EDCs) and non-steroidal anti-inflammatory drugs (NSAIDs) are two groups of emerging pollutants the significance of which rests on their persistent detection in the aquatic environment and their possible adverse effects. Wastewater treatment plants are one of the major ways for transporting such chemicals in the aquatic environment. Chlorination is usually the last stage of treatment before wastewater being disposed to the aquatic environment. This work focuses on the evaluation of the effect of chlorine dose and specific wastewater characteristics (pH, total suspended solids and humic acids) on the removal of target EDCs and NSAIDs through chlorination. Another objective of this study is the identification of chlorination by-products of specific EDCs and NSAIDs and their dependence on contact time. Based on the results it is concluded that the effect of chlorine dose and humic acids concentration on the degradation of target compounds during chlorination is minimal. On the contrary, pH is a critical parameter which highly affects process performance. Moreover, it is concluded that not only the free available chlorine species, but also the properties of EDCs and NSAIDs under different pH conditions can affect chlorination process performance. The effect of TSS on the degradation of the target compounds during chlorination is more profound for chemicals with high Kow values and therefore higher affinity to partition to the particulate phase (i.e. nonylphenols, triclosan). Several degradation by-products were identified through chlorination of nonylphenol, bisphenol A and diclofenac. The dependence of these by-products on chlorination contact time is also demonstrated.

  16. Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: Increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL.

    PubMed

    Woo, Jong Kyu; Kang, Ju-Hee; Jang, Yeong-Su; Ro, Seonggu; Cho, Joong Myung; Kim, Hwan-Mook; Lee, Sang-Jin; Oh, Seung Hyun

    2015-04-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested as the potential new class of preventive or therapeutic antitumor agents. The aim of the present study was to evaluate the antitumor activity of the novel NSAID, CG100649. CG100649 is a novel NSAID dual inhibitor for COX-2 and carbonic anhydrase (CA)-I/-II. In the present study, we investigated the alternative mechanism by which CG100649 mediated suppression of the colon cancer growth and development. The anchorage‑dependent and -independent clonogenic assay showed that CG100649 inhibited the clonogenicity of human colon cancer cells. The flow cytometric analysis showed that CG100649 induced the G2/M cell cycle arrest in colon cancer cells. Animal studies showed that CG100649 inhibited the tumor growth in colon cancer xenograft in nude mice. Furthermore, quantitative PCR and FACS analysis demonstrated that CG100649 upregulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4 and DR5) but decreased the expression of decoy receptors (DcR1 and DcR2) in colon cancer cells. The results showed that CG100649 treatment sensitized TRAIL‑mediated growth suppression and apoptotic cell death. The combination treatment resulted in significant repression of the intestinal polyp formation in APCmin/+ mice. Our data clearly demonstrated that CG100649 contains preventive and therapeutic activity for colon cancer. The present study may be useful for identification of the potential benefit of the NSAID CG100649, for the achievement of a better treatment response in colon cancer.

  17. The proinflammatory function of lymphocytes in non-immune inflammation: effect of steroidal and non-steroidal anti-inflammatory agents.

    PubMed Central

    Leme, J. G.; Bechara, G. H.; Sudo, L. S.

    1977-01-01

    Leucopenia rendered rats unresponsive to various inflammatory stimuli. The intensity of the inflammatory response in such animals was restored by i.v. administration of suspensions of lymphocytes, but not of granulocytes. This restorative effect was blocked by both steroidal and non-steroidal anti-inflammatory drugs. Utilizing carrageenin to induce inflammatory responses in the rat's paw, the effect of these drugs on lymphocytes was observed in two circumstances. First, following incubation of the cells with the drugs in concentrations not exceeding the peak plasma levels estimated for these substances in man or laboratory animals; the effect of the drugs seemed selective, since anti-histamine and anti-serotonin agents, as well as amethopterin, were devoid of action. Second, when lymphocytes were collected from rats previously treated with the various anti-inflammatory agents, injected 6-hourly during periods of 18 and 36 h, respectively, for steroidal and non-steroidal anti-inflammatory substances. The total amounts given were lower than those required to produce consistent anti-inflammatory effects in normal animals, when the drug was given as a single dose before injection of the irritant. It is concluded that the pro-inflammatory function of lymphocytes in non-immune inflammation can be blocked by steroidal and non-steroidal anti-inflammatory agents. PMID:607989

  18. The attitudes of owners and veterinary professionals in the United Kingdom to the risk of adverse events associated with using non-steroidal anti-inflammatory drugs (NSAIDs) to treat dogs with osteoarthritis.

    PubMed

    Belshaw, Zoe; Asher, Lucy; Dean, Rachel S

    2016-09-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed by veterinary surgeons for the treatment of canine osteoarthritis, and affected dogs may receive these drugs for long periods of time. Whilst short term administration of NSAIDs to dogs is linked to adverse events such as gastrointestinal haemorrhage and renal injury, reports of adverse events associated with their long-term administration are limited in the veterinary literature. This study aimed to investigate the attitudes towards the long term use of NSAIDs for canine osteoarthritis held by three groups who manage osteoarthritic dogs in the United Kingdom: dog owners, veterinary surgeons and veterinary nurses. A qualitative methodology was adopted, using semi-structured interviews and focus groups. Thematic analysis of these data identified three themes: awareness of potential risks; recognition of adverse events; and influence of risk perception on the use of NSAIDs. Awareness of, and concern about, the risk of adverse events associated with NSAID administration to dogs with osteoarthritis was high in all groups, with veterinary surgeons being one of a variety of information sources used by owners to acquire this knowledge. Veterinary surgeons described difficulty in recognising, managing and avoiding adverse events associated with NSAIDs. When adverse events occurred, a wide range of management approaches were adopted ranging from a brief drug respite to permanent cessation of administration of any NSAIDs to that dog. Commonly employed approaches to minimise risk included dose reduction and screening blood tests. This study describes a high level of concern about the risks associated with long term NSAID administration to dogs with osteoarthritis and highlights a diverse range of strategies employed to minimise these risks. The evidence base for these strategies is poor, and this may present a risk to animal welfare if the affected dogs are not receiving adequate analgesia. In order to

  19. Online eluent-switching technique coupled anion-exchange liquid chromatography–ion trap tandem mass spectrometry for analysis of non-steroidal anti-inflammatory drugs in pig serum.

    PubMed

    Chang, Kai Chun; Lin, Jyh Shiun; Cheng, Cheanyeh

    2015-11-27

    A novel method for online extraction, pH-gradient separation, and analysis of nine non-steroidal anti-inflammatory drugs (NSAIDs) was developed by coupling online eluent-switching technique to single anion-exchange chromatographic column/ion trap mass spectrometer (MS) and used for monitoring NSAIDs residues in pig serum. A neutral eluent and a pH-gradient eluent were used for extraction and separation of NSAIDs, respectively. Each of nine NSAIDs has an MS precursor ion of either [M−H]− or [M−Na]−. The extracted ion chromatogram for a specific product ion of each NSAID was used for its quantitative analysis. The dynamic linear ranges of calibration curves were all 0–200 ng mL−1 (R2 > 0.9950). The analysis accuracies estimated by spiking standard concentrations at 20, 100, and 200 ng mL−1 were 80.5–99.9%. The corresponding intra-day and inter-day precisions (RSD%) were 2.5–14.5% and 2.9–15.2%, respectively. The limit of detection/limit of quantitation of NSAIDs were 1.3/4.3, 0.5/1.6, 0.2/0.5, 2.5/8.2, 1.5/4.9, 0.6/2.1, 0.6/2.0, 0.5/1.7, and 0.6/2.1 ng mL−1 for carprofen, diclofenac, flunixin, ibuprofen, ketoprofen, meclofenamic acid sodium, mefenamic acid, niflumic acid, and tolfenamic acid, respectively. After 1 h injection of a dose containing 2 mg kg−1 weight pig of flunixin and tolfenamic acid to the pigs, a residue amount of 3480 ± 36 ng mL−1 and 431 ± 13 ng mL−1, respectively, was reached for the incurred pig serum specimens and both residues were reduced to about 20 ng mL−1 at the time of 24 h.

  20. Safety and efficacy of long-term esomeprazole 20 mg in Japanese patients with a history of peptic ulcer receiving daily non-steroidal anti-inflammatory drugs

    PubMed Central

    2013-01-01

    Background Non-steroidal anti-inflammatory drugs (NSAIDs) are an effective and common treatment for chronic pain disorders, but long-term use is associated with risk of potentially life-threatening gastrointestinal adverse events (AEs). The proton pump inhibitor esomeprazole has been found to be effective for gastroprotection in NSAID users, but few long-term studies have been conducted in Japan. Methods This was an open-label, multicentre, single-arm, prospective 1-year study of treatment with esomeprazole (20 mg once daily) in Japanese patients (aged ≥20 years) with endoscopic evidence of previous peptic ulcer and receiving daily oral NSAID therapy (at a stable dose) for a chronic condition. Eligibility was not dictated by type of oral NSAID. The primary objective was to determine long-term safety and tolerability of esomeprazole. Efficacy for prevention of peptic ulcers was also determined (Kaplan-Meier method). All statistical analyses were descriptive. Results A total of 130 patients (73.1% women, mean age 62.1 years, 43.8% Helicobacter pylori-positive) received treatment with esomeprazole in addition to long-term NSAID therapy (most commonly for rheumatoid arthritis [n=42] and osteoarthritis [n=34]). Loxoprofen, meloxicam and diclofenac were the most commonly used NSAIDs; cyclo-oxygenase (COX)-2 selective agents were used by 16.2% of patients (n=21). Long-term compliance with esomeprazole (capsule counts) was >75% for the majority of patients. Although 16.9% of patients (n=22) experienced AEs judged to be possibly related to treatment with esomeprazole, they were mostly mild and transient. The most commonly reported possibly treatment-related AEs were abnormal hepatic function, headache, increased γ-glutamyltransferase levels and muscle spasms (2 patients each). Overall, 95.9% (95% confidence interval: 92.3, 99.4) of patients remained ulcer free at 1 year. Conclusion Long-term treatment with esomeprazole (20 mg once daily) is well tolerated and

  1. The effect of a non-steroidal anti-inflammatory drug on two important predictors for accidental falls: postural balance and manual reaction time. A randomized, controlled pilot study.

    PubMed

    Hegeman, Judith; Nienhuis, Bart; van den Bemt, Bart; Weerdesteyn, Vivian; van Limbeek, Jacques; Duysens, Jacques

    2011-04-01

    Accidental falls in older individuals are a major health and research topic. Increased reaction time and impaired postural balance have been determined as reliable predictors for those at risk of falling and are important functions of the central nervous system (CNS). An essential risk factor for falls is medication exposure. Amongst the medications related to accidental falls are the non-steroidal anti-inflammatory drugs (NSAIDs). About 1-10% of all users experience CNS side effects. These side effects, such as dizziness, headaches, drowsiness, mood alteration, and confusion, seem to be more common during treatment with indomethacin. Hence, it is possible that maintenance of (static) postural balance and swift reactions to stimuli are affected by exposure to NSAIDs, indomethacin in particular, consequently putting older individuals at a greater risk for accidental falls. The present study investigated the effect of a high indomethacin dose in healthy middle-aged individuals on two important predictors of falls: postural balance and reaction time. Twenty-two healthy middle-aged individuals (59.5 ± 4.7 years) participated in this double-blind, placebo-controlled, randomized crossover trial. Three measurements were conducted with a week interval each. A measurement consisted of postural balance as a single task and while concurrently performing a secondary cognitive task and reaction time tasks. For the first measurement indomethacin 75 mg (slow-release) or a visually identical placebo was randomly assigned. In total, five capsules were taken orally in the 2.5 days preceding assessment. The second measurement was without intervention, for the final one the first placebo group got indomethacin and vice versa. Repeated measures GLM revealed no significant differences between indomethacin, placebo, and baseline in any of the balance tasks. No differences in postural balance were found between the single and dual task conditions, or on the performance of the dual task

  2. Simultaneous analysis of non-steroidal anti-inflammatory drugs using electrochemically controlled solid-phase microextraction based on nanostructure molecularly imprinted polypyrrole film coupled to ion mobility spectrometry.

    PubMed

    Ameli, Akram; Kalhor, Hamideh; Alizadeh, Naader

    2013-06-01

    A simple, rapid, and highly sensitive method for simultaneous analysis of anti-inflammatory drugs (naproxen, ibuprofen, and mefenamic acid) in diluted human serum was developed using the electrochemically controlled solid-phase microextraction coupled to ion mobility spectrometry. A conducting molecularly imprinted polymer film based on polypyrrole was synthesized for the selective uptake and release of drugs. The film was prepared by incorporation of a template molecule (naproxen) during the electropolymerization of pyrrole onto a platinum electrode using cyclic voltammetry method. The measured ion mobility spectrometry intensity was related to the concentration of analytes taken up into the films. The calibration graphs (naproxen, ibuprofen, and mefenamic acid) were linear in the range of 0.1-30 ng/mL and detection limits were 0.07-0.37 ng/mL and relative standard deviation was lower than 6%. On the basis of the results obtained in this work, the conducting molecularly imprinted polymer films as absorbent have been applied in the electrochemically controlled solid-phase microextraction and ion mobility spectrometry system for the selective clean-up and quantification of trace amounts of anti-inflammatory drugs in human serum samples. Scanning electron microscopy has confirmed the nano-structure morphology of the polypyrrole film.

  3. Non-steroidal anti-inflammatory drugs as potent inhibitors of phospholipase A2: structure of the complex of phospholipase A2 with niflumic acid at 2.5 Angstroms resolution.

    PubMed

    Jabeen, Talat; Singh, Nagendra; Singh, Rajendra K; Sharma, Sujata; Somvanshi, Rishi K; Dey, Sharmistha; Singh, Tej P

    2005-12-01

    Phospholipase A(2) (PLA(2); EC 3.1.3.4) catalyzes the first step of the production of proinflammatory compounds collectively known as eicosanoids. The binding of phospholipid substrates to PLA(2) occurs through a well formed hydrophobic channel. Surface plasmon resonance studies have shown that niflumic acid binds to Naja naja sagittifera PLA(2) with an affinity that corresponds to a dissociation constant (K(d)) of 4.3 x 10(-5) M. Binding studies of PLA(2) with niflumic acid were also carried out using a standard PLA(2) kit that gave an approximate binding constant, K(i), of 1.26 +/- 0.05 x 10(-6) M. Therefore, in order to establish the viability of PLA(2) as a potential target molecule for drug design against inflammation, arthritis and rheumatism, the three-dimensional structure of the complex of PLA(2) with the known anti-inflammatory agent niflumic acid [2-[3-(trifluoromethyl)anilino]nicotinic acid] has been determined at 2.5 Angstroms resolution. The structure of the complex has been refined to an R factor of 0.187. The structure determination reveals the presence of one niflumic acid molecule at the substrate-binding site of PLA(2). It shows that niflumic acid interacts with the important active-site residues His48 and Asp49 through two water molecules. It is observed that the niflumic acid molecule is completely buried in the substrate-binding hydrophobic channel. The conformations of the binding site in PLA(2) as well as that of niflumic acid are not altered upon binding. However, the orientation of the side chain of Trp19, which is located at the entry of the substrate-binding site, has changed from that found in the native PLA(2), indicating its familiar role.

  4. Non-steroidal drug-induced glaucoma

    PubMed Central

    Razeghinejad, M R; Pro, M J; Katz, L J

    2011-01-01

    Numerous systemically used drugs are involved in drug-induced glaucoma. Most reported cases of non-steroidal drug-induced glaucoma are closed-angle glaucoma (CAG). Indeed, many routinely used drugs that have sympathomimetic or parasympatholytic properties can cause pupillary block CAG in individuals with narrow iridocorneal angle. The resulting acute glaucoma occurs much more commonly unilaterally and only rarely bilaterally. CAG secondary to sulfa drugs is a bilateral non-pupillary block type and is due to forward movement of iris–lens diaphragm, which occurs in individuals with narrow or open iridocorneal angle. A few agents, including antineoplastics, may induce open-angle glaucoma. In conclusion, the majority of cases with glaucoma secondary to non-steroidal medications are of the pupillary block closed-angle type and preventable if the at-risk patients are recognized and treated prophylactically. PMID:21637303

  5. Anti-inflammatory agents and inducibility of hepatic drug metabolism.

    PubMed

    Pappas, P; Stephanou, P; Vasiliou, V; Marselos, M

    1998-01-01

    Two rat liver cytosolic aldehyde dehydrogenases, ALDH1 and ALDH3c, are of particular interest because they are inducible by different classes of xenobiotics. ALDHI is mainly increased by phenobarbital-type inducers; polycyclic aromatic hydrocarbons (PAHs), such as 3- methylcholanthrene (3MC), increase ALDH3c enzyme activity in all rat species currently tested. In addition, ALDH3c has been found to reflect the subfamily CYPIA of cytochrome P-450, as well as other enzymes functionally related to the aryl hydrocarbon receptor (the "Ah-receptor enzyme battery"), which is activated by the same type of inducers. In the present study we investigated whether the induction of ALDH3c might be connected with a chemically produced aseptic inflammation of the hepatocyte. To answer this question, we examined the relationship between the induction of ALDH3c by 3MC and the arachidonic acid cascade. Different non-steroid anti-inflammatory drugs (NSAIDs) were tested in combination with 3MC and in post-treatment. The 3MC-induced ALDH3c activity was significantly diminished by the co-administered anti-inflammatory agents. Two microsomal enzyme activities (ethoxyresorufin-O-deethylase, EROD; aryl-hydrocarbon-hydroxylase, AHH) were also decreased. Similar results were obtained with NSAIDs administered to animals pre- treated with 3MC, as far as the ALDH3c activity was concerned, but not for the microsomal enzyme activity (EROD and AHH). In conclusion, the induction of ALDH3c, after PAH treatment, may be related to an aseptic inflammation of the hepatocytes. This effect is reduced by commonly used steroid and non-steroid anti- inflammatory drugs, and although the mechanism of inhibition has not yet been elucidated, it appears likely that ALDH3c and CYP1A activities are associated with the "acute phase" response.

  6. Nonsteroidal Anti-Inflammatory Drugs and the Kidney

    PubMed Central

    Hörl, Walter H.

    2010-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the isoenzymes COX-1 and COX-2 of cyclooxygenase (COX). Renal side effects (e.g., kidney function, fluid and urinary electrolyte excretion) vary with the extent of COX-2-COX-1 selectivity and the administered dose of these compounds. While young healthy subjects will rarely experience adverse renal effects with the use of NSAIDs, elderly patients and those with co-morbibity (e.g., congestive heart failure, liver cirrhosis or chronic kidney disease) and drug combinations (e.g., renin-angiotensin blockers, diuretics plus NSAIDs) may develop acute renal failure. This review summarizes our present knowledge how traditional NSAIDs and selective COX-2 inhibitors may affect the kidney under various experimental and clinical conditions, and how these drugs may influence renal inflammation, water transport, sodium and potassium balance and how renal dysfunction or hypertension may result. PMID:27713354

  7. The Effects of Topical Sesame (Sesamum indicum) Oil on Pain Severity and Amount of Received Non-Steroid Anti-Inflammatory Drugs in Patients With Upper or Lower Extremities Trauma

    PubMed Central

    Bigdeli Shamloo, Marzieh Beigom; Nasiri, Morteza; Dabirian, Aazam; Bakhtiyari, Ali; Mojab, Faraz; Alavi Majd, Hamid

    2015-01-01

    Background: Most patients with trauma experience different levels of pain. Due to side effects as well as economic burden of drugs used for pain relief after trauma commonly, it is important to use low-cost methods independently or combined with drugs to alleviate pain. Objectives: Therefore, this study aimed to investigate the effects of topical sesame oil on pain severity and frequency of received NSAIDs of patients with trauma. Patients and Methods: This randomized clinical trial study was conducted on 150 patients with upper or lower extremities trauma in Dezful Ganjavian Hospital, Ahvaz, Iran, in 2014. Data was collected by a researcher-made questionnaire and Visual Analogue Scale (VAS). Patients were divided into two groups of control (n = 75) and intervention (n = 75) randomly. In the intervention group, patients applied topical sesame oil beside the routine cares, while in the control group patients just received routine cares. Severity of pain and frequency of received NSAIDs was assessed in the first, third, seventh and tenth days after the intervention in the both groups. Data was analyzed by SPSS19 software using descriptive and analytic (Chi-square and independent sample t-test) statistical methods. Results: Based on student sample t-test, there was a significant difference between intervention and control groups regarding the pain severity in the first (P = 0.06), third (P = 0.001), seventh (P = 0.001) and tenth (P = 0.001) days after the intervention. Besides, the frequency of received NSAIDs in the intervention group and the control group showed significant difference in four days after the intervention (for four days P = 0.001). Conclusions: Topical application of sesame oil could reduce pain severity and frequency of received NSAIDs in patients with upper or lower extremities trauma. Therefore, it is recommended to use this oil in complementary medicine for pain relief due to low cost, easy usage and lack of adverse effects. PMID:26161326

  8. Pharmacokinetics and dosage regimens of anti-inflammatory drugs.

    PubMed

    Lees, P; May, S A; White, D

    1990-01-01

    The term anti-inflammatory drug, in its broadest sense, encompasses a number of very diverse compounds, ranging from steroids to non-steroidal anti-inflammatory drugs (NSAIDs) and from disease modifying agents (used in the treatment of canine rheumatoid arthritis) to chondroprotective agents (used in the treatment of osteoarthrosis and traumatic arthritis in the horse). For many of these drugs (eg, chondroprotective and disease modifying agents) the mode of action is unknown and even with steroids and NSAIDs there is no universal agreement on mechanism of action. It is therefore in many cases impossible to link pharmacokinetic data to a drug's pharmacodynamics, for example to an effect on a specific biochemical marker. Some agents, including corticosteroids, may have indirect modes of action, so that the pharmacodynamic half-life can be much longer than (and not clearly related to) the pharmacokinetic half-life. In other cases, clinical benefits may only become apparent after several weeks or even months. It can therefore be difficult or impossible to use classical pharmacokinetic approaches to set dosing intervals and dose rates for clinical use. To some extent, the position is more straightforward with NSAIDs. However, even with these drugs simple approaches are not possible and this paper will review briefly some of the studies undertaken in our laboratory which have attempted to utilize NSAID kinetics to set dosage schedules for clinical use.

  9. Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in rats.

    PubMed

    Sikiric, P; Seiwerth, S; Grabarevic, Z; Rucman, R; Petek, M; Jagic, V; Turkovic, B; Rotkvic, I; Mise, S; Zoricic, I; Konjevoda, P; Perovic, D; Simicevic, V; Separovic, J; Hanzevacki, M; Ljubanovic, D; Artukovic, B; Bratulic, M; Tisljar, M; Rekic, B; Gjurasin, M; Miklic, P; Buljat, G

    1997-01-01

    Besides a superior protection of the pentadecapeptide BPC 157 (an essential fragment of an organoprotective gastric juice peptide BPC) against different gastrointestinal and liver lesions, an acute anti-inflammatory and analgetic activity was also noted. Consequently, its effect on chronic inflammation lesions, such as adjuvant arthritis, and non-steroidal anti-inflammatory agents (NSAIAs)-induced gastrointestinal lesions was simultaneously studied in rats. In gastrointestinal lesions (indomethacin (30 mg/kg s.c.), aspirin (400 mg/kg i.g.) and diclofenac (125 mg/kg i.p.) studies, BPC 157 (10 micrograms or 10 ng/kg i.p.) was regularly given simultaneously and/or 1 h prior to drug application (indomethacin). In the adjuvant arthritis (tail-application of 0.2 mL of Freund's adjuvant) studies (14 days, 30 days, 1 year) BPC 157 (10 micrograms or 10 ng/kg i.p.), it was given as a single application (at 1 h either before or following the application of Freund's adjuvant) or in a once daily regimen (0-14th day, 14-30th day, 14th day-1 year). Given with the investigated NSAIAs, BPC 157 consistently reduced the otherwise prominent lesions in the stomach of the control rats, as well as the lesions in the small intestine in the indomethacin groups. In the adjuvant arthritis studies, the lesion's development seems to be considerably reduced after single pentadecapeptide medication, and even more attenuated in rats daily treated with BPC 157. As a therapy of already established adjuvant arthritis, its salutary effect consistently appeared already after 2 weeks of medication and it could be clearly seen also after 1 year of application. Taking together all these results, the data likely point to a special anti-inflammatory and mucosal integrity protective effect.

  10. Is carprofen, a non-steroidal anti-inflammatory analgesic, safe for use in Pekin ducks

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Carprofen (Rymadyl) is a common systemic analgesic used to relieve chronic pain states in dogs, such as osteoarthritis. There is no comparable drug recommended to treat pain, such as that originating from bill trimming procedures, in ducks. The aim of this study was to evaluate if carprofen could be...

  11. [Colonic stenosis secondary to non-steroid anti-inflammatory agents as a cause of anemia and chronic diarrhea].

    PubMed

    Remes-Troche, José María; Contreras-Zurita, Karina; Ríos-Luna, Nina Paola; Sierra-Ascencio, Manuel; Valdovinos, Angel Miguel

    2002-01-01

    Gastroduodenal mucosal injury is a widely recognized side effect of non-steroidal antiinflammatory agents (NSAID). Distal small bowel and colon are additional organs of the gastrointestinal tract exposed to deleterious effects of these drugs. Inflammation and ulceration have been described as pathologic damage associated with NSAID. Strictures of colon induced by NSAID are a new entity characterized by diaphragm-like strictures. Most patients present with anemia, obstructive symptoms, diarrhea, or weight loss. Endoscopic dilation, surgical resection, symptomatic treatment, and interruption of NSAID ingestion are treatment of choice. Only 23 cases of NSAID-related, colonic, diaphragm-like strictures have been reported. Here we describe a case of concentric colonic stricture related to naproxen and clinical features of this entity are discussed.

  12. [The role of cellular mediators in the development of the phenomenon of inhibition induced by barium sulfate luminol-dependent chemiluminescence of blood under the influence of non-steroidal anti-inflammatory drugs in patients with intolerance to these drugs].

    PubMed

    Chausova, S V; Gurevich, K G; Bondareva, G P; Filatov, O Ju; Malyshev, I Y

    2015-01-01

    We investigated contribution mediator mechanism in the development of the phenomenon of inhibition induced by barium sulfate luminol-dependent chemiluminescence (SLCHL) of blood under the influence of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with intolerance to these drugs. It was found that the phenomenon of suppression SLCHL blood under the influence of NSAIDs in patients with intolerance is mediated by the participation of mediators, and the contribution of H1--and H2--histamine receptors, 5-HT2 serotonin receptors and Cys-leukotriene receptors in the development of that phenomenon depends on the chemical nature of NSAIDs and the clinical manifestations of intolerance.

  13. Org 214007-0: A Novel Non-Steroidal Selective Glucocorticoid Receptor Modulator with Full Anti-Inflammatory Properties and Improved Therapeutic Index

    PubMed Central

    Laskewitz, Anke J.; Dijkema, Rein; van der Maaden, Hans M.; Smit, Martin J.; Plate, Ralf; Conti, Paolo G. M.; Jans, Christan G. J. M.; Timmers, C. Marco; van Boeckel, Constant A. A.; Lusher, Scott J.; McGuire, Ross; van Schaik, Rene C.; de Vlieg, Jacob; Smeets, Ruben L.; Hofstra, Claudia L.; Boots, Annemieke M. H.; van Duin, Marcel; Ingelse, Benno A.; Schoonen, Willem G. E. J.; Grefhorst, Aldo; van Dijk, Theo H.; Kuipers, Folkert; Dokter, Wim H. A.

    2012-01-01

    Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects. PMID:23152771

  14. Increased temperature and entropy production in cancer: the role of anti-inflammatory drugs.

    PubMed

    Pitt, Michael A

    2015-02-01

    Some cancers have been shown to have a higher temperature than surrounding normal tissue. This higher temperature is due to heat generated internally in the cancer. The higher temperature of cancer (compared to surrounding tissue) enables a thermodynamic analysis to be carried out. Here I show that there is increased entropy production in cancer compared with surrounding tissue. This is termed excess entropy production. The excess entropy production is expressed in terms of heat flow from the cancer to surrounding tissue and enzymic reactions in the cancer and surrounding tissue. The excess entropy production in cancer drives it away from the stationary state that is characterised by minimum entropy production. Treatments that reduce inflammation (and therefore temperature) should drive a cancer towards the stationary state. Anti-inflammatory agents, such as aspirin, other non-steroidal anti-inflammatory drugs, corticosteroids and also thyroxine analogues have been shown (using various criteria) to reduce the progress of cancer.

  15. Nonsteroidal Anti-inflammatory Drug Use in Horses.

    PubMed

    Knych, Heather K

    2017-04-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective anti-inflammatory and analgesic agents and are arguably the most commonly used class of drugs in equine medicine. This article provides a brief review of the mechanism of action, therapeutic uses, pharmacokinetics, and adverse effects associated with their use in horses. The use of COX-2 selective NSAIDs in veterinary medicine has increased over the past several years and special emphasis is given to the use of these drugs in horses. A brief discussion of the use of NSAIDs in performance horses is also included.

  16. Cannabinoids as novel anti-inflammatory drugs.

    PubMed

    Nagarkatti, Prakash; Pandey, Rupal; Rieder, Sadiye Amcaoglu; Hegde, Venkatesh L; Nagarkatti, Mitzi

    2009-10-01

    Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ9-tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.

  17. Bioengineered Colorectal Cancer Drugs: Orally Delivered Anti-Inflammatory Agents.

    PubMed

    Urbanska, Aleksandra Malgorzata; Zhang, Xiaoying; Prakash, Satya

    2015-07-01

    Intestinal inflammation is one of the major factors that increase colorectal cancer (CRC) incidence worldwide. Inflammation in the gastrointestinal tract is directly linked to tumor development at the early stages of the disease, thus a key issue toward the prevention and the treatment of colonic neoplasia. Thus, the use of anti-inflammatory drugs has emerged first as a strategy to reduce chronic inflammation in case of many inflammatory bowel diseases (IBD), but it has proven its efficacy by reducing the risk of colonic neoplasia. This comprehensive review highlights the role of chronic inflammation, mainly in IBD, in the development of CRC including molecular and immune mechanisms that have tumorigenic effects. Multiple lines of evidence indicate that several bioactive and phytochemical compounds used as anti-inflammatory drugs have also antitumoral attributes. The uses of orally delivered cytokines and small molecules, as well as key dietary supplementation as anti-inflammatory therapeutics are discussed. In addition, comprehensive knowledge about CRC and intestinal inflammation, and the importance of the intestinal mucosal wall as a mucosal immunological barrier that comes into play during interactions with gut microbiota (pathogens and commensal), luminal secretions (bile acids, and bacterial and epithelial metabolites), and ingested chemicals (food components, high fat content, heterocyclic amines, and low intake of dietary fiber) are underscored. The multifunctionality of several anti-inflammatory drugs opens a line for their application in the treatment and prevention not only in IBD but also in CRC. Current bioengineering approaches for oral delivery of anti-inflammatory agents including cytokines, genetically modified bacteria, or small molecule inhibitors of inflammation directly contribute to the early management of CRC. Limitations of the current therapeutics, which stem from the lack of complete understanding of the complex molecular interactions

  18. Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach

    PubMed Central

    Bosquesi, Priscila Longhin; Melo, Thais Regina Ferreira; Vizioli, Ednir Oliveira; dos Santos, Jean Leandro; Chung, Man Chin

    2011-01-01

    The design of new drugs with better physiochemical properties, adequate absorption, distribution, metabolism, and excretion, effective pharmacologic potency and lacking toxicity remains is a challenge. Inflammation is the initial trigger of several different diseases, such as Alzheimer's disease, asthma, atherosclerosis, colitis, rheumatoid arthritis, depression, cancer; and disorders such as obesity and sexual dysfunction. Although inflammation is not the direct cause of these disorders, inflammatory processes often increase related pain and suffering. New anti-inflammatory drugs developed using molecular hybridization techniques to obtain multiple-ligand drugs can act at one or multiple targets, allowing for synergic action and minimizing toxicity. This work is a review of new anti-inflammatory drugs developed using the molecular modification approach. PMID:27721332

  19. Effects of β-d-mannuronic acid, as a novel non-steroidal anti-inflammatory medication within immunosuppressive properties, on IL17, RORγt, IL4 and GATA3 gene expressions in rheumatoid arthritis patients

    PubMed Central

    Barati, Anis; Jamshidi, Ahmad Reza; Ahmadi, Hossein; Aghazadeh, Zahra; Mirshafiey, Abbas

    2017-01-01

    Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis characterized by pain, swelling and destruction of joints, with a resultant disability. Disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs can interfere with the disease process. In this study, the effect of β-d-mannuronic acid (M2000) as a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive and anti-inflammatory effects together with antioxidant effects was evaluated on IL17, RORγt, IL4 and GATA3 gene expression in 12 RA patients. Previously, M2000 driven from sodium alginate (natural product; patented, DEU: 102016113018.4) has shown a notable efficacy in experimental models of multiple sclerosis, RA and nephrotic syndrome. This study was performed on 12 patients with RA who had an inadequate response to conventional treatments. During this trial, patients were permitted to continue the conventional therapy excluding NSAIDs. M2000 was administered orally at a dose of 500 mg twice daily for 12 weeks. The peripheral blood mononuclear cells (PBMCs) were collected before and after treatment to evaluate the expression levels of IL4, GATA3, IL17 and RORγt. The gene expression results showed that M2000 has a potent efficacy, so that it could not only significantly decrease IL17 and RORγt levels but also increase IL4 and GATA3 levels after 12 weeks of treatment. Moreover, the gene expression results were in accordance with the clinical and preclinical assessments. In conclusion, M2000 as a natural novel agent has therapeutic and immunosuppressive properties on RA patients (identifier: IRCT2014011213739N2).

  20. Anti-inflammatory drugs and experimental bronchitis.

    PubMed

    Jeffery, P K

    1986-01-01

    Chronic bronchitis (chronic hypersecretion) and chronic bronchiolitis (small airways disease) are two conditions associated with cigarette smoking: both contribute to airflow obstruction in man, the latter associated with progressive deterioration in lung function. Mucous metaplasia and hyperplasia are characteristic histological changes. Experimentally, cigarette smoke given daily for two weeks, induces similar histological changes in the airways of specific pathogen-free rats, providing a suitable animal model for study: an early proliferation of basal cells, accompanied by mucous metaplasia of surface epithelial serous cells is followed by proliferation of newly formed mucous cells. There is also a significant increase in epithelial thickness due to cell hypertrophy without stratification or prior ulceration. Experimentally, secretory cell hyperplasia is inhibited completely or to varying degrees by prophylactic administration (intraperitoneal injection) of either indomethacin, flurbiprofen, dexamethasone, prednisolone, hydrocortisone (each at 2 or 4 mg/kg body weight) or a mucolytic drug, N-acetylcysteine(Nac), given orally as a 1% solution of the drinking water. Nac also inhibits the associated mucus-hypersecretion. It takes between 21 and 84 days, depending on airway level, for the increase in secretory cell number to return to control values (ie recover). Indomethacin and flurbiprofen (4 mg/kg, by ip injection) shorten recovery to between 4 and 9 days in intrapulmonary airways but have no effect on recovery time in the rat trachea. Nac is effective in 6 of 7 airway levels which showed cigarette smoke-induced mucous cell hyperplasia. In conclusion, in the rat, the response to cigarette smoke is one of mucous cell metaplasia and both basal and mucous cell proliferation. Cigarette smoke-induced mucous cell hyperplasia can be inhibited when selected drugs are given concurrently with the cigarette smoke: indomethacin, fluriprofen and Nac are also therapeutic.

  1. Anti-inflammatory and immunosuppressive drugs and reproduction

    PubMed Central

    Østensen, Monika; Khamashta, Munther; Lockshin, Michael; Parke, Ann; Brucato, Antonio; Carp, Howard; Doria, Andrea; Rai, Raj; Meroni, Pierluigi; Cetin, Irene; Derksen, Ronald; Branch, Ware; Motta, Mario; Gordon, Caroline; Ruiz-Irastorza, Guillermo; Spinillo, Arsenio; Friedman, Deborah; Cimaz, Rolando; Czeizel, Andrew; Piette, Jean Charles; Cervera, Ricard; Levy, Roger A; Clementi, Maurizio; De Carolis, Sara; Petri, Michelle; Shoenfeld, Yehuda; Faden, David; Valesini, Guido; Tincani, Angela

    2006-01-01

    Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given. PMID:16712713

  2. Aerosolized Surfactants, Anti-Inflammatory Drugs, and Analgesics.

    PubMed

    Willson, Douglas F

    2015-06-01

    Drug delivery by aerosol may have several advantages over other modes, particularly if the lung is the target organ. Aerosol delivery may allow achievement of higher concentrations while minimizing systemic effects and offers convenience, rapid onset of action, and avoidance of the needles and sterile technique necessary with intravenous drug administration. Aerosol delivery may change the pharmacokinetics of many drugs, however, and an awareness of the caveats of aerosolized drug delivery is mandatory to ensure both safety and adequate drug delivery. This paper discusses the administration of surfactants, anti-inflammatory agents, and analgesics by the aerosol route.

  3. Evaluation of anti-inflammatory drug-conjugated silicon quantum dots: their cytotoxicity and biological effect.

    PubMed

    Hanada, Sanshiro; Fujioka, Kouki; Futamura, Yasuhiro; Manabe, Noriyoshi; Hoshino, Akiyoshi; Yamamoto, Kenji

    2013-01-10

    Silicon quantum dots (Si-QDs) have great potential for biomedical applications, including their use as biological fluorescent markers and carriers for drug delivery systems. Biologically inert Si-QDs are less toxic than conventional cadmium-based QDs, and can modify the surface of the Si-QD with covalent bond. We synthesized water-soluble alminoprofen-conjugated Si-QDs (Ap-Si). Alminoprofen is a non-steroid anti-inflammatory drug (NSAID) used as an analgesic for rheumatism. Our results showed that the "silicon drug" is less toxic than the control Si-QD and the original drug. These phenomena indicate that the condensed surface integration of ligand/receptor-type drugs might reduce the adverse interaction between the cells and drug molecules. In addition, the medicinal effect of the Si-QDs (i.e., the inhibition of COX-2 enzyme) was maintained compared to that of the original drug. The same drug effect is related to the integration ratio of original drugs, which might control the binding interaction between COX-2 and the silicon drug. We conclude that drug conjugation with biocompatible Si-QDs is a potential method for functional pharmaceutical drug development.

  4. [Non-steroidal anti-inflammatory agents and pregnancy. A study of renal and digestive toxicity of niflumic acid in the perinatal period].

    PubMed

    Alessandri, J L; Abossolo, T; Reynaud, I; Montbrun, A; Sommer, J C; Tilmont, P

    1994-01-01

    We report a case of intrauterine exposure to niflumic acid in a preterm neonate (35 weeks of gestation). The mother received niflumic acid (750 mg daily) during the last four days of gestation. Severe oligohydramnios was present. A transient neonatal renal failure, but also abdominal complications were observed for several days. Maternal and neonate niflumic acid levels were studied and showed an important placental transfer. Niflumic acid is a prostaglandin synthetase inhibitor. It is important that the nephrotoxicity of this vasoactive drug be known. Maternal administration of niflumic acid during the last days of gestation can induce fetal and neonatal adverse effects, especially renal failure. Prescription of all nonsteroidal anti-inflammatory drugs must be very cautious during pregnancy.

  5. Layered double hydroxides as drug carriers and for controlled release of non-steroidal antiinflammatory drugs (NSAIDs): a review.

    PubMed

    Rives, Vicente; Del Arco, Margarita; Martín, Cristina

    2013-07-10

    Non-steroidal anti-inflammatory drugs constitute one of the groups most widely currently used, but show several problems for administration due to low solubility and delivery control. For this reason, several matrices have been tested to support them in order to overcome these drawbacks. Among them, layered double hydroxides have been used in recent years. The aim of this review is to update the current knowledge and findings on this hybrid system, namely, layered double hydroxides intercalated with different NSAIDs. The basic nature of the matrix introduces an additional advantage, i.e., to decrease ulceration damages. We have focused our review mostly on the preparation procedures, as these control, define and determine the performance of the systems in vitro and also in living organisms.

  6. Use of anti-inflammatory and analgesic drugs in dogs and cats.

    PubMed

    Watson, A D; Nicholson, A; Church, D B; Pearson, M R

    1996-09-01

    Responses (486) were collared from a survey of 5054 Australian veterinarians on their use of anti-inflammatory and analgesic drugs in dogs and cats. Almost all respondents used glucocorticoids (usually prednisolone) to treat allergic, pruritic dermatoses in dogs, while two-thirds also gave fatty acid supplements and one-half used antihistamines. Almost 60% of respondents initially injected a glucocorticoid (frequently a long-acting preparation) when treating inflammatory skin diseases in dogs. More than 90% of respondents used glucocorticoids to treat immune-mediated haemolytic anaemia or thrombocytopenia, and about one-third also gave cytotoxic drugs. Administration of prednisolone on alternate days was generally favoured for long-term enteral steroid therapy. Phenylbutazone was the most preferred treatment for painful or inflammatory musculoskeletal disorders of dogs, but aspirin and pentosan polysulphate were also used widely. Regarding the use of analgesics drugs generally, both narcotic analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) were used more widely in dogs than in cats, but alpha-2 agonists were used similarly in both species. The most commonly used narcotic analgesics were pethidine and buprenorphine in both species, while the NSAIDs used most often were flunixin and dipyrone in dogs and ketoprofen in cats. More than 80% of respondents generally used analgesic drugs with potentially painful surgical procedures, with doses given usually before anaesthetic recovery. Analgesic use rates varied with the condition, ranging from 94% for patients with acute severe trauma, through 60% for cruciate ligament repair and 29% for perineal herniorrahphy, to about 5% for ovariohysterectomy and dog castration. The three clinical signs most frequently nominated as indicators of pain in dogs and cats were (in descending order) vocalisation, response to handling or palpating the affected area, and mental depression. Other items mentioned frequently were

  7. COX-Independent Mechanisms of Cancer Chemoprevention by Anti-Inflammatory Drugs

    PubMed Central

    Gurpinar, Evrim; Grizzle, William E.; Piazza, Gary A.

    2013-01-01

    Epidemiological and clinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2 selective inhibitors, reduce the risk of developing cancer. Experimental studies in human cancer cell lines and rodent models of carcinogenesis support these observations by providing strong evidence for the antineoplastic properties of NSAIDs. The involvement of COX-2 in tumorigenesis and its overexpression in various cancer tissues suggest that inhibition of COX-2 is responsible for the chemopreventive efficacy of these agents. However, the precise mechanisms by which NSAIDs exert their antiproliferative effects are still a matter of debate. Numerous other studies have shown that NSAIDs can act through COX-independent mechanisms. This review provides a detailed description of the major COX-independent molecular targets of NSAIDs and discusses how these targets may be involved in their anticancer effects. Toxicities resulting from COX inhibition and the suppression of prostaglandin synthesis preclude the long-term use of NSAIDs for cancer chemoprevention. Furthermore, chemopreventive efficacy is incomplete and treatment often leads to the development of resistance. Identification of alternative NSAID targets and elucidation of the biochemical processes by which they inhibit tumor growth could lead to the development of safer and more efficacious drugs for cancer chemoprevention. PMID:23875171

  8. [Pharmacoepidemiological study of the use of non-steroid antiinflamatory drugs in high-risk cardiovascular patients].

    PubMed

    Machado-Alba, Jorge Enrique; Alzate-Carvajal, Verónica; Echeverri-Cataño, Luis

    2013-01-01

    In order to determine the frequency of extended use of non-steroidal anti-inflammatory drugs (NSAID) in Colombian patients with high cardiovascular risk (HCVR), a retrospective study was developed which identified HCVR patients who used NSAID for over five continuous months from January 2011 and March 2013. Patients chronically receiving nitrates, digitalis and clopidogrel and acetylsalicylic acid (ASA), known as HCVR, were identified. An analysis of the frequencies of use based on the co-medication received was performed. Concomitant use of NSAID was found in 0,35% of consumers of nitrates (average time: 9,5 ± 4,4 months), in 0,36% of consumers of clopidogrel and ASA (average time: 9,3 ± 3,4 months), and in 0,4% of consumers of digitalis (10,2 ± 4,6 months). It is concluded that there is a low proportion of chronic use of NSAID in high-risk cardiovascular patients.

  9. Non-Steroidal Anti-Inflammatory Drugs in the Carcinogenesis of the Gastrointestinal Tract

    PubMed Central

    Compare, Debora; Nardone, Olga; Nardone, Gerardo

    2010-01-01

    It is estimated that underlying infections and inflammatory responses are linked to 15–20% of all deaths from cancer worldwide. Inflammation is a physiologic process in response to tissue damage resulting from microbial pathogen infection, chemical irritation, and/or wounding. Tissues injured throughout the recruitment of inflammatory cells such as macrophages and neutrophils, generate a great amount of growth factors, cytokines, and reactive oxygen and nitrogen species that may cause DNA damage that in turn predisposes to the transformation from chronic inflammation to neoplasia. Cyclooxygenase (COX), playing a key role in cell homeostasis, angiogenesis and tumourigenesis, may represent the link between inflammation and cancer. Currently COX is becoming a pharmacological target for cancer prevention and treatment. PMID:27713364

  10. In vitro interactions between anidulafungin and nonsteroidal anti-inflammatory drugs on biofilms of Candida spp.

    PubMed

    Rosato, Antonio; Catalano, Alessia; Carocci, Alessia; Carrieri, Antonio; Carone, Addolorata; Caggiano, Giuseppina; Franchini, Carlo; Corbo, Filomena; Montagna, Maria Teresa

    2016-03-01

    Candida spp. are responsible for many biomaterial-related infections; they give rise to infective pathologies typically associated with biofilm formation. We recently reported that the echinocandin anidulafungin (ANF) showed a strong in vitro activity against both planktonic and biofilms cells. Herein, we report the antifungal activities of ANF alone and in association with some non-steroidal anti-inflammatory drugs (NSAIDs) against nine Candida strain biofilms: four Candida albicans, two Candida glabrata and three Candida guilliermondii. The activity of ANF was assessed using an in vitro microbiological model relevant for clinical practice. ANF proved oneself to be active against biofilms cells, and a clear-cut synergism was found against Candida species biofilms when ANF was used in combination with three NSAIDs: aspirin, diclofenac, ibuprofen. The positive synergism against Candida spp. of ANF in association with aspirin or the other NSAIDs proved to be a very effective antifungal treatment (FICI<0.5). These results may provide the starting point for new combination therapies of ANF with NSAIDs against Candida biofilm pathologies.

  11. Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen.

    PubMed

    Hodkinson, Duncan J; Khawaja, Nadine; OʼDaly, Owen; Thacker, Michael A; Zelaya, Fernando O; Wooldridge, Caroline L; Renton, Tara F; Williams, Steven C R; Howard, Matthew A

    2015-07-01

    Nonopioid agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are the most commonly used class of analgesics. Increasing evidence suggests that cyclooxygenase (COX) inhibition at both peripheral and central sites can contribute to the antihyperalgesic effects of NSAIDs, with the predominant clinical effect being mediated centrally. In this study, we examined the cerebral response to ibuprofen in presurgical and postsurgical states and looked at the analgesic interaction between surgical state and treatment. We used an established clinical pain model involving third molar extraction, and quantitative arterial spin labelling (ASL) imaging to measure changes in tonic/ongoing neural activity. Concurrent to the ASL scans, we presented visual analogue scales inside the scanner to evaluate the subjective experience of pain. This novel methodology was incorporated into a randomized double-blind placebo-controlled design, with an open method of drug administration. We found that independent of its antinociceptive action, ibuprofen has no effect on regional cerebral blood flow under pain-free conditions (presurgery). However, in the postsurgical state, we observed increased activation of top-down modulatory circuits, which was accompanied by decreases in the areas engaged because of ongoing pain. Our findings demonstrate that ibuprofen has a measurable analgesic response in the human brain, with the subjective effects of pain relief reflected in two distinct brain networks. The observed activation of descending modulatory circuits warrants further investigation, as this may provide new insights into the inhibitory mechanisms of analgesia that might be exploited to improve safety and efficacy in pain management.

  12. Nonsteroidal anti-inflammatory drug gastropathy: new avenues for safety

    PubMed Central

    Roth, Sanford H

    2011-01-01

    Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID) therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less frequent. These complications can be life-threatening in at-risk populations such as older adults, who are common users of long-term oral systemic NSAID therapy. Topical NSAID formulations deliver effective doses of analgesics directly to the affected joints, thereby limiting systemic exposure and potentially the risk of systemic adverse events, such as gastropathy and serious cardiovascular events. There are currently two topical NSAIDs approved by the US Food and Drug Administration for osteoarthritis-associated pain, as well as for the signs and symptoms of osteoarthritis. This review discusses the relative safety, and the gastrointestinal, cardiovascular, and renal risks of chronic oral or systemic NSAID therapy and topical NSAID formulations in patients with osteoarthritis. PMID:21753867

  13. [Coxib: a feasible therapeutic alternative in patients with intolerance or hypersensitivity to acetilsallicilic acid, non-steroidal antiinflammatory drugs and paracetamol].

    PubMed

    Ramos-Bello, Dolores; Ramos-Niembro, Francisco

    2009-01-01

    Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are the most frequent drugs used worldwide for the management of pain, inflammation and fever associated with many acute and chronic conditions. Despite of its analgesic, anti-inflammatory and antipyretic properties, all display adverse effects mediated by the same mechanisms by which they control pain, inflammation and fever. A relatively frequent problem with the use of NSAIDs and/or aspirin, and less frequently with paracetamol, is the development of intolerance and hypersensitivity reactions, a situation for which diverse alternatives have been proposed. One of these includes the use of cyclo-oxigenase-2 specific inhibitors (COXIB), a therapeutic modality analyzed in the present paper.

  14. Topical nonsteroidal anti-inflammatory drugs for osteoarthritis.

    PubMed

    Barthel, H Richard; Axford-Gatley, Robert A

    2010-11-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are mainstays of the treatment of osteoarthritis (OA) but have dose- and age-related risks of gastrointestinal, cardiovascular, and renal adverse events (AEs). As a result, US and international guidelines recommend caution when prescribing oral NSAIDs, particularly in older patients and those with significant comorbidities. For OA of the hands and knees, topical NSAIDs provide efficacy similar to oral NSAIDs, with far less systemic distribution. Treatment-related cardiovascular, renal, and other serious AEs with topical NSAIDs have not been reported. At present, only 2 topical NSAIDs are approved in the United States for the treatment of OA: diclofenac sodium 1% gel for hand or knee OA and diclofenac sodium 1.5% in 45.5% dimethylsulfoxide solution for knee OA. Clinical trial data for these products have demonstrated efficacy superior to placebo or similar to oral diclofenac with AE profiles similar to placebo, except for application site reactions. In large double-blind trials, gastrointestinal AEs were infrequent and did not include ulcers, perforations, or bleeding. The purpose of this brief review is to examine the data from controlled double-blind trials evaluating the use of topical NSAIDs in patients with OA. Articles included were identified via a search of PubMed covering the period from January 1, 2005 through March 31, 2010. Reference lists from OA treatment guidelines and meta-analyses were reviewed for additional citations of importance.

  15. Preventing peridural fibrosis with nonsteroidal anti-inflammatory drugs

    PubMed Central

    Hernandez-Vaquero, Daniel

    2008-01-01

    Peridural fibrosis is one of the more frequent complications of lumbar surgery. Nonsteroidal anti-inflammatory drugs inhibit the inflammatory and fibroblastic response. We performed lumbar laminectomies in 24 rabbits, divided into two groups. The experimental group received 5 mg/kg/day of aceclofenac for 7 days and the control group received 1 cm3 of physiological saline. The samples were stained using immunohistochemical methods. The cellular populations in the inflammatory reaction and the thickness of the fibrous membrane were quantified. The mean of the fibrous area was always less in the rabbits of the experimental group compared to controls (47% less at 2 weeks and 41% less at 4 weeks). We observed an 8% decrease in the number of fibroblasts with antivimentin monoclonal antibodies in the experimental group. In this model, aceclofenac inhibits the presence of inflammatory cells in the fibrous scar in the early stages and reduces the extension of adhesions without adverse reactions. PMID:18172695

  16. Impact of Anti-Inflammatory Drugs on Pyogenic Vertebral Osteomyelitis: A Prospective Cohort Study

    PubMed Central

    Jean, Maxime; Bouchand, Frédérique; Davido, Benjamin; Descatha, Alexis; Duran, Clara; Gras, Guillaume; Perronne, Christian; Mulleman, Denis; Salomon, Jérôme; Bernard, Louis

    2016-01-01

    Objective. Pyogenic vertebral osteomyelitis (PVO) are frequently misdiagnosed and patients often receive anti-inflammatory drugs for their back pain. We studied the impact of these medications. Methods. We performed a prospective study enrolling patients with PVO and categorized them depending on their drugs intake. Then, we compared diagnosis delay, clinical presentation at hospitalization, incidence of complications, and cure rate. Results. In total, 79 patients were included. Multivariate analysis found no correlation between anti-inflammatory drug intake and diagnosis delay, clinical presentation, complications, or outcome. Conclusion. Anti-inflammatory drugs intake does not affect diagnostic delay, severity at diagnosis, or complications of PVO. PMID:27833642

  17. Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard

    SciTech Connect

    Chang, Yoke-Chen; Wang, James D.; Hahn, Rita A.; Gordon, Marion K.; Joseph, Laurie B.; Heck, Diane E.; Heindel, Ned D.; Young, Sherri C.; Sinko, Patrick J.; Casillas, Robert P.; Laskin, Jeffrey D.; Laskin, Debra L.; Gerecke, Donald R.

    2014-10-15

    Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme mediating activation of cholinergic inflammatory pathways in a model of SM-induced skin injury. Adult SKH-1 hairless male mice were exposed to SM using a dorsal skin vapor cup model. NDH 4338 was applied topically to the skin 24, 48, and 72 h post-SM exposure. After 96 h, SM was found to induce skin injury characterized by edema, epidermal hyperplasia, loss of the differentiation marker, keratin 10 (K10), upregulation of the skin wound marker keratin 6 (K6), disruption of the basement membrane anchoring protein laminin 322, and increased expression of epidermal COX2. NDH 4338 post-treatment reduced SM-induced dermal edema and enhanced skin re-epithelialization. This was associated with a reduction in COX2 expression, increased K10 expression in the suprabasal epidermis, and reduced expression of K6. NDH 4338 also restored basement membrane integrity, as evidenced by continuous expression of laminin 332 at the dermal–epidermal junction. Taken together, these data indicate that a bifunctional anti-inflammatory prodrug stimulates repair of SM induced skin injury and may be useful as a medical countermeasure. - Highlights: • Bifunctional anti-inflammatory prodrug (NDH4338) tested on SM exposed mouse skin • The prodrug NDH4338 was designed to target COX2 and acetylcholinesterase. • The application of NDH4338 improved cutaneous wound repair after SM induced injury. • NDH4338 treatment demonstrated a reduction in COX2 expression on SM injured skin. • Changes of skin repair

  18. Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance.

    PubMed

    Uzgören-Baran, Ayşe; Tel, Banu Cahide; Sarıgöl, Deniz; Oztürk, Elif İnci; Kazkayası, Inci; Okay, Gürol; Ertan, Mevlüt; Tozkoparan, Birsen

    2012-11-01

    In an effort to establish new candidates with improved analgesic and anti-inflammatory activities and lower ulcerogenic risk, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives of ibuprofen were synthesized. All compounds were evaluated for their in vivo anti-inflammatory and analgesic activities in mice. Furthermore, the ulcerogenic risks of the compounds were determined. In general, none of the compounds represent a risk for developing stomach injury as much as observed in the reference drugs ibuprofen and indomethacin. The compounds carrying a 3-phenyl-2-propenylidene (1a), (biphenyl-4-yl)methylidene (1f) and (1-methylpyrrol-2-yl)methylidene (1n) at the 6th position of the fused ring have been evaluated as potential analgesic/anti-inflammatory agents without a gastrointestinal side effect. These new compounds, therefore, deserve further attention to develop new lead drugs.

  19. Cutaneous reactions to analgesic-antipyretics and nonsteroidal anti-inflammatory drugs. Analysis of reports to the spontaneous reporting system of the Gruppo Italiano Studi Epidemiologici in Dermatologia.

    PubMed

    1993-01-01

    We analyzed the cutaneous reactions to systemic analgesic-antipyretics and non-steroidal anti-inflammatory drugs reported to the spontaneous reporting system of the Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED). The system has been active since 1988, with periodic intensive surveillance exercises, and 202 dermatologists have collaborated. Up to December 1991, 2,137 reactions had been collected, of which 713 were reactions to systemic analgesic-antipyretics and nonsteroidal anti-inflammatory drugs. A general profile of the reactions was identifiable. It included, in order of frequency, urticaria/angioedema, fixed eruptions, exanthemas, erythema multiforme and Stevens Johnson syndrome. Fixed eruptions and Stevens Johnson syndrome were reported with exceedingly high frequency in association with feprazone. Our system also revealed previously unreported reactions, including fixed eruption to nimesulide, fixed eruption to piroxicam and fixed eruption to flurbiprofen.

  20. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions

    PubMed Central

    Daniel, Sharon; Koren, Gideon; Lunenfeld, Eitan; Bilenko, Natalya; Ratzon, Ronit; Levy, Amalia

    2014-01-01

    Background: Spontaneous abortion is the most common complication of pregnancy. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used during pregnancy. Published data are inconsistent regarding the risk of spontaneous abortion following exposure to NSAIDs. Methods: We performed a historical cohort study involving all women who conceived between January 2003 and December 2009 and who were admitted for delivery or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. We constructed time-varying Cox regression models and adjusted for maternal age, diabetes mellitus, hypothyroidism, obesity, hypercoagulation or inflammatory conditions, recurrent miscarriage, in vitro fertilization of the current pregnancy, intrauterine contraceptive device, ethnic background, tobacco use and year of admission. Results: The cohort included 65 457 women who conceived during the study period; of these, 58 949 (90.1%) were admitted for a birth and 6508 (9.9%) for spontaneous abortion. A total of 4495 (6.9%) pregnant women were exposed to NSAIDs during the study period. Exposure to NSAIDs was not an independent risk factor for spontaneous abortion (nonselective cyclooxygenase [COX] inhibitors: adjusted hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.99–1.22; selective COX-2 inhibitors: adjusted HR 1.43, 95% CI 0.79–2.59). There was no increased risk for specific NSAID drugs, except for a significantly increased risk with exposure to indomethacin (adjusted HR 2.8, 95% CI 1.70–4.69). We found no dose–response effect. Interpretation: We found no increased risk of spontaneous abortion following exposure to NSAIDs. Further research is needed to assess the risk following exposure to selective COX-2 inhibitors. PMID:24491470

  1. Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard.

    PubMed

    Chang, Yoke-Chen; Wang, James D; Hahn, Rita A; Gordon, Marion K; Joseph, Laurie B; Heck, Diane E; Heindel, Ned D; Young, Sherri C; Sinko, Patrick J; Casillas, Robert P; Laskin, Jeffrey D; Laskin, Debra L; Gerecke, Donald R

    2014-10-15

    Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme mediating activation of cholinergic inflammatory pathways in a model of SM-induced skin injury. Adult SKH-1 hairless male mice were exposed to SM using a dorsal skin vapor cup model. NDH 4338 was applied topically to the skin 24, 48, and 72 h post-SM exposure. After 96 h, SM was found to induce skin injury characterized by edema, epidermal hyperplasia, loss of the differentiation marker, keratin 10 (K10), upregulation of the skin wound marker keratin 6 (K6), disruption of the basement membrane anchoring protein laminin 322, and increased expression of epidermal COX2. NDH 4338 post-treatment reduced SM-induced dermal edema and enhanced skin re-epithelialization. This was associated with a reduction in COX2 expression, increased K10 expression in the suprabasal epidermis, and reduced expression of K6. NDH 4338 also restored basement membrane integrity, as evidenced by continuous expression of laminin 332 at the dermal-epidermal junction. Taken together, these data indicate that a bifunctional anti-inflammatory prodrug stimulates repair of SM induced skin injury and may be useful as a medical countermeasure.

  2. Therapeutic Potential of a Non-Steroidal Bifunctional Anti-Inflammatory and Anti-Cholinergic Agent against Skin Injury Induced by Sulfur Mustard

    PubMed Central

    Chang, Yoke-Chen; Wang, James D.; Hahn, Rita A.; Gordon, Marion K.; Joseph, Laurie B.; Heck, Diane E.; Heindel, Ned D.; Young, Sherri C.; Sinko, Patrick J.; Casillas, Robert P.; Laskin, Jeffrey D.; Laskin, Debra L.; Gerecke, Donald R.

    2014-01-01

    Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme mediating activation of cholinergic inflammatory pathways in a model of SM-induced skin injury. Adult SKH-1 hairless male mice were exposed to SM using a dorsal skin vapor cup model. NDH 4338 was applied topically to the skin 24, 48, and 72 hr post-SM exposure. After 96 hr, SM was found to induce skin injury characterized by edema, epidermal hyperplasia, loss of the differentiation marker, keratin 10 (K10), upregulation of the skin wound marker keratin 6 (K6), disruption of the basement membrane anchoring protein laminin 322, and increased expression of epidermal COX2. NDH 4338 post-treatment reduced SM-induced dermal edema and enhanced skin re-epithelialization. This was associated with a reduction in COX2 expression, increased K10 expression in the suprabasal epidermis, and reduced expression of K6. NDH 4338 also restored basement membrane integrity, as evidenced by continuous expression of laminin 332 at the dermalepidermal junction. Taken together, these data indicate that a bifunctional anti-inflammatory prodrug stimulates repair of SM induced skin injury and may be useful as a medical countermeasure. PMID:25127551

  3. Drug Targets for Cardiovascular-Safe Anti-Inflammatory: In Silico Rational Drug Studies

    PubMed Central

    Shahbazi, Sajad; Sahrawat, Tammanna R.; Ray, Monalisa; Dash, Swagatika; Kar, Dattatreya; Singh, Shikha

    2016-01-01

    Cyclooxygenase-2 (COX-2) plays an important role in memory consolidation and synaptic activity, the most fundamental functions of the brain. It converts arachidonic acid to prostaglandin endoperoxide H2. In contrast, if over-expressed, it causes inflammation in response to cytokine, pro-inflammatory molecule, and growth factor. Anti-inflammatory agents, by allosteric or competitive inhibition of COX-2, alleviate the symptoms of inflammation. Coxib family drugs, particularly celecoxib, are the most famous anti-inflammatory agents available in the market showing significant inhibitory effect on COX-2 activity. Due to high cardiovascular risk of this drug group, recent researches are focused on the investigation of new safer drugs for anti-inflammatory diseases. Natural compounds, particularly, phytochemicals are found to be good candidates for drug designing and discovery. In the present study, we performed in silico studies to quantitatively scrutinize the molecular interaction of curcumin and its structural analogs with COX-2, COX-1, FXa and integrin αIIbβIII to investigate their therapeutic potential as a cardiovascular-safe anti-inflammatory medicine (CVSAIM). The results of both ADMET and docking study indicated that out of all the 39 compounds studied, caffeic acid had remarkable interaction with proteins involved in inflammatory response. It was also found to inhibit the proteins that are involved in thrombosis, thereby, having the potential to be developed as therapeutic agent. PMID:27258084

  4. [Synthesis and biological evaluation of indole derivatives acting as anti-inflammatory or antitumoral drugs].

    PubMed

    Le Borgne, M; Duflos, M; Le Baut, G; Nicholls, P J; Hartmann, R W

    2000-10-01

    Two axes of research have been explored, one about promising non-acidic non-steroidal anti-inflammatory derivatives, with indolin-2-one as structural core and another one about aromatase inhibitors, characterized by azolylmethyl or alpha-azolylbenzyl chain on indole nucleus. Knoevenagel reaction led to indolin-2-ones substituted by either 2,6-di-tert-butylphenol chain or 1, 4-dihydropyridine chain, revealing antioxydant or anti-inflammatory activities. Aromatase is a logical target in the treatment of hormono-dependent breast cancer in postmenopausal women. Among non steroidal inhibitors of this enzyme, diverse compounds with anilino or azaheterocyclic moiety are currently used or undergoing clinical trials. Our pharmacomodulation in azolylmethylindole or alpha-azolylbenzylindole series led to compounds with high level aromatase inhibitory activity. Work to determine their selectivity by measuring their inhibitory effect on P450 17alpha enzyme was also carried out. A first molecular modeling approach with Discover software was performed to evaluate interactions between our molecules and the catalytic site of P450cam.

  5. Effect of COX-2 inhibitors and other non-steroidal inflammatory drugs on breast cancer risk: a meta-analysis.

    PubMed

    de Pedro, María; Baeza, Sara; Escudero, María-Teresa; Dierssen-Sotos, Trinidad; Gómez-Acebo, Inés; Pollán, Marina; Llorca, Javier

    2015-01-01

    Evidence on non-steroidal anti-inflammatory drugs (NSAID) use and breast cancer risk shows a slightly protective effect of these drugs, but previous studies lack randomized clinical trial results and present high heterogeneity in exposure measurement. This systematic review and meta-analysis widens the knowledge about NSAID use and breast cancer risk, updating the information from the last meta-analysis, focusing on evidence on specific effects of COX-2 inhibitors and differential expression patterns of hormonal receptors. A PubMed-database search was conducted to include all entries published with the keywords "BREAST CANCER NSAID ANTI-INFLAMMATORY" until 10/24/2013 providing original results from cohort studies, case-control studies, or randomized clinical trials with at least one reported relative risk (RR) or odds ratio (OR) on the association between any NSAID use and incidence of invasive breast cancer. This resulted in 49 publications, from which the information was retrieved about type of study, exposure characteristics, breast cancer characteristics, and breast cancer-NSAID association. Meta-analyses were performed separately for case-control and cohort studies and for different hormone-receptor status. NSAID use reduced invasive breast cancer risk by about 20 %. A similar effect was found for aspirin, acetaminophen, COX-2 inhibitors and, to a lesser extent, ibuprofen. The effect of aspirin was similar in preventing hormone-receptor-positive breast cancer. This meta-analysis suggests a slightly protective effect of NSAIDs-especially aspirin and COX-2 inhibitors- against breast cancer, which seems to be restricted to ER/PR+tumors.

  6. [Helicobacter pylori, nonsteroidal anti-inflammatory agents and gastroduodenal changes].

    PubMed

    Teixeira, A V

    1995-09-01

    The author discusses the possible interactions between non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (Hp) which may play an important role in the unleashing of gastroduodenal lesions. To our knowledge, AINEs have no influence on the prevalence of infection by Hp and the latter does not seem to influence the development and intensity of the lesions caused by NSAIDs.

  7. Non-steroidal anti-inflamatory drugs as guest of dendronized polymeric nanocomposites

    NASA Astrophysics Data System (ADS)

    Schmidt, Mathias; Alvarado, Nancy; Alegría, Luz; Saldías, César; Fuentes, Irma; Menares, Pamela; Gargallo, Ligia; Leiva, Angel; Radić, Deodato

    2016-05-01

    The study of dendronized polymeric nanocomposites like poly(diethylaminoethyl methacrylamide) (PEAM), poly(acryloil tris nitrile/(methylester)) (PATCN) and dendronized poly(ɛ-caprolactone) as carriers of different non- steroidal antiinflamatory drugs like ibuprofen (IBU), ketoprofen (KTP), naproxen (NPX) and indomethacin (IMTh) are reported.

  8. Rose geranium essential oil as a source of new and safe anti-inflammatory drugs

    PubMed Central

    Boukhatem, Mohamed Nadjib; Kameli, Abdelkrim; Ferhat, Mohamed Amine; Saidi, Fairouz; Mekarnia, Maamar

    2013-01-01

    Background Since the available anti-inflammatory drugs exert an extensive variety of side effects, the search for new anti-inflammatory agents has been a priority of pharmaceutical industries. Aims The aim of the present study was to assess the anti-inflammatory activities of the essential oil of rose geranium (RGEO). Methods The chemical composition of the RGEO was investigated by gas chromatography. The major components were citronellol (29.13%), geraniol (12.62%), and citronellyl formate (8.06%). In the carrageenan-induced paw edema, five different groups were established and RGEO was administered orally in three different doses. Results RGEO (100 mg/kg) was able to significantly reduce the paw edema with a comparable effect to that observed with diclofenac, the positive control. In addition, RGEO showed a potent anti-inflammatory activity by topical treatment in the method of croton oil-induced ear edema. When the dose was 5 or 10 µl of RGEO per ear, the inflammation was reduced by 73 and 88%, respectively. This is the first report to demonstrate a significant anti-inflammatory activity of Algerian RGEO. In addition, histological analysis confirmed that RGEO inhibited the inflammatory responses in the skin. Conclusion Our results indicate that RGEO may have significant potential for the development of novel anti-inflammatory drugs with improved safety profile. PMID:24103319

  9. Rose geranium essential oil as a source of new and safe anti-inflammatory drugs.

    PubMed

    Nadjib Boukhatem, Mohamed; Kameli, Abdelkrim; Amine Ferhat, Mohamed; Saidi, Fairouz; Mekarnia, Maamar

    2013-01-01

    Background Since the available anti-inflammatory drugs exert an extensive variety of side effects, the search for new anti-inflammatory agents has been a priority of pharmaceutical industries. Aims The aim of the present study was to assess the anti-inflammatory activities of the essential oil of rose geranium (RGEO). Methods The chemical composition of the RGEO was investigated by gas chromatography. The major components were citronellol (29.13%), geraniol (12.62%), and citronellyl formate (8.06%). In the carrageenan-induced paw edema, five different groups were established and RGEO was administered orally in three different doses. Results RGEO (100 mg/kg) was able to significantly reduce the paw edema with a comparable effect to that observed with diclofenac, the positive control. In addition, RGEO showed a potent anti-inflammatory activity by topical treatment in the method of croton oil-induced ear edema. When the dose was 5 or 10 µl of RGEO per ear, the inflammation was reduced by 73 and 88%, respectively. This is the first report to demonstrate a significant anti-inflammatory activity of Algerian RGEO. In addition, histological analysis confirmed that RGEO inhibited the inflammatory responses in the skin. Conclusion Our results indicate that RGEO may have significant potential for the development of novel anti-inflammatory drugs with improved safety profile.

  10. The multifunctional anti-inflammatory drugs used in the therapy of Alzheimer's disease.

    PubMed

    Shi, S; Wang, Z; Qiao, Z

    2013-01-01

    Inflammation has recently been implicated as a critical mechanism in Alzheimer's disease (AD). Microglia are the resident immune cells in the central nervous system (CNS), and they mediate the inflammatory response in the AD brain. Thus, suppression of microglial activation and subsequent neuroinflammation may be a potential therapeutic approach against AD. In the following review, we briefly discuss the limitations and advantages of current drug targets for AD and then summarize several anti-inflammatory drugs in trial, including natural nonsteroidal anti-inflammatory drugs (NSAIDs), polyphenols and new drugs synthesized based on multi-target directed ligand (MTDL) design. In addition to their anti-inflammatory effects, these drugs can act as anti-oxidants and reduce microglial activation or amyloid-β (Aβ) plaques. Thus, the studies focused on multiple factors in AD processes might reveal the best potential treatment strategy for the future.

  11. From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclooxygenase in beta-amyloidosis and clinical dementia.

    PubMed

    Pasinetti, Giulio Maria

    2002-10-01

    Epidemiological evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) may protect against Alzheimer's disease (AD). However, therapeutic studies with NSAIDs, including cyclooxygenase (COX) inhibitors and steroids have not supported such epidemiological evidence. The apparent inconsistency may be due to the fact that the epidemiological evidence is based on studies examining AD before clinical manifestations are apparent, while therapeutic studies have been carried out on people with illnesses severe enough to exceed the clinical detection threshold. Thus, it is conceivable that therapeutic strategies administered during early AD dementia or moderate dementia may not be optimally effective. Alternatively, the influence of inflammatory activity in the brain for cases at high risk to develop AD, e.g., mild cognitive impairment (MCI) cases, as a potential target of anti-inflammatory drugs in clinical studies maybe more suitable to be studied. The primary action of NSAIDs is inhibition of the COX enzymes. COX enzymes exist in an inducible form COX-2, that has been found to be elevated in the AD brain, and a constitutive form COX-1. Both COX-1 and COX-2 are known to be involved in numerous inflammatory activities as well as normal neuronal functions. In vitro, it has been demonstrated that non-selective inhibitors of COX can preferentially decrease the levels of the highly amyloidogenic amyloid-beta (Abeta)(1-42)peptide. Recent studies testing non-selective NSAIDs in murine models of AD neuropathology indicated that the frequency of Abeta plaque deposits in the brains of these animals can be significantly reduced by treatment with the non-selective COX inhibitor ibuprofen. These studies and epidemiological data strongly support a therapeutic potential for NSAIDs in the treatment of AD. Upon this premise, industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of AD. However, given the

  12. Nonsteroidal anti-inflammatory drug administration in children with history of wheeze

    PubMed Central

    Sih, Kendra; Goldman, Ran D.

    2016-01-01

    Question A child in my clinic who recently sprained his ankle is experiencing pain and having trouble bearing weight on the affected leg. His mother has been giving him acetaminophen, as she was told never to use nonsteroidal anti-inflammatory drugs (NSAIDs) because of his pharmacologically controlled asthma. Is asthma in children a contraindication to giving NSAIDs? Is NSAID-exacerbated respiratory disease (NERD) a real entity? Answer Nonsteroidal anti-inflammatory drugs are effective analgesic and antipyretic medications. While described in adults with some predisposing conditions, NERD has not been clearly described in a large number of children. Nonsteroidal anti-inflammatory drugs can be recommended to children with known wheeze who do not have a history of NERD reaction. PMID:27521389

  13. Anti-inflammatory properties of drugs from saffron crocus.

    PubMed

    Poma, Anna; Fontecchio, Gabriella; Carlucci, Giuseppe; Chichiriccò, Giuseppe

    2012-01-01

    The medicinal uses of saffron (Crocus sativus Linnaeus) have a long history beginning in Asian countries since the Late Bronze Age. Recent studies have validated its potential to lower the risk of several diseases. Some metabolites derived from saffron stigmas exert numerous therapeutic effects due to hypolipidemic, antitussive, antioxidant, antidiabetic activities and many others. Water and ethanol extracts of Crocus sativus L. are cardioprotective and counteract neurodegenerative disorders. Many of these medicinal properties of saffron can be attributed to a number of its compounds such as crocetin, crocins and other substances having strong antioxidant and radical scavenger properties against a variety of radical oxygen species and pro-inflammatory cytokines. Botany, worldwide spreading of cultivars, biochemical pathways, active constituents and chemical detection methods are reviewed. Therapeutic uses of saffron principles with particular regard to those exhibiting antioxidant and thus anti-inflammatory features are discussed. To date, very few adverse health effects of saffron have been demonstrated. At high doses (more than 5 g/die day), it should be avoided in pregnancy owing to its uterine stimulation activity.

  14. Repositioning drugs for inflammatory disease – fishing for new anti-inflammatory agents

    PubMed Central

    Hall, Christopher J.; Wicker, Sophie M.; Chien, An-Tzu; Tromp, Alisha; Lawrence, Lisa M.; Sun, Xueying; Krissansen, Geoffrey W.; Crosier, Kathryn E.; Crosier, Philip S.

    2014-01-01

    Inflammation is an important and appropriate host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation, underlies a broad range of pathological processes, from inflammatory dermatoses to type 2 diabetes and cancer. As such, identifying new drugs to suppress inflammation is an area of intense interest. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat inflammation. Traditional drug discovery, including structure-based drug design, have largely fallen short of satisfying this unmet need. With faster development times and reduced safety and pharmacokinetic uncertainty, drug repositioning – the process of finding new uses for existing drugs – is emerging as an alternative strategy to traditional drug design that promises an improved risk-reward trade-off. Using a zebrafish in vivo neutrophil migration assay, we undertook a drug repositioning screen to identify unknown anti-inflammatory activities for known drugs. By interrogating a library of 1280 approved drugs for their ability to suppress the recruitment of neutrophils to tail fin injury, we identified a number of drugs with significant anti-inflammatory activity that have not previously been characterized as general anti-inflammatories. Importantly, we reveal that the ten most potent repositioned drugs from our zebrafish screen displayed conserved anti-inflammatory activity in a mouse model of skin inflammation (atopic dermatitis). This study provides compelling evidence that exploiting the zebrafish as an in vivo drug repositioning platform holds promise as a strategy to reveal new anti-inflammatory activities for existing drugs. PMID:25038060

  15. Structural investigation of chitosan-based microspheres with some anti-inflammatory drugs

    NASA Astrophysics Data System (ADS)

    Dreve, Simina; Kacso, Iren; Popa, Adriana; Raita, Oana; Dragan, Felicia; Bende, A.; Borodi, Gh.; Bratu, I.

    2011-06-01

    The use of chitosan as an excipient in oral formulations, as a drug delivery vehicle for ulcerogenic anti-inflammatory drugs and as base in polyelectrolyte complex systems, to prepare solid release systems as sponges was investigated. The preparation by double emulsification of chitosan hydrogels carrying diclofenac, acetyl-salycilic acid and hydrocortisone acetate as anti-inflammatory drugs is reported. The concentration of anti-inflammatory drug in the chitosan hydrogel generating the sponges was 0.08 mmol. Chitosan-drug loaded sponges with anti-inflammatory drugs were prepared by freeze-drying at -60 °C and 0.009 atm. Structural investigations of the solid formulations were done by Fourier-transformed infrared and ultraviolet-visible spectroscopy, spectrofluorimetry, differential scanning calorimetry and X-ray diffractometry. The results indicated that the drug molecules are forming temporary chelates in chitosan hydrogels and sponges. Electron paramagnetic resonance demonstrates the presence of free radicals in a wide range and the antioxidant activity for chitosan-drug supramolecular cross-linked assemblies.

  16. Development of anti-inflammatory drugs - the research and development process.

    PubMed

    Knowles, Richard Graham

    2014-01-01

    The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, 'improving on the Beatles' in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti-inflammatory medicines.

  17. Purification and properties of a 3 alpha-hydroxysteroid dehydrogenase of rat liver cytosol and its inhibition by anti-inflammatory drugs.

    PubMed Central

    Penning, T M; Mukharji, I; Barrows, S; Talalay, P

    1984-01-01

    An NAD(P)-dependent 3 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.50) was purified to homogeneity from rat liver cytosol, where it is responsible for most if not all of the capacity for the oxidation of androsterone, 1-acenaphthenol and benzenedihydrodiol (trans-1,2-dihydroxycyclohexa-3,5-diene). The dehydrogenase has many properties (substrate specificity, pI, Mr, amino acid composition) in common with the dihydrodiol dehydrogenase (EC 1.3.1.20) purified from the same source [Vogel, Bentley, Platt & Oesch (1980) J. Biol. Chem. 255, 9621-9625]. Since 3 alpha-hydroxysteroids are by far the most efficient substrates, the enzyme is more appropriately designated a 3 alpha-hydroxysteroid dehydrogenase. It also promotes the NAD(P)H-dependent reductions of quinones (e.g. 9,10-phenanthrenequinone, 1,4-benzoquinone), aromatic aldehydes (4-nitrobenzaldehyde) and aromatic ketones (4-nitroacetophenone). The dehydrogenase is not inhibited by dicoumarol, disulfiram, hexobarbital or pyrazole. The mechanism of the powerful inhibition of this enzyme by both non-steroidal and steroidal anti-inflammatory drugs [Penning & Talalay (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 4504-4508] was examined with several substrates. Most non-steroidal anti-inflammatory drugs are competitive inhibitors (e.g. Ki for indomethacin, 0.20 microM for 9,10-phenanthrenequinone reduction at pH 6.0, and 0.835 microM for androsterone oxidation at pH 7.0), except for salicylates, which act non-competitively (e.g. Ki for aspirin, 650 microM for androsterone oxidation). The inhibitory potency of these agents falls sharply as the pH is increased from 6 to 9. Most anti-inflammatory steroids are likewise competitive inhibitors, except for the most potent (betamethasone and dexamethasone), which act non-competitively. The enzyme is inhibited competitively by arachidonic acid and various prostaglandins. PMID:6435601

  18. Optimization of the Ion Source-Mass Spectrometry Parameters in Non-Steroidal Anti-Inflammatory and Analgesic Pharmaceuticals Analysis by a Design of Experiments Approach.

    PubMed

    Paíga, Paula; Silva, Luís M S; Delerue-Matos, Cristina

    2016-10-01

    The flow rates of drying and nebulizing gas, heat block and desolvation line temperatures and interface voltage are potential electrospray ionization parameters as they may enhance sensitivity of the mass spectrometer. The conditions that give higher sensitivity of 13 pharmaceuticals were explored. First, Plackett-Burman design was implemented to screen significant factors, and it was concluded that interface voltage and nebulizing gas flow were the only factors that influence the intensity signal for all pharmaceuticals. This fractionated factorial design was projected to set a full 2(2) factorial design with center points. The lack-of-fit test proved to be significant. Then, a central composite face-centered design was conducted. Finally, a stepwise multiple linear regression and subsequently an optimization problem solving were carried out. Two main drug clusters were found concerning the signal intensities of all runs of the augmented factorial design. p-Aminophenol, salicylic acid, and nimesulide constitute one cluster as a result of showing much higher sensitivity than the remaining drugs. The other cluster is more homogeneous with some sub-clusters comprising one pharmaceutical and its respective metabolite. It was observed that instrumental signal increased when both significant factors increased with maximum signal occurring when both codified factors are set at level +1. It was also found that, for most of the pharmaceuticals, interface voltage influences the intensity of the instrument more than the nebulizing gas flowrate. The only exceptions refer to nimesulide where the relative importance of the factors is reversed and still salicylic acid where both factors equally influence the instrumental signal. Graphical Abstract ᅟ.

  19. Optimization of the Ion Source-Mass Spectrometry Parameters in Non-Steroidal Anti-Inflammatory and Analgesic Pharmaceuticals Analysis by a Design of Experiments Approach

    NASA Astrophysics Data System (ADS)

    Paíga, Paula; Silva, Luís M. S.; Delerue-Matos, Cristina

    2016-10-01

    The flow rates of drying and nebulizing gas, heat block and desolvation line temperatures and interface voltage are potential electrospray ionization parameters as they may enhance sensitivity of the mass spectrometer. The conditions that give higher sensitivity of 13 pharmaceuticals were explored. First, Plackett-Burman design was implemented to screen significant factors, and it was concluded that interface voltage and nebulizing gas flow were the only factors that influence the intensity signal for all pharmaceuticals. This fractionated factorial design was projected to set a full 22 factorial design with center points. The lack-of-fit test proved to be significant. Then, a central composite face-centered design was conducted. Finally, a stepwise multiple linear regression and subsequently an optimization problem solving were carried out. Two main drug clusters were found concerning the signal intensities of all runs of the augmented factorial design. p-Aminophenol, salicylic acid, and nimesulide constitute one cluster as a result of showing much higher sensitivity than the remaining drugs. The other cluster is more homogeneous with some sub-clusters comprising one pharmaceutical and its respective metabolite. It was observed that instrumental signal increased when both significant factors increased with maximum signal occurring when both codified factors are set at level +1. It was also found that, for most of the pharmaceuticals, interface voltage influences the intensity of the instrument more than the nebulizing gas flowrate. The only exceptions refer to nimesulide where the relative importance of the factors is reversed and still salicylic acid where both factors equally influence the instrumental signal.

  20. Anti-inflammatory drugs and uterine cervical cancer cells: Antineoplastic effect of meclofenamic acid

    PubMed Central

    SORIANO-HERNANDEZ, ALEJANDRO D.; MADRIGAL-PÉREZ, DANIELA; GALVAN-SALAZAR, HECTOR R.; MARTINEZ-FIERRO, MARGARITA L.; VALDEZ-VELAZQUEZ, LAURA L.; ESPINOZA-GÓMEZ, FRANCISCO; VAZQUEZ-VUELVAS, OSCAR F.; OLMEDO-BUENROSTRO, BERTHA A.; GUZMAN-ESQUIVEL, JOSE; RODRIGUEZ-SANCHEZ, IRAM P.; LARA-ESQUEDA, AGUSTIN; MONTES-GALINDO, DANIEL A.; DELGADO-ENCISO, IVAN

    2015-01-01

    Uterine cervical cancer (UCC) is one of the main causes of cancer-associated mortality in women. Inflammation has been identified as an important component of this neoplasia; in this context, anti-inflammatory drugs represent possible prophylactic and/or therapeutic alternatives that require further investigation. Anti-inflammatory drugs are common and each one may exhibit a different antineoplastic effect. As a result, the present study investigated different anti-inflammatory models of UCC in vitro and in vivo. Celecoxib, sulindac, nimesulide, dexamethasone, meclofenamic acid, flufenamic acid and mefenamic acid were tested in UCC HeLa, VIPA, INBL and SiHa cell lines. The cytotoxicity of the drugs was evaluated in vitro. Celecoxib, sulindac, nimesulide, mefenamic acid and flufenamic acid presented with slight to moderate toxicity (10–40% of cell death corresponding to 100 µM) in certain cell lines, while meclofenamic acid exhibited significant cytotoxicity in all essayed cell lines (50–90% of cell death corresponding to 100 µM). The meclofenamic acid was tested in murine models (immunodeficient and immunocompetent) of UCC, which manifested a significant reduction in tumor growth and increased mouse survival. It was demonstrated that of the evaluated anti-inflammatory drugs, meclofenamic acid was the most cytotoxic, with a significant antitumor effect in murine models. Subsequent studies are necessary to evaluate the clinical utility of this drug. PMID:26622892

  1. Conservative Nonhormonal Options for the Treatment of Male Infertility: Antibiotics, Anti-Inflammatory Drugs, and Antioxidants

    PubMed Central

    Condorelli, Rosita A.

    2017-01-01

    The nonhormonal medical treatment can be divided into empirical, when the cause has not been identified, and nonempirical, if the pathogenic mechanism causing male infertility can be solved or ameliorated. The empirical nonhormonal medical treatment has been proposed for patients with idiopathic or noncurable oligoasthenoteratozoospermia and for normozoospermic infertile patients. Anti-inflammatory, fibrinolytic, and antioxidant compounds, oligo elements, and vitamin supplementation may be prescribed. Infection, inflammation, and/or increased oxidative stress often require a specific treatment with antibiotics, anti-inflammatory drugs, and/or antioxidants. Combined therapies can contribute to improve sperm quality. PMID:28164122

  2. Chromones: A Promising Ring System for New Anti-inflammatory Drugs.

    PubMed

    Silva, Carlos F M; Pinto, Diana C G A; Silva, Artur M S

    2016-10-19

    The quest for safer anti-inflammatory drugs is still the focus of several medicinal chemistry programs. Chromones (4H-chromen-4-ones) are a group of naturally occurring compounds ubiquitous in plants, and the chromone core has proven to be a privileged scaffold in medicinal chemistry. Herein we provide an overview of the relevance of chromones as anti-inflammatory agents, specifically as inhibitors of cyclooxygenase (COX), 5-lipoxygenase (5-LOX), interleukin-5 (IL-5), and nitric oxide ((.) NO) production. Numerous structure-activity relationships and mechanisms of action are discussed. This review is therefore intended to provide a foundation for the design and synthesis of novel chromone-based compound libraries for further development into safer and more efficient anti-inflammatory agents.

  3. Effects of Anti-Inflammatory Drugs in Shock Caused by Injection of Living E. Coli Cells

    DTIC Science & Technology

    Injection of live E . coli organisms to dogs iv causes a lethal shock. Administrations of anti-inflammatory drugs (indomethacin, aminopyrine...the injection of E . coli were significantly different in the treated animals from those in the control group. Some of the other agents tested were

  4. Neutrophilia and an Anti-Inflammatory Drug as Markers of Inflammation in Delayed Muscle Soreness.

    ERIC Educational Resources Information Center

    Smith, Lucille L.; And Others

    This study reexamined the concept that delayed muscle soreness (DMS) is a form of inflammatory pain. This was accomplished by having 32 male volunteers perform exercise known to induce DMS and then assess the total and differential white blood cell changes. In addition, an anti-inflammatory drug, idomethacin, was administered to determine whether…

  5. Acetylsalicylic-acid-containing drugs and nonsteroidal anti-inflammatory drugs available in Canada.

    PubMed

    Brigden, M; Smith, R E

    1997-04-01

    A large number of drugs containing acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are available by prescription and over the counter in Canada. The possibility of serious side effects and drug interactions is therefore high. The authors have compiled a comprehensive list of products containing these drugs from information supplied by pharmaceutical databases, independent marketing researchers and Health Canada's Drug Directorate. Physicians should ensure that additional ASA-containing drugs or NSAIDs are not inadvertently taken by patients, especially those receiving oral anticoagulant therapy or those with a qualitative platelet defect. Patients at risk should be cautioned to check with their physician before taking any new medication, even over-the-counter products.

  6. Nonsteroidal anti-inflammatory drugs attenuate amyloid-β protein-induced actin cytoskeletal reorganization through Rho signaling modulation.

    PubMed

    Ferrera, Patricia; Zepeda, Angélica; Arias, Clorinda

    2017-01-25

    Amyloid-β protein (Aβ) neurotoxicity occurs along with the reorganization of the actin-cytoskeleton through the activation of the Rho GTPase pathway. In addition to the classical mode of action of the non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin, and ibuprofen have Rho-inhibiting effects. In order to evaluate the role of the Rho GTPase pathway on Aβ-induced neuronal death and on neuronal morphological modifications in the actin cytoskeleton, we explored the role of NSAIDS in human-differentiated neuroblastoma cells exposed to Aβ. We found that Aβ induced neurite retraction and promoted the formation of different actin-dependent structures such as stress fibers, filopodia, lamellipodia, and ruffles. In the presence of Aβ, both NSAIDs prevented neurite collapse and formation of stress fibers without affecting the formation of filopodia and lamellipodia. Similar results were obtained when the downstream effector, Rho kinase inhibitor Y27632, was applied in the presence of Aβ. These results demonstrate the potential benefits of the Rho-inhibiting NSAIDs in reducing Aβ-induced effects on neuronal structural alterations.

  7. Nonsteroidal anti-inflammatory drugs modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways

    PubMed Central

    Mozolewski, Paweł; Moskot, Marta; Jakóbkiewicz-Banecka, Joanna; Węgrzyn, Grzegorz; Bocheńska, Katarzyna; Banecki, Bogdan; Gabig-Cimińska, Magdalena

    2017-01-01

    In this report, selected non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin and nimesulide, and analgesics acetaminophen, alone, as well as in combination with isoflavone genistein as potential glycosaminoglycan (GAG) metabolism modulators were considered for the treatment of mucopolysaccharidoses (MPSs) with neurological symptoms due to the effective blood-brain barrier (BBB) penetration properties of these compounds. We found that indomethacin and nimesulide, but not acetaminophen, inhibited GAG synthesis in fibroblasts significantly, while the most pronounced impairment of glycosaminoglycan production was observed after exposure to the mixture of nimesulide and genistein. Phosphorylation of the EGF receptor (EGFR) was inhibited even more effective in the presence of indomethacin and nimesulide than in the presence of genistein. When examined the activity of phosphatidylinositol-3-kinase (PI3K) production, we observed its most significant decrease in the case of fibroblast exposition to nimesulide, and afterwards to indomethacin and genistein mix, rather than indomethacin used alone. Some effects on expression of individual GAG metabolism-related and lysosomal function genes, and significant activity modulation of a number of genes involved in intracellular signal transduction pathways and metabolism of DNA and proteins were detected. This study documents that NSAIDs, and their mixtures with genistein modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways. PMID:28240227

  8. Anti-Inflammatory Iridoids of Botanical Origin

    PubMed Central

    Viljoen, A; Mncwangi, N; Vermaak, I

    2012-01-01

    Inflammation is a manifestation of a wide range of disorders which include; arthritis, atherosclerosis, Alzheimer’s disease, inflammatory bowel syndrome, physical injury and infection amongst many others. Common treatment modalities are usually non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, paracetamol, indomethacin and ibuprofen as well as corticosteroids such as prednisone. These however, may be associated with a host of side effects due to non-selectivity for cyclooxygenase (COX) enzymes involved in inflammation and those with selectivity may be highly priced. Thus, there is a continuing search for safe and effective anti-inflammatory molecules from natural sources. Research has confirmed that iridoids exhibit promising anti-inflammatory activity which may be beneficial in the treatment of inflammation. Iridoids are secondary metabolites present in various plants, especially in species belonging to the Apocynaceae, Lamiaceae, Loganiaceae, Rubiaceae, Scrophulariaceae and Verbenaceae families. Many of these ethnobotanicals have an illustrious history of traditional use alluding to their use to treat inflammation. Although iridoids exhibit a wide range of pharmacological activities such as cardiovascular, hepatoprotection, hypoglycaemic, antimutagenic, antispasmodic, anti-tumour, antiviral, immunomodulation and purgative effects this review will acutely focus on their anti-inflammatory properties. The paper aims to present a summary for the most prominent iridoid-containing plants for which anti-inflammatory activity has been demonstrated in vitro and / or in vivo. PMID:22414102

  9. Effect of anti-inflammatory drugs on sulphated glycosaminoglycan synthesis in aged human articular cartilage.

    PubMed Central

    McKenzie, L S; Horsburgh, B A; Ghosh, P; Taylor, T K

    1976-01-01

    The anti-inflammatory drugs, sodium salicylate, indomethacin, hydrocortisone, ibuprofen, and flurbiprofen, were examined for their effects on sulphated glycosaminoglycan synthesis in aged human cartilage in vitro. Cartilage was obtained from femoral heads removed during surgery and drug effects were found to vary significantly from one head to another. Statistical analysis of the results showed that sodium salicylate exhibits concentration-dependent inhibition of glycosaminoglycan synthesis over the concentration range used. Indomethacin, hydrocortisone, and ibuprofen, at concentrations comparable to those attained in man, caused a statistically significant depression of sulphated glycosaminoglycan synthesis in cartilage from some femoral heads but not others, reflecting the variable response of human articular cartilage to anti-inflammatory drugs. Sodium salicylate and indomethacin at higher doses produced significant (Pless than 0-005) inhibition of sulphated glycosaminoglycan synthesis in all femoral heads studied. The results for flurbiprofen were less conclusive; this compound appears not to inhibit glycosaminoglycan synthesis over the concentration range used. PMID:1008617

  10. Vasorelaxant effect of nitric oxide releasing steroidal and nonsteroidal anti-inflammatory drugs

    PubMed Central

    Keeble, J; Al-Swayeh, O A; Moore, P K

    2001-01-01

    The effect of several nitric oxide releasing-non-steroidal anti-inflammatory drugs (NO-NSAID) and nitroprednisolone on blood vessel relaxation in vitro and in vivo was studied. Nitroflurbiprofen (NOF; EC50, 688.8±93.8 μM), nitroaspirin (NOA; EC50, 57.9±6.5 μM), nitroparacetamol (NOPARA; EC50, 71.5±14.6 μM) and nitroprednisolone (EC50, 15.1±1.4 μM) caused concentration-related relaxation of noradrenaline (NA)-contracted rat aortic rings. All NO releasing compounds tested were approximately three orders of magnitude less potent than sodium nitroprusside (SNP, EC50, 35.7±3.5 nM).The vasorelaxant effect of NOF and NOPARA in the rat aorta was potentiated by zaprinast (5 μM) and reduced by ODQ (5 μM). Flurbiprofen and paracetamol (100 μM) caused minimal (<10%) relaxation of the rat aorta and did not affect the response to SNP. The effect of NOF was unchanged in the presence of L-NAME (100 μM; EC30, 181.8±35.1 μM cf. EC30, 125.1±17.0 μM, P>0.05) but increased by removal of the endothelium (EC30, 164.3±26.3 μM cf. EC50, 688.8±93.8 μM, P<0.05).NOF (0.1–50 μM) produced a small but not concentration-related vasodilation of the NA-preconstricted (i.e. ‘high tone') perfused rat mesentery preparation (cf. SNP, EC30, 4.4±0.7 μM). In contrast, NOF (1–100 μM) produced concentration-related vasodilation of the ‘high tone' perfused rat kidney with an EC50 of 33.1±4.4 μM.Neither NOF (74 mg kg−1, i.p.) nor NOA (91.9 mg kg−1, i.p.) nor equimolar doses of flurbiprofen (50 mg kg−1, i.p.) or aspirin (50 mg kg−1, i.p.) affected mean arterial blood pressure (MAP) or heart rate (HR) of pentobarbitone-anaesthetized rats over a 1 h period.NO-NSAID relax blood vessels in vitro by an NO-dependent mechanism. The absolute vasorelaxant effect of NO releasing drug varies greatly with the choice of compound and between blood vessel preparations. PMID:11487511

  11. What we know about nonsteroidal anti-inflammatory drug hypersensitivity

    PubMed Central

    Pham, Duy Le; Kim, Ji-Hye; Trinh, Tu Hoang Kim; Park, Hae-Sim

    2016-01-01

    Nonsteroidal anti-inf lammatory drugs (NSAIDs) are widely prescribed for the treatment of inflammatory diseases, but their use is frequently related to hypersensitivity reactions. This review outlines our current knowledge of NSAID hypersensitivity (NHS) with regard to its pathogenic, molecular, and genetic mechanisms, as well as diagnosis and treatment. The presentation of NHS varies from a local (skin and/or airways) reaction to systemic reactions, including anaphylaxis. At the molecular level, NHS reactions can be classified as cross-reactive (mediated by cyclooxygenase inhibition) or selective (specific activation of immunoglobulin E antibodies or T cells). Genetic polymorphisms and epigenetic factors have been shown to be closely associated with NHS, and may be useful as predictive markers. To diagnose NHS, inhalation or oral challenge tests are applied, with the exclusion of any cross-reactive NSAIDs. For patients diagnosed with NHS, absolute avoidance of NSAIDs/aspirin is essential, and pharmacological treatment, including biologics, is often used to control their respiratory and cutaneous symptoms. Finally, desensitization is recommended only for selected patients with NHS. However, further research is required to develop new diagnostic methods and more effective treatments against NHS. PMID:27030979

  12. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

    PubMed Central

    Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin’ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD. PMID:27621596

  13. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors.

    PubMed

    Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin'ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

  14. [Chemical-physical compatibility of thiocolchicoside and nonsteroidal anti-inflammatory drugs].

    PubMed

    Pifferi, G

    1993-06-01

    The combined therapy requires the knowledge of possible interactions between the drugs used. In the case of parenteral formulations the physiochemical stability must be preliminarily verified in an extemporary mixture. The study protocol should be able to make evident possible variations of the main physicochemical parameters at room temperature and in stress conditions. Examples of drug-drug interactions are taken from literature to better define the issue of compatibility in solution. The results of an experimental study between an injectable thiocolchicoside, a well-known miorelaxants and some non-steroidal antiinflammatory drugs are also reported.

  15. Anti-inflammatory drugs interacting with Zn (II) metal ion based on thiocyanate and azide ligands: Synthesis, spectroscopic studies, DFT calculations and antibacterial assays

    NASA Astrophysics Data System (ADS)

    Chiniforoshan, Hossein; Tabrizi, Leila; Hadizade, Morteza; Sabzalian, Mohammad R.; Chermahini, Alireza Najafi; Rezapour, Mehdi

    2014-07-01

    Zinc (II) complexes with non-steroidal anti-inflammatory drugs (NSAIDs) naproxen (nap) and ibuprofen (ibu) were synthesized in the presence of nitrogen donor ligands (thiocyanate or azide). The complexes were characterized by elemental analysis, FT-IR, 1H NMR and UV-Vis spectroscopes. The binding modes of the ligands in complexes were established by means of molecular modeling of the complexes, and calculation of their IR, NMR and absorption spectra at DFT (TDDFT)/B3LYP level were studied. The experimental and calculated data verified monodentate binding through the carboxylic oxygen atoms of anti-inflammatory drugs in the zinc complexes. The calculated 1H, FT-IR and UV-Vis data are in better agreement with the experimental results, and confirm the predicted tetrahedral structures for the Zn (II) complexes. In addition to DFT calculations of complexes, natural bond orbital (NBO) was performed at B3LYP/6-31+G(d,p) level of theory. Biological studies showed the antibacterial activity of zinc complexes against Gram-positive and Gram-negative bacterial strains.

  16. The effect of nonsteroidal anti-inflammatory drugs on the equine intestine.

    PubMed

    Marshall, J F; Blikslager, A T

    2011-08-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the management of pain and endotoxaemia associated with colic in the horse. While NSAIDs effectively treat the symptoms of colic, there is evidence to suggest that their administration is associated with adverse gastrointestinal effects including right dorsal colitis and inhibition of mucosal barrier healing. Several studies have examined the pathophysiology of NSAID associated effects on the large and small intestine in an effort to avoid these complications and identify effective alternative medications. Differences in the response of the large and small intestines to injury and NSAID treatment have been identified. Flunixin meglumine has been shown in the small intestine to inhibit barrier function recovery and increase permeability to lipopolysaccharide (LPS). A range of NSAIDs has been examined in the small intestine and experimental evidence suggests that those NSAIDs with cyclooxygenase independent anti-inflammatory effects or a COX-2 selective mode of action may offer significant advantages over traditional NSAIDs.

  17. Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review

    PubMed Central

    Qandil, Amjad M.

    2012-01-01

    The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action. PMID:23247285

  18. Helicobacter pylori and non-steroidal anti-inflammatory drugs: does infection affect the outcome of NSAID therapy?

    PubMed Central

    McCarthy, D. M.

    1998-01-01

    1. H. pylori gastritis appears to increase the likelihood of developing dyspeptic symptoms on NSAID therapy. 2. There is preliminary evidence that the histologic severity of H. pylori gastritis may be adversely affected by NSAID therapy, with a consequent increase in the risk of developing a peptic ulcer, possibly with complications. Whether this results from an effect on the inflammatory process or results from a quantitative increase in H. pylori colonization is unknown. In these respects, ASA may differ from other NSAIDs. 3. Ulcers are more likely to develop during the course of NSAID therapy in those infected with H. pylori; eradication of the infection reduces ulcer recurrence in the face of continued NSAID therapy, and it seems likely that this must reduce but not abolish the risk of GI bleeding in those using NSAIDs. Eradication also reduces the damage (and possibly risks) of low-dose aspirin therapy. 4. While H. pylori and NSAID use are independent risk factors for GI bleeding, whether or not they are interactive remains unresolved. 5. The effect of H. pylori infection on the risk of perforation during NSAID therapy, or conversely, the contribution of NSAID therapy to the risk of perforation in H. pylori-infected subjects, is also unclear at the present time. 6. Only large outcome studies of accurately diagnosed patients (with regard to H. pylori gastritis), and with much more specific detail as to the type of NSAID, dose and duration of therapy, employing only well-defined end-points, such as significant hemorrhage, perforation or death, and avoiding all surrogate markers short of these end points can hope to unravel this tangled web. PMID:10378355

  19. Effects of a non-steroidal anti-inflammatory drug on delayed onset muscle soreness and indices of damage.

    PubMed Central

    Donnelly, A E; McCormick, K; Maughan, R J; Whiting, P H; Clarkson, P M

    1988-01-01

    Twenty untrained male volunteers were required to run downhill for 45 minutes on a motor driven treadmill to induce muscle soreness. The volunteers took diclofenac or placebo before and for 72 hours after two runs 10 weeks apart, in a randomised double blind crossover design. Subjective soreness was assessed before and at intervals up to 72 hours after each run; venous blood samples, collected at the same time intervals, were used to estimate serum activities of creatine kinase, lactate dehydrogenase and aspartate aminotransferase and serum concentrations of creatinine and urea. Subjective soreness and the biochemical parameters increased after both runs, although the serum enzyme response to the second run was reduced. Diclofenac had no influence on the serum biochemical response to downhill running. Although overall soreness was not affected by diclofenac, individual soreness measurements were reduced by diclofenac at the first period of the study. These results suggest that diclofenac does not influence muscle damage, but may slightly reduce the associated soreness. PMID:3370401

  20. Solubility enhancement of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) using polypolypropylene oxide core PAMAM dendrimers.

    PubMed

    Koç, Fatma Ebru; Senel, Mehmet

    2013-07-15

    The aim of the present study was to evaluate the aqueous solubility enhancement properties of polypropylene oxide cored PAMAM (PPO@PAMAM) dendrimers. The solubility of NSAIDs (Ketoprofen, Ibuprofen and Diflunisal) was investigated in the presence of PPO@PAMAM dendrimers at room temperature in buffer solution. The effects of dendrimer concentration, generation and core size on the solubility of NSAIDs have been investigated. The experimental results showed that the solubility of the NSAIDs was approximately proportional to dendrimer concentration and generation. In addition, the effect of core size on the solubility of NSAIDs in constant generation and concentration of PPO@PAMAM dendrimer was Ketoprofen>Diflunisal>Ibuprofen. Under optimized conditions, PPO@PAMAM dendrimers are highly effective solubility enhancer for NSAIDs due to its new polypropylene oxide core.

  1. Adjunctive treatment of decompression illness with a non-steroidal anti-inflammatory drug (tenoxicam) reduces compression requirement.

    PubMed

    Bennett, M; Mitchell, S; Dominguez, A

    2003-01-01

    We report a randomized trial examining adjunctive administration of the NSAID, tenoxicam, to divers suffering with DCI. 180 subjects were graded for severity on admission and randomized according to a stratified random number schedule. Subjects were recompressed and treatment continued daily until symptom stabilization or complete resolution. Tenoxicam 20 mg or a placebo preparation was administered at the first air break during the initial recompression and continued daily for seven days. The subjects were assessed using a recovery status score at the completion of treatment and at 4-6 weeks. The proportion of patients with mild residual symptoms at discharge and final follow-up was not significantly different (discharge placebo 30% versus tenoxicam 37%, P=0.41; six weeks placebo 20% versus tenoxicam 17%, P=0.58). There was a significant reduction in the number of treatments required to achieve discharge (median treatments placebo 3, tenoxicam 2, P=0.01). 61% of patients in the tenoxicam group required less than 3 compressions, versus 40% in the placebo group (P=0.01, RRR 33 % [95%CI 9%-56%], NNT=5 [95%CI 3-18]). There was no evidence of increased complications of treatment in the tenoxicam group. When given this NSAID, patients with DCI require fewer hyperbaric oxygen (HBO2) sessions to achieve a standard clinical end-point and there is likely to be an associated cost saving.

  2. Deep Tissue Massage and Nonsteroidal Anti-Inflammatory Drugs for Low Back Pain: A Prospective Randomized Trial

    PubMed Central

    Kocur, Piotr

    2014-01-01

    Objective. To investigate whether chronic low back pain therapy with deep tissue massage (DTM) gives similar results to combined therapy consisting of DTM and non-steroid anti-inflammatory drugs (NSAID). Design. Prospective controlled randomized single blinded trial. Settings. Ambulatory care of rehabilitation. Participants. 59 patients, age 51.8 ± 9.0 years, with chronic low back pain. Interventions. 2 weeks of DTM in the treatment group (TG) versus 2 weeks of DTM combined with NSAID in the control group (CG). Main Outcome Measures. Visual analogue scale, Oswestry disability index (ODI), and Roland-Morris questionnaire (RM). Results. In both the TG and the CG, a significant pain reduction and function improvement were observed. VAS decreased from 58.3 ± 18.2 to 42.2 ± 21.1 (TG) and from 51.8 ± 18.8 to 30.6 ± 21.9 (CG). RM value decreased from 9.8 ± 5.1 to 6.4 ± 4.4 (TG), and from 9.3 ± 5.5 to 6.1 ± 4.6 (CG). ODI value decreased from 29.2 ± 17.3 to 21.4 ± 15.1 (TG) and from 21.4 ± 9.4 to 16.6 ± 9.4 (CG). All pre-post-treatment differences were significant; however, there was no significant difference between the TG and the CG. Conclusion. DTM had a positive effect on reducing pain in patients with chronic low back pain. Concurrent use of DTM and NSAID contributed to low back pain reduction in a similar degree that the DTM did. PMID:24707200

  3. [Role of anti-inflammatory drugs in the treatment of acute coronary syndromes. From athero-inflammation to athero-thrombosis].

    PubMed

    Altman, Raúl; Scazziota, Alejandra

    2003-01-01

    Coronary thrombosis is the most important cause of morbidity and mortality and the most severe manifestation of atherosclerosis. Knowledge of the pathophysiology of atheroma formation and the causes of atheroma accidents have allowed the development of new therapeutic measures for reducing thrombotic events after a coronary episode. Treating the thrombosis after plaque rupture is useful, but a late measure once coronary flow is disturbed. Therefore, treatment at an earlier stage, which we call athero-inflammation, a central event in atheroma progression leading to atherothrombosis, seems wise. There is evidence of an inflammatory component in the pathogenesis of atheroma rupture in acute coronary events. Earlier studies of anti-inflammatory medication have not demonstrated a reduction in thrombotic complications after an acute coronary episode. However, there are pathophysiological arguments and clinical findings that suggest that it would be advisable to include anti-inflammatory medications, especially those that inhibit preferentially COX-2, in the therapeutic arsenal for this pathology. We postulated that blocking athero-inflammation could prevent thrombosis. A pilot study was carried out in 120 patients with acute coronary syndrome without ST-segment elevation in which 60 patients were treated with meloxicam, a preferential COX-2 inhibitor. All patients received heparin and aspirin. During the stay in the coronary care unit, as well as after 90 days, meloxicam lowered composite outcomes (myocardial infarction, death and revascularization procedures) compared with the control group. These results and available pathophysiological and clinical evidence support the hypothesis of potential benefits of non-steroidal anti-inflammatory drugs with preferential inhibitory activity on COX-2 in patients with acute coronary syndromes. More trials are needed to confirm their preventive effect.

  4. Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs.

    PubMed

    Perez-Caballero, L; Pérez-Egea, R; Romero-Grimaldi, C; Puigdemont, D; Molet, J; Caso, J-R; Mico, J-A; Pérez, V; Leza, J-C; Berrocoso, E

    2014-05-01

    Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.

  5. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs

    PubMed Central

    Ong, C.K.S.; Lirk, P.; Tan, C.H.; Seymour, R.A.

    2007-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclooxygenase (COX)-2 inhibitors, are widely used for their anti-inflammatory and analgesic effects. NSAIDs are a necessary choice in pain management because of the integrated role of the COX pathway in the generation of inflammation and in the biochemical recognition of pain. This group of drugs has recently come under scrutiny because of recent focus in the literature on the various adverse effects that can occur when applying NSAIDs. This review will provide an educational update on the current evidence of the efficacy and adverse effects of NSAIDs. It aims to answer the following questions: (1) are there clinically important differences in the efficacy and safety between the different NSAIDs, (2) if there are differences, which are the ones that are more effective and associated with fewer adverse effects, and (3) which are the effective therapeutic approaches that could reduce the adverse effects of NSAIDs. Finally, an algorithm is proposed which delineates a general decision-making tree to select the most appropriate analgesic for an individual patient based on the evidence reviewed. PMID:17456832

  6. Lemon grass (Cymbopogon citratus) essential oil as a potent anti-inflammatory and antifungal drugs.

    PubMed

    Boukhatem, Mohamed Nadjib; Ferhat, Mohamed Amine; Kameli, Abdelkrim; Saidi, Fairouz; Kebir, Hadjer Tchoketch

    2014-01-01

    Background Volatile oils obtained from lemon grass [Cymbopogon citratus (DC.) Stapf, Poaceae family] are used in traditional medicine as remedies for the treatment of various diseases. Aims In the present study, lemon grass essential oil (LGEO) was evaluated for its in vivo topical and oral anti-inflammatory effects, and for its in vitro antifungal activity using both liquid and vapor phases. Methods The chemical profile of LGEO as determined by gas chromatography-mass spectrometry analysis revealed two major components: geranial (42.2%), and neral (31.5%). The antifungal activity of LGEO was evaluated against several pathogenic yeasts and filamentous fungi using disc diffusion and vapor diffusion methods. Results LGEO exhibited promising antifungal effect against Candida albicans, C.tropicalis, and Aspergillus niger, with different inhibition zone diameters (IZDs) (35-90 mm). IZD increased with increasing oil volume. Significantly, higher anti-Candida activity was observed in the vapor phase. For the evaluation of the anti-inflammatory effect, LGEO (10 mg/kg, administered orally) significantly reduced carrageenan-induced paw edema with a similar effect to that observed for oral diclofenac (50 mg/kg), which was used as the positive control. Oral administration of LGEO showed dose-dependent anti-inflammatory activity. In addition, topical application of LGEO in vivo resulted in a potent anti-inflammatory effect, as demonstrated by using the mouse model of croton oil-induced ear edema. To our knowledge, this is the first such report to be published. The topical application of LGEO at doses of 5 and 10 µL/ear significantly reduced acute ear edema induced by croton oil in 62.5 and 75% of the mice, respectively. In addition, histological analysis clearly confirmed that LGEO inhibits the skin inflammatory response in animal models. Conclusion Results of the present study indicate that LGEO has a noteworthy potential for the development of drugs for the treatment of

  7. Lemon grass (Cymbopogon citratus) essential oil as a potent anti-inflammatory and antifungal drugs

    PubMed Central

    Boukhatem, Mohamed Nadjib; Ferhat, Mohamed Amine; Kameli, Abdelkrim; Saidi, Fairouz; Kebir, Hadjer Tchoketch

    2014-01-01

    Background Volatile oils obtained from lemon grass [Cymbopogon citratus (DC.) Stapf, Poaceae family] are used in traditional medicine as remedies for the treatment of various diseases. Aims In the present study, lemon grass essential oil (LGEO) was evaluated for its in vivo topical and oral anti-inflammatory effects, and for its in vitro antifungal activity using both liquid and vapor phases. Methods The chemical profile of LGEO as determined by gas chromatography–mass spectrometry analysis revealed two major components: geranial (42.2%), and neral (31.5%). The antifungal activity of LGEO was evaluated against several pathogenic yeasts and filamentous fungi using disc diffusion and vapor diffusion methods. Results LGEO exhibited promising antifungal effect against Candida albicans, C. tropicalis, and Aspergillus niger, with different inhibition zone diameters (IZDs) (35–90 mm). IZD increased with increasing oil volume. Significantly, higher anti-Candida activity was observed in the vapor phase. For the evaluation of the anti-inflammatory effect, LGEO (10 mg/kg, administered orally) significantly reduced carrageenan-induced paw edema with a similar effect to that observed for oral diclofenac (50 mg/kg), which was used as the positive control. Oral administration of LGEO showed dose-dependent anti-inflammatory activity. In addition, topical application of LGEO in vivo resulted in a potent anti-inflammatory effect, as demonstrated by using the mouse model of croton oil-induced ear edema. To our knowledge, this is the first such report to be published. The topical application of LGEO at doses of 5 and 10 µL/ear significantly reduced acute ear edema induced by croton oil in 62.5 and 75% of the mice, respectively. In addition, histological analysis clearly confirmed that LGEO inhibits the skin inflammatory response in animal models. Conclusion Results of the present study indicate that LGEO has a noteworthy potential for the development of drugs for the treatment of

  8. Influence of Anti-inflammatory Drugs on the Rheological Properties of Synovial Fluid and Its Components

    NASA Astrophysics Data System (ADS)

    Krause, Wendy E.; Klossner, Rebecca R.; Liang, Jing; Colby, Ralph H.

    2006-03-01

    The polyelectrolyte hyaluronic acid (HA, hyaluronan), its interactions with anti-inflammatory drugs and other biopolymers, and its role in synovial fluid are being studied. We are investigating the rheological properties of sodium hyaluronate (NaHA) solutions and an experimental model of synovial fluid (comprised of NaHA, and the plasma proteins albumin and γ-globulins). Steady shear measurements on bovine synovial fluid, the synovial fluid model, and plasma protein solutions indicate that the fluids are rheopectic (stress increases with time under steady shear). In addition, the influence of anti-inflammatory agents on these solutions is being explored. Initial results indicate that D-penicillamine and hydroxychloroquine (HCQ) affect the rheology of the synovial fluid model and its components. While HCQ has no effect on the viscosity of NaHA solutions, it inhibits/suppresses the observed rheopexy of the synovial fluid model and plasma protein solutions. In contrast, D-penicillamine has a complex, time dependent effect on the viscosity of NaHA solutions,---reducing the zero shear rate viscosity of a 3 mg/mL NaHA (in phosphate buffered saline) by ca. 40% after 44 days. The potential implications of these results will be discussed.

  9. Photodegradation mechanism of nonsteroidal anti-inflammatory drugs containing thiophene moieties: suprofen and tiaprofenic acid.

    PubMed

    Musa, Klefah A K; Eriksson, Leif A

    2009-08-13

    The photodegradation of nonsteroid anti-inflammatory drugs suprofen, 2-[4-(2-thienoyl)phenyl]propionic acid, and tiaprofenic acid, 2-(5-benzoyl-2-thienyl)propanoic acid, is studied by means of density functional theory. Besides the redox properties of the neutral species, we report on absorption spectra and degradation pathways involving excitation, intersystem crossing to the T(1) state, and spontaneous decarboxylation of the deprotonated species of each drug. The energetics and properties of the suprofen and tiaprofenic acid systems are found to be very similar to those of the highly photolabile benzyl analogue ketoprofen. Mechanisms leading to the formation of a closed-shell decarboxylated ethyl species, as well as peroxyl radicals capable of initiating lipid peroxidation reactions, are discussed.

  10. Prevention and treatment of ulcers induced by nonsteroidal anti-inflammatory drugs: an update.

    PubMed

    Dajani, E Z; Agrawal, N M

    1995-03-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are most frequently used for the treatment of rheumatic disease due to their anti-inflammatory and analgesic properties. All NSAIDs have the potential to cause damage to the gastrointestinal (GI) tract and have been associated with the induction of peptic ulcers and massive life-threatening bleeding. The therapeutic approaches for the treatment and prevention of NSAID-induced ulcers is critically reviewed using data derived from carefully controlled, world-wide clinical studies with anti-ulcer drugs. Histamine (H2) antagonists, omeprazole, sucralfate and E-prostaglandin (PGE) analogs are effective for the treatment of NSAID-induced gastric and duodenal ulcers, if NSAIDs are discontinued. However, if NSAIDs are continued while GI damage is present, the PGE analogs misoprostol, arbaprostil and enprostil have shown efficacy in healing NSAID-induced ulcers. Furthermore, one limited clinical study demonstrated that omeprazole has efficacy in healing NSAID-associated ulcers. Neither H2 antagonists, sucralfate and sulglycotide (a cytoprotective drug) have shown efficacy in preventing NSAID-induced gastric ulcers. However H2 antagonists have shown efficacy in preventing NSAID-induced duodenal ulcers. In contrast, only misoprostol prevents the development of NSAID-induced gastric and duodenal ulcers. Such pharmacological observations suggest that the pathophysiologic mechanisms for the induction of NSAID-induced gastric ulcer are distinctly different from those of NSAID-induced duodenal ulcers. Mild diarrhea and GI intolerance were the predominant adverse reactions experienced by patients receiving synthetic PGEs, particularly enprostil and arbaprostil. From the published data, we conclude that misoprostol is the only anti-ulcer drug proven to be well tolerated and effective for the treatment and prevention of NSAID-induced gastric and duodenal ulcers in patients receiving chronic NSAIDs therapy.

  11. Rheology-sensitive response of zeolite-supported anti-inflammatory drug systems.

    PubMed

    Pasquino, R; Di Domenico, M; Izzo, F; Gaudino, D; Vanzanella, V; Grizzuti, N; de Gennaro, B

    2016-10-01

    Drug release from inorganic supports is a challenge for the scientific community for various reasons, related to the low costs of the systems and the possibility of easily regulating the drug release. In the present work, surface-modified zeolite particles are used as carriers for non steroidal antiflammatory drugs (NSAIDs). The release of the drug has been studied in a solution that simulates the intestinal fluid as well as in a gel-like system, based on a surfactant and a binding salt. In the solution case, the quantity of drug released has been tracked via spectrophotometric assay. Release in the gel has been monitored by rheological methods. The molecular conformation of the NSAIDs is fundamental for the interaction with the zeolite surface, whose modified surface has a strong binding energy. It has been proven that the main mechanism for the drug release is anion exchange. It has been found that the NSAIDs, used in their sodic form, can act as binding salts by themselves in the gel-like system, thus changing the viscoelastic response of the overall solution. Drug release kinetics in the solution compare quantitatively well with the released drug in the gel-like fluid, as measured by rheometry.

  12. PMMA/polysaccharides nanofilm loaded with adenosine deaminase inhibitor for targeted anti-inflammatory drug delivery.

    PubMed

    Redolfi Riva, Eugenio; Desii, Andrea; Sartini, Stefania; La Motta, Concettina; Mazzolai, Barbara; Mattoli, Virgilio

    2013-10-29

    A novel drug delivery vector, a free-standing polymeric ultrathin film (nanofilm) composed of PMMA and a polysaccharides multilayer, is presented. Chitosan and sodium alginate are alternatively deposited by spin-assisted LbL assembly onto a plasma-treated PMMA thin film. Hydrophobic anti-inflammatory drugs, an adenosine deaminase inhibitor (APP) and its fluorescent dansyl derivate (APP-Dns), are encapsulated inside the LbL multilayer using a simple casting deposition procedure. The resulting drug loaded nanofilm can be suspended in water upon dissolution of a PVA sacrificial layer. Morphological characterization of the nanofilm shows that PMMA/LbL nanofilms possess nanometric thickness (<200 nm) and very low surface roughness (1-2 nm for drug loaded nanofilms and <1 nm for blank nanofilm). Drug loaded films exhibit a diffusion controlled release mechanism following the Korsmayer-Peppas release model, confirmed by the fit of release data with a characteristic power law. Drug release is impaired through the PMMA layer, which acts effectively as a barrier for drug transport. This ultrathin polymer film can find application as a nanopatch for targeted inflammatory drug delivery to treat localized pathologies as inflammatory bowel disease.

  13. [Myocarditis in a cachectic female, nonsteroidal anti-inflammatory drugs abuser, in a course of progressive systemic sclerosis].

    PubMed

    Wozakowska-Kapłon, Beata; Gorczyca, Iwona; Maciejowska-Roge, Maria

    2009-11-01

    A case of 70-year-old cachectic female, nonsteroid anti-inflammatory drugs abuser, with progressive systemic sclerosis, who was admitted to our hospital due to joint pain and fatigue is presented. During hospitalisation the patient developed symptoms of acute myocarditis. Angiography of coronary arteries did not reveal narrowing of the vessels. Alimentary supplementation and therapy for heart failure (diuretics, vasodilators, angiotensin-converting enzyme inhibitor and beta-blocker) were used. In repeated echocardiography examinations ejection fraction systematically improved and hemodynamic stabilisation was obtained. Scleroderma, malnutrition, toxicity of nonsteroid anti-inflammatory drugs and infectious agents were considered as a cause of myocarditis.

  14. Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-{gamma}-induced expression of the chemokine CXCL9 gene in mouse macrophages

    SciTech Connect

    Sakaeda, Yoshiichi; Hiroi, Miki; Shimojima, Takahiro; Iguchi, Mayumi; Kanegae, Haruhide; Ohmori, Yoshihiro . E-mail: ohmori@dent.meikai.ac.jp

    2006-11-17

    Sulindac, a non-steroidal anti-inflammatory drug, has been shown to exert an anti-tumor effect on several types of cancer. To determine the effect of sulindac on intracellular signaling pathways in host immune cells such as macrophages, we investigated the effect of the drug on interferon gamma (IFN{gamma})-induced expression of signal transducer and activator of transcription 1 (STAT1) and other genes in mouse macrophage-like cell line RAW264.7 cells. Sulindac, but not aspirin or sodium salicylate, inhibited IFN{gamma}-induced expression of the CXC ligand 9 (CXCL9) mRNA, a chemokine for activated T cells, whereas the interferon-induced expression of CXCL10 or IFN regulatory factor-1 was not affected by sulindac. Luciferase reporter assay demonstrated that sulindac inhibited IFN{gamma}-induced promoter activity of the CXCL9 gene. Surprisingly, sulindac had no inhibitory effect on IFN{gamma}-induced STAT1 activation; however, constitutive nuclear factor {kappa}B activity was suppressed by the drug. These results indicate that sulindac selectively inhibited IFN{gamma}-inducible gene expression without inhibiting STAT1 activation.

  15. Graphene nanoparticles as pseudostationary phase for the electrokinetic separation of nonsteroidal anti-inflammatory drugs.

    PubMed

    Benítez-Martínez, Sandra; Simonet, Bartolomé M; Valcárcel, Miguel

    2013-09-01

    The exceptional properties of graphene (G) were exploited here to facilitate capillary electrokinetic separations. Two types of commercially available G consisting of nanoparticles containing-one to three and-four to six G sheets, respectively, were compared for this purpose. Both proved effective in separating the arylpropyl derivatives of nonsteroidal anti-inflammatory drugs. The highest resolution and shortest migration times were obtained with G containing high amount of single and double G nanosheets. G affords higher resolution than other types of nanoparticles; stable suspensions can be easily prepared and used as BGE without the need of adding an additional surfactant. This results in a high reproducibility in migration times and stability in background noise. The LOD and LOQ obtained by using G nanoparticles as pseudostationary phases spanned the range 0.29-1.18 mg/L and 0.95-3.95 mg/L, respectively, and the RSD was less than 4.7% in all instances.

  16. Novel self-assembly graft copolymers as carriers for anti-inflammatory drug delivery.

    PubMed

    Bury, Katarzyna; Neugebauer, Dorota

    2014-01-02

    Indomethacin (IMC) and quercetin (QUE) as typical models of anti-inflammatory drugs were loaded into the micelles of new amphiphilic graft copolymers, comprising caprolactone 2-(methacryloyloxy)ethyl ester (CLMA) units in the main chain and poly(meth)acrylic acid side chains (PAA/PMAA), which were studied as the carriers of drugs. The macromolecules were self-assembled by solvent evaporation or dialysis. The critical micelle concentration (CMC) ranged from 0.015 to 0.199 mg/ml. The copolymer composition, grafting degree and length of side chains, nature and content of hydrophobic/hydrophilic part, were investigated as the main parameters responsible for the properties of nanoparticles including their stability, core-drug interactions, improved drug solubility, and in consequence the efficiency of drug-loading and drug release profiles. The hydrodynamic diameters of particles measured by dynamic light scattering (DLS) ranged from 50 to 275 nm, and increased after loading with drug. In vitro release experiments performed at various pH (5.0 and 7.4) indicated faster release behavior from nanoparticles in acidic conditions (55-95% vs. 25-45% within 75 h).

  17. Anti-Inflammatory Chemical Profiling of the Australian Rainforest Tree Alphitonia petriei (Rhamnaceae).

    PubMed

    Raju, Ritesh; Gunawardena, Dhanushka; Ahktar, Most Afia; Low, Mitchell; Reddell, Paul; Münch, Gerald

    2016-11-11

    Chronic inflammation is an important pathological condition in many human diseases, and due to the side effects of the currently used non-steroidal anti-inflammatory drugs, discovery of novel anti-inflammatory drugs is of general interest. Anti-inflammatory activity guided compound isolation from the plant Alphitonia petriei led to the isolation of the known plant sterols emmolic acid (1), alphitolic acid (2), trans- and cis-coumaroyl esters of alphitolic acid (3 and 4) and betulinic acid (5). A detailed spectroscopic analysis led to the structure elucidation of the alphitolic acid derivatives (1-5), and the semi-synthetic emmolic acid acetate (6). When tested in LPS (Lipopolysaccharides) + IFN-γ (Interferon gamma) activated RAW 264.7 macrophages, all compounds except (1) exhibited potent anti-inflammatory activity (IC50 values as low as 1.7 μM) in terms of downregulation of NO and TNF-α production, but also demonstrated some considerable cytotoxicity.

  18. Nonsteroidal Anti-Inflammatory Drug Use and Endurance During Running in Male Long-Distance Runners

    PubMed Central

    Da Silva, Eduardo; Pinto, Ronei S.; Cadore, Eduardo L.; Kruel, Luiz F.

    2015-01-01

    Context: The effect of ibuprofen on pain tolerance during exercise is controversial, and its effects on endurance performance have been poorly investigated. Objective: To investigate the effect of prophylactic administration of the nonsteroidal anti-inflammatory drug ibuprofen on the time until the self-report of fatigue (tlim) in runners with exercise-induced muscle damage. Design: Randomized controlled clinical trial. Setting: Laboratory. Patients or Other Participants: Twenty healthy male long-distance runners (age = 18.8 ± 0.4 years, maximal oxygen consumption = 55.5 ± 5.9 mL·kg−1·min−1). Intervention(s): Participants were assigned to 2 groups (ibuprofen group = 10, placebo group = 10) to perform tlim trials (speed corresponded to their previously determined secondventilatory thresholds) 48 hours before and 48 hours after the induction of a lower limb muscle-damage protocol (isokinetic dynamometry). One hour before the second tlim trial, the ibuprofen group received 1.2 g ibuprofen, and the placebo group received lactose orally. Main Outcome Measure(s): Time until self-reported fatigue, heart rate, respiratory quotient, oxygen consumption, and perceived exertion were recorded during each tlim test. Results: Both groups reported increases in muscle pain in the knee extensors and flexors 48 hours after the muscle-damage protocol. We observed a reduction in the endurance performance of both groups (P < .01) but no difference between groups (P = .55). Conclusions: Ibuprofen did not reduce the effect of muscle damage and pain on performance. Prophylactic use of nonsteroidal anti-inflammatory drugs did not have an ergogenic effect on running performance after exercise-induced muscle damage in male long-distance runners. PMID:25622243

  19. Micronization of anti-inflammatory drugs for pulmonary delivery by a controlled crystallization process.

    PubMed

    Rasenack, Norbert; Steckel, Hartwig; Müller, Bernd W

    2003-01-01

    Jet-milling as the common way for micronization of drugs shows several disadvantages. Drug powder properties are decisive for pulmonary use because, besides a small particle size, a good deagglomeration behavior is required. In this study, several anti-inflammatory drugs [beclomethasone-17,21-dipropionate (BDP), betamethasone-17-valerate (BV), triamcinolone acetonide, ECU-R2, budesonide, and prednisolone] were micronized by controlled crystallization without any milling processes. First the drug is dissolved in an organic solvent (BDP/BV: 4%; ECU-R2: 1% in acetone) and precipitated by a solvent change method in the presence of a cellulose ether (hydroxypropylmethylcellulose) as stabilizing hydrocolloid. By rapid pouring the solution of hydroxypropylmethylcellulose in water (BDP/BV: 0.005%; ECU-R2: 0.025%) into the drug solution under stirring in a relationship (v/v) of 1:16 (BDP/BV), 1:4 (ECU-R2), the previously molecularly dispersed drug was associated to small particles and stabilized against crystal growth simultaneously. This dispersion was spray-dried, resulting in a drug powder with a uniform particle-size distribution and a drug load of up to 98% (BDP, BV). The mean particle size of the drug was lower than 5 microm in most cases and consequently in the respirable range. Whereas the fine particle fraction (<5 microm, measured without excipients and without an inhalation device) of jet-milled drugs is 9.5 (BDP) or 13.1 (ECU-R2), fine particle fractions of 25.6% (BDP) resp. 78.2% (ECU-R2) are obtained with the spray-dried powders. As the formation of the small crystals requires a rapid solvent change process, the affinity of the hydrocolloid, and a high difference between the solubility in the solvent and nonsolvent, the drug's partition coefficient limits the method as drugs which are more hydrophilic form larger particles.

  20. Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials

    PubMed Central

    Gold, Ben; Pingle, Maneesh; Brickner, Steven J.; Shah, Nilesh; Roberts, Julia; Rundell, Mark; Bracken, W. Clay; Warrier, Thulasi; Somersan, Selin; Venugopal, Aditya; Darby, Crystal; Jiang, Xiuju; Warren, J. David; Fernandez, Joseph; Ouerfelli, Ouathek; Nuermberger, Eric L.; Cunningham-Bussel, Amy; Rath, Poonam; Chidawanyika, Tamutenda; Deng, Haiteng; Realubit, Ronald; Glickman, J. Fraser; Nathan, Carl F.

    2012-01-01

    Existing drugs are slow to eradicate Mycobacterium tuberculosis (Mtb) in patients and have failed to control tuberculosis globally. One reason may be that host conditions impair Mtb’s replication, reducing its sensitivity to most antiinfectives. We devised a high-throughput screen for compounds that kill Mtb when its replication has been halted by reactive nitrogen intermediates (RNIs), acid, hypoxia, and a fatty acid carbon source. At concentrations routinely achieved in human blood, oxyphenbutazone (OPB), an inexpensive anti-inflammatory drug, was selectively mycobactericidal to nonreplicating (NR) Mtb. Its cidal activity depended on mild acid and was augmented by RNIs and fatty acid. Acid and RNIs fostered OPB’s 4-hydroxylation. The resultant 4-butyl-4-hydroxy-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione (4-OH-OPB) killed both replicating and NR Mtb, including Mtb resistant to standard drugs. 4-OH-OPB depleted flavins and formed covalent adducts with N-acetyl-cysteine and mycothiol. 4-OH-OPB killed Mtb synergistically with oxidants and several antituberculosis drugs. Thus, conditions that block Mtb’s replication modify OPB and enhance its cidal action. Modified OPB kills both replicating and NR Mtb and sensitizes both to host-derived and medicinal antimycobacterial agents. PMID:23012453

  1. Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Natural products are rich source of gene modulators for prevention and treatment of cancer. In recent days, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a new target of diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural...

  2. Nonsteroidal Anti-Inflammatory Drugs in the Treatment of Retinal Diseases.

    PubMed

    Rodrigues, Eduardo Büchele; Farah, Michel Eid; Bottós, Juliana Mantovani; Bom Aggio, Fabio

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of drugs in medicine and ophthalmology. Several NSAIDs have been commercially available for many years: diclofenac, flurbiprofen, indomethacin, ketorolac and suprofen. The purpose of this chapter is to review the clinical use of earlier and newer pharmacologic agents of the NSAID class. NSAIDs may have a modulating effect on ocular inflammation and pain through the prevention of prostaglandin synthesis via cyclooxygenase inhibition. Newer-generation NSAIDs have emerged in recent years for the treatment of ocular pain and inflammation. Nepafenac ophthalmic suspension 0.1% is a new topical NSAID prodrug that has been approved by the Food and Drug Administration for the treatment of pain and inflammation after cataract surgery. Preliminary data suggest nepafenac may also provide unique efficacy in the posterior segment, since its corneal permeability characteristics are superior to those of other NSAIDs. Nevanac, diclofenac, ketorolac and bromfenac are some notable NSAID candidates which should be investigated intravitreally or topically for retinal pharmacotherapy. In addition, for intraocular surgery, NSAIDs can help to prevent intraoperative miosis, reduce ocular pain, decrease postoperative inflammation and prevent cystoid macular edema. Retinal, choroidal and vitreous diseases may be the target of future nepafenac studies, either as monotherapy or as combination treatments.

  3. Extractive spectrophotometric determination of some nonsteroidal anti-inflammatory drugs using methylene blue.

    PubMed

    El-Kommos, Michael E; Mohamed, Niveen A; Hakiem, Ahmed F Abdel

    2013-01-01

    A simple, rapid, sensitive, and accurate extractive spectrophotometric method has been developed for the determination of seven nonsteroidal anti-inflammatory drugs (NSAIDs)--namely diclofenac sodium, ibuprofen, indomethacin, ketoprofen, ketorolac tromethamine, mefenamic acid, and naproxen-in pure forms as well as their pharmaceutical dosage forms (tablets, capsules, effervescent granules, syrups, oral drops, ampules, eye drops, gels, and suppositories). The method depends on the formation of an intensely colored ion-pair complex between the acidic drug and methylene blue in alkaline medium. The complex is stable and extractable into methylene chloride. All parameters were optimized. Beer-Lambert's law was obeyed in concentrations ranging from 0.04 to 9 microg/mL. Statistical analysis of the calibration data was carried out, and correlation coefficients were in the range from 0.9996 to 0.9998. The developed method was fully validated according to International Conference on Harmonization guidelines, and complied with U.S. Pharmacopeia guidelines. The proposed method was applied to the analysis of the investigated drugs in their pharmaceutical formulations, and good recoveries were obtained. The results obtained were compared with those of reported and official methods, and no significant differences were found with t- and F-tests. Interference effects of some compounds usually present in combination with NSAIDs were studied, and the tolerance limits of these compounds were determined.

  4. New Knowledge About Old Drugs: The Anti-Inflammatory Properties of Cardiac Glycosides.

    PubMed

    Fürst, Robert; Zündorf, Ilse; Dingermann, Theo

    2017-03-15

    In the 19th century, cardio-active steroid glycosides, shortly cardiac glycosides, were scientifically established as drugs against heart failure. Their in vivo, cellular, and molecular actions as well as their predominant target, Na(+)-K(+)-ATPase, have been comprehensively investigated in the 20th century and the discovery of endogenous cardiac glycosides has fostered this research field. In the last years, however, results from clinical trials and meta-analyses have questioned their therapeutic value due to efficacy and safety issues. This has led to a considerable decline of their usage. Beyond the cardiovascular system, cardiac glycosides have been increasingly recognized as antitumor compounds and Na(+)-K(+)-ATPase has evolved into a promising drug target in oncology. A wealth of review articles exists that intensively discuss these topics. Surprisingly, the anti-inflammatory actions of cardiac glycosides, which were discovered in the 1960s, have so far hardly been perceived and have not yet been summarized. This review provides an overview of the in vivo and in vitro actions of cardiac glycosides on inflammatory processes and of the signaling mechanisms responsible for these effects: cardiac glycosides have been found to decrease inflammatory symptoms in different animal models of acute and chronic inflammation. Regarding the underlying mechanisms most research has focused on leukocytes. In these cells, cardiac glycosides primarily inhibit cell proliferation and the secretion of proinflammatory cytokines.

  5. Risk of asthma exacerbation associated with nonsteroidal anti-inflammatory drugs in childhood asthma

    PubMed Central

    Lo, Pei-Chia; Tsai, Yueh-Ting; Lin, Shun-Ku; Lai, Jung-Nien

    2016-01-01

    Abstract Patients allergic to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) who develop respiratory reactions such as bronchospasm or asthma exacerbation have aspirin-induced asthma or NSAIDs-exacerbated respiratory disease. However, large-scale studies have not been conducted to investigate the risk of aspirin/NSAIDs exposure in children with asthma. Therefore, this study evaluated the relationship between aspirin/NSAIDs and the risk of asthma exacerbation in children with asthma. This retrospective cohort study was conducted using the data of 1 million random beneficiaries of the Taiwan National Health Insurance program between 1997 and 2012. Children aged ≦18 years diagnosed with asthma by physicians were enrolled. The study population was divided into the index group (concurrently using antiasthmatic agents and NSAIDs patients) and reference group (using antiasthmatic drugs alone), and the relative risks (RRs) of hospitalizations resulting from asthma exacerbation in both groups were estimated. The rate of asthma exacerbation was higher in the index group than the reference group, resulting in asthma-related hospitalizations (RR: 1.49, 95% confidence interval [CI]: 1.37–1.61; adjusted RR: 1.41, 95% CI: 1.30–1.53). Short-term aspirin, ibuprofen, and diclofenac use probably correlated with asthma exacerbation in children with asthma. No association between long-term aspirin, ibuprofen, and diclofenac consumption and the risk of asthma exacerbation was identified in this study. PMID:27741128

  6. An Overview Of The Physiology And Pharmacology Of Aspirin And Nonsteroidal Anti-inflammatory Drugs

    PubMed Central

    Koester, Michael C.

    1993-01-01

    In this article, I present an overview of the actions and effects of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Although athletic trainers cannot prescribe or dispense prescription medications, they should be as aware of their effects as they are of other methods of injury treatment. To set the discussion in proper perspective, the inflammatory process and its mediators are reviewed briefly. The eicosanoids are a family of very active chemicals, which include: the prostaglandins, thromboxane, and the leukotrienes. They affect inflammation as well as numerous other body processes. Ingesting aspirin and NSAIDs blocks the production of prostaglandins and thromboxane, resulting in desired and undesired effects. The NSAIDs were developed to have the same action as aspirin, but with fewer adverse side effects. Many NSAIDs are currently available, and the decision as to which agent to use depends upon various factors. Surprisingly, recent studies suggest that some NSAIDs may hinder the healing process. Although not a NSAID, acetaminophen has many important clinical uses. Armed with an understanding of how these drugs act, and their potentially harmful aspects, the athletic trainer can assist the team physician in designing an aspirin- or NSAID-therapy regimen. PMID:16558240

  7. Do nonsteroidal anti-inflammatory drugs affect the outcome of arthroscopic Bankart repair?

    PubMed Central

    Blomquist, J; Solheim, E; Liavaag, S; Baste, V; Havelin, L I

    2014-01-01

    To achieve pain control after arthroscopic shoulder surgery, nonsteroidal anti-inflammatory drugs (NSAIDs) are a complement to other analgesics. However, experimental studies have raised concerns that these drugs may have a detrimental effect on soft tissue-to-bone healing and, thus, have a negative effect on the outcome. We wanted to investigate if there are any differences in the clinical outcome after the arthroscopic Bankart procedure for patients who received NSAIDs prescription compared with those who did not. 477 patients with a primary arthroscopic Bankart procedure were identified in the Norwegian shoulder instability register and included in the study. 32.5% received prescription of NSAIDs post-operatively. 370 (78%) of the patients answered a follow-up questionnaire containing the Western Ontario Shoulder Instability index (WOSI). Mean follow-up was 21 months. WOSI at follow-up were 75% in the NSAID group and 74% in the control group. 12% of the patients in the NSAID group and 14% in the control group reported recurrence of instability. The reoperation rate was 5% in both groups. There were no statistically significant differences between the groups. Prescription of short-term post-operative NSAID treatment in the post-operative period did not influence on the functional outcome after arthroscopic Bankart procedures. PMID:24750379

  8. Topical Anti-inflammatory Activity of New Hybrid Molecules of Terpenes and Synthetic Drugs.

    PubMed

    Theoduloz, Cristina; Delporte, Carla; Valenzuela-Barra, Gabriela; Silva, Ximena; Cádiz, Solange; Bustamante, Fernanda; Pertino, Mariano Walter; Schmeda-Hirschmann, Guillermo

    2015-06-18

    The aim of the study was to assess changes in the activity of anti-inflammatory terpenes from Chilean medicinal plants after the formation of derivatives incorporating synthetic anti-inflammatory agents. Ten new hybrid molecules were synthesized combining terpenes (ferruginol (1), imbricatolic acid (2) and oleanolic acid (3)) with ibuprofen (4) or naproxen (5). The topical anti-inflammatory activity of the compounds was assessed in mice by the arachidonic acid (AA) and 12-O-tetradecanoyl phorbol 13-acetate (TPA) induced ear edema assays. Basal cytotoxicity was determined towards human lung fibroblasts, gastric epithelial cells and hepatocytes. At 1.4 µmol/mouse, a strong anti-inflammatory effect in the TPA assay was observed for oleanoyl ibuprofenate 12 (79.9%) and oleanoyl ibuprofenate methyl ester 15 (80.0%). In the AA assay, the best activity was observed for 12 at 3.2 µmol/mouse, with 56.8% reduction of inflammation, in the same range as nimesulide (48.9%). All the terpenyl-synthetic anti-inflammatory hybrids showed better effects in the TPA assay, with best activity for 6, 12 and 15. The cytotoxicity of the compounds 8 and 10 with a free COOH, was higher than that of 2. The derivatives from 3 were less toxic than the triterpene. Several of the new compounds presented better anti-inflammatory effect and lower cytotoxicity than the parent terpenes.

  9. Liver Injury from Nonsteroidal Anti-inflammatory Drugs in the United States

    PubMed Central

    Schmeltzer, Paul A.; Kosinski, Andrzej S.; Kleiner, David E.; Hoofnagle, Jay H.; Stolz, Andrew; Fontana, Robert J.; Russo, Mark W.

    2016-01-01

    Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of medications and have been associated with hepatotoxicity. Studies of liver injury from NSAIDs have been retrospective and prospective data are lacking that provide details of cases. Aim To report the presenting feature and outcomes of subjects with severe drug induced liver injury from NSAIDS. Methods The U.S. Drug Induced Liver Injury Network is a prospective registry of severe idiosyncratic drug hepatotoxicity. All patients are evaluated in a standard fashion and followed for at least 6 months after onset. Results Of 1,221 DILIN cases that were adjudicated, 30 cases were attributed to 8 different NSAIDs. The mean age was 52 years old, 24 (80%) were women, and 21 (70%) were Caucasian. The mean latency to onset of laboratory abnormalities was 67 days. Common signs and symptoms at presentation were nausea (73%), jaundice (67%), and dark urine (67%). Mean peak serum AST, ALT, total bilirubin, and alkaline phosphatase were 898 U/L, 1060 U/L, 12.2 mg/dL, and 326 U/L, respectively. The most common pattern of injury was hepatocellular (70%) and autoantibodies were detected in 33% of cases. Diclofenac, was the most frequently implicated NSAID (16/30 cases), and characterized by hepatocellular injury in all cases. Seventeen cases resulted in hospitalization or prolongation of hospitalization and one patient died from complications of Stevens-Johnson syndrome rather than liver failure due to diclofenac. Conclusions Hepatocellular injury is the most common pattern seen with NSAID hepatotoxicity and diclofenac is the most frequently implicated agent. Given the number of available NSAID alternatives, diclofenac use should be limited to patients who fail other NSAIDs and a high level of suspicion for hepatotoxicity should be maintained. PMID:26601797

  10. Prawns, barnacles, and nonsteroidal anti-inflammatory drugs: effect modifiers or diagnostic confounders [corrected].

    PubMed

    Vidal, C; Bartolomé, B; González-Quintela, A; Rodríguez, V; Armisén, M

    2007-01-01

    A 42-year-old woman with no history of atopy reported several episodes of generalized urticaria and shortness of breath after eating shellfish (prawns and barnacles) but with good tolerance of the same foods between episodes. Skin prick tests (SPTs), serum enzyme allergosorbent tests (EAST) for specific immunoglobulin (Ig) E, Western blot and inhibition assays, and oral challenge tests with prawns, barnacles, nonsteroidal anti-inflammatory drugs (NSAIDs), and alcohol as potential effect modifiers were performed. Specific IgE to both barnacle and prawn were detected by SPTs and EAST. Results from a Western blot of raw prawn revealed an IgE binding band of 37 kDa and IgE binding bands of 143, 83, 38, 32, and 20 kDa appeared in the raw barnacle assay. Oral challenge tests were positive with prawns and prawn extract only if preceded by NSAIDs. Oral challenges with NSAIDs alone, prawns alone, barnacles with or without NSAIDs and alcohol led to no reaction. A synergistic effect of NSAIDs in inducing anaphylaxis after prawn intake was confirmed. No similar effect was achieved with barnacles despite the presence of specific IgE. Additional factors needed to elicit a clinical reaction in food allergy may not be obvious and several oral challenge protocols are mandatory in such cases.

  11. Binding of anti-inflammatory drug cromolyn sodium to bovine serum albumin.

    PubMed

    Hu, Yan-Jun; Liu, Yi; Sun, Ting-Quan; Bai, Ai-Min; Lü, Jian-Quan; Pi, Zhen-Bang

    2006-11-15

    Fluorescence spectroscopy in combination with circular dichroism (CD) and UV-vis absorption spectroscopy were employed to investigate the binding of anti-inflammatory drug cromolyn sodium (Intal) to bovine serum albumin (BSA) under the physiological conditions with Intal concentrations of 0-6.4 x 10(-5)mol L(-1). In the mechanism discussion, it was proved that the fluorescence quenching of BSA by Intal is a result of the formation of Intal-BSA complex. Quenching constants were determined using the Stern-Volmer equation to provide a measure of the binding affinity between Intal and BSA. The thermodynamic parameters Delta G, Delta H, Delta S at different temperatures (298, 304, and 310 K) were calculated and the results indicate the electrostatic interactions play a major role in Intal-BSA association. Binding studies concerning the number of binding sites (n=1) and apparent binding constant K(b) were performed by fluorescence quenching method. Utilizing fluorescence resonant energy transfer (FRET) the distance R between the donor (BSA) and acceptor (Intal) has been obtained. Furthermore, CD and synchronous fluorescence spectrum were used to investigate the structural change of BSA molecules with addition of Intal, the results indicate that the secondary structure of BSA molecules was changed in the presence of Intal.

  12. Anti-inflammatory drug (BW755C) inhibits airway hyperresponsiveness induced by ozone in dogs

    SciTech Connect

    Fabbri, L.M.; Aizawa, H.; O'Byrne, P.M.; Bethel, R.A.; Walters, E.H.; Holtzman, M.J.; Nadel, J.A.

    1985-08-01

    To follow up a previous observation that airway hyperresponsiveness induced by ozone is linked to airway inflammation, the authors investigated the effect of BW755C, an anti-inflammatory drug, on ozone-induced hyperresponsiveness in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in two sets of experiments. In one set (placebo treatment), five dogs were given only saline solution treatment and were studied before treatment or ozone exposure and then after treatment both before and after ozone (3.0 ppm, 2 hours); in another set (BW755C treatment), the same dogs were studied before BW755C treatment or ozone and then after treatment (10 mg/kg intravenously) both before and after ozone. When the dogs were given no BW755C treatment, ozone induced a marked increase in airway responsiveness to acetylcholine. When the dogs were given BW755C, responsiveness was no different during treatment than before treatment but, more importantly, responsiveness did not increase significantly after ozone. The authors conclude that BW755C markedly inhibits ozone-induced airway hyperresponsiveness in dogs, probably by inhibiting the formation of oxygenation products of arachidonic acid.

  13. Fractals and self-organized criticality in anti-inflammatory drugs

    NASA Astrophysics Data System (ADS)

    Phillips, J. C.

    2014-12-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX-1 and COX-2) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective inhibitors. Extensive structural studies of the biology of prostaglandin synthesis and inhibition have explained some of the differences between COX-1 and COX-2 functionality, but others are still unexplained. Notably these include molecular differences that cause COX-1 inhibitors to produce a slight decrease, and COX-2 inhibitors to induce a significant increase, in heart attacks and strokes. These differences were unexpected because of the 60% overall COX-1 and COX-2 sequence similarity and the 1-2 conservation of catalytic sites. Hydropathic analysis shows important bicyclic differences between COX-1 and COX-2 on a large scale outside the catalytic pocket. These differences involve much stronger amphiphilic interactions in COX-2 than in COX-1, and may explain the selective antiplatelet effectiveness of COX-2. Success of the non-Euclidean structural analysis is the result of using the new Brazilian hydropathicity scale based on self-organized criticality (SOC) of universal protein modules.

  14. Nonsteroidal Anti-Inflammatory Drugs for Wounds: Pain Relief or Excessive Scar Formation?

    PubMed Central

    Su, Wen-Hsiang; Cheng, Ming-Huei; Lee, Wen-Ling; Tsou, Tsung-Shan; Chang, Wen-Hsun; Chen, Chien-Sheng; Wang, Peng-Hui

    2010-01-01

    The inflammatory process has direct effects on normal and abnormal wound healing. Hypertrophic scar formation is an aberrant form of wound healing and is an indication of an exaggerated function of fibroblasts and excess accumulation of extracellular matrix during wound healing. Two cytokines—transforming growth factor-β (TGF-β) and prostaglandin E2 (PGE2)—are lipid mediators of inflammation involving wound healing. Overproduction of TGF-β and suppression of PGE2 are found in excessive wound scarring compared with normal wound healing. Nonsteroidal anti-inflammatory drugs (NSAIDs) or their selective cyclooxygenase-2 (COX-2) inhibitors are frequently used as a pain-killer. However, both NSAIDs and COX-2 inhibitors inhibit PGE2 production, which might exacerbate excessive scar formation, especially when used during the later proliferative phase. Therefore, a balance between cytokines and medication in the pathogenesis of wound healing is needed. This report is a literature review pertaining to wound healing and is focused on TGF-β and PGE2. PMID:20671960

  15. Topical nonsteroidal anti-inflammatory drugs for management of osteoarthritis in long-term care patients

    PubMed Central

    Argoff, Charles E; Gloth, F Michael

    2011-01-01

    Osteoarthritis is common in patients ≥65 years of age. Although nonsteroidal anti-inflammatory drugs (NSAIDs) are often prescribed for osteoarthritis pain, they pose age-related cardiovascular, renal, and gastrointestinal risks. Two topical NSAIDs, diclofenac sodium 1% gel (DSG) and diclofenac sodium 1.5% in 45.5% dimethylsulfoxide solution (D-DMSO), are approved in the US for the treatment of osteoarthritis pain. Topical NSAIDs have shown efficacy and safety in knee (DSG, D-DMSO) and hand (DSG) osteoarthritis. Analyses of data from randomized controlled trials of DSG in hand and knee osteoarthritis demonstrate significant improvement of pain and function in both younger patients (<65 years) and older patients (≥65 years) and suggest good safety and tolerability. However, long-term safety data in older patients are limited. Topical NSAIDs can ease medication administration and help address barriers to pain management in older patients, such as taking multiple medications and inability to swallow, and are a valuable option for long-term care providers. PMID:22076115

  16. Newer, safer nonsteroidal anti-inflammatory drugs. Rational NSAID selection for arthritis.

    PubMed Central

    Bensen, W.; Zizzo, A.

    1998-01-01

    OBJECTIVE: To summarize current evidence that three new additions to nonsteroidal anti-inflammatory drugs (NSAIDs) offer comparable efficacy with fewer adverse effects than established NSAIDs. QUALITY OF EVIDENCE: No large randomized controlled trials (RCTs) have compared all important NSAIDs. Several RCTs have shown that H2 antagonists do not protect against NSAID side effects, but some RCTs compared the protective effect of misoprostol (Cytotec) used with other NSAIDs; others have compared etodolac (Ultradol) or nabumetone (Relafen) with placebo and naproxen (eg, Naprosyn). Postmarketing surveys have been used to support claims that the new NSAIDs have few gastric or renal side effects. MAIN FINDINGS: Using misoprostol in conjunction with traditional NSAIDs reduces gastric and renal adverse effects. Misoprostol can be taken at the same time as NSAIDs or in a combination tablet. Two new NSAIDS, etodolac and nabumetone, do not inhibit cyclooxygenase 1 prostaglandins, which occur in the stomach and kidneys, but more selectively block cyclooxygenase 2 prostaglandins, which cause arthritic inflammation. These two NSAIDs have efficacy profiles comparable to older NSAIDs but have markedly fewer side effects. CONCLUSIONS: Safer treatment for arthritis can be achieved by combining misoprostol with traditional NSAIDs or by using one of two new agents, nabumetone or etodolac. PMID:9481468

  17. Selective amplification of glucocorticoid anti-inflammatory activity through synergistic multi-target action of a combination drug

    PubMed Central

    Zimmermann, Grant R; Avery, William; Finelli, Alyce L; Farwell, Melissa; Fraser, Christopher C; Borisy, Alexis A

    2009-01-01

    Introduction Glucocorticoids are a mainstay of anti-inflammatory therapy, but significant adverse effects ultimately limit their utility. Previous efforts to design glucocorticoid structures with an increased therapeutic window have focused on dissociating anti-inflammatory transcriptional repression from adverse effects primarily driven by transcriptional activation. An alternative to this medicinal chemistry approach is a systems biology based strategy that seeks to amplify selectively the anti-inflammatory activity of very low dose glucocorticoid in immune cells without modulating alternative cellular networks that mediate glucocorticoid toxicity. Methods The combination of prednisolone and the antithrombotic drug dipyridamole was profiled using in vitro and in vivo models of anti-inflammatory activity and glucocorticoid-induced adverse effects to demonstrate a dissociated activity profile. Results The combination synergistically suppresses release of proinflammatory mediators, including tumour necrosis factor-α, IL-6, chemokine (C-C motif) ligand 5 (RANTES), matrix metalloproteinase-9, and others, from human peripheral blood mononuclear cells and mouse macrophages. In rat models of acute lipopolysaccharide-induced endotoxemia and delayed-type hypersensitivity, and in chronic models of collagen-induced and adjuvant-induced arthritis, the combination produced anti-inflammatory activity that required only a subtherapeutic dose of prednisolone. The immune-specific amplification of prednisolone anti-inflammatory activity by dipyridamole did not extend to glucocorticoid-mediated adverse effects, including corticosterone suppression or increased expression of tyrosine aminotransferase, in vivo after repeat dosing in rats. After 8 weeks of oral dosing in mice, treatment with the combination did not alter prednisolone-induced reduction in osteocalcin and mid-femur bone density, which are markers of steroid-induced osteoporosis. Additionally, amplification was not

  18. Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats.

    PubMed

    Funatsu, Toshiyuki; Chono, Koji; Hirata, Takuya; Keto, Yoshihiro; Kimoto, Aishi; Sasamata, Masao

    2007-01-05

    The mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) suppress gastric mucosal blood flow is not fully understood, although the depletion of mucosal prostaglandin E2 has been proposed as one possible explanation. We investigated the role of gastric acid on gastric mucosal blood flow in NSAID-treated rats. A rat stomach was mounted in an ex vivo chamber, and gastric mucosal blood flow was measured sequentially in a 5-mm2 area of the gastric corpus using a scanning laser Doppler perfusion image system. Results showed that diclofenac (5 mg/kg s.c.) and indomethacin (10 mg/kg s.c.) did not affect gastric mucosal blood flow, although both strongly decreased mucosal prostaglandin E2 when saline was instilled into the gastric chamber. On replacement of the saline in the chamber with 100 mM hydrochloric acid, these drugs caused a decrease in gastric mucosal blood flow levels within 30 min. The specific cyclooxygenase (COX)-2 inhibitors celecoxib (50 mg/kg s.c.) and rofecoxib (25 mg/kg s.c.) did not affect mucosal prostaglandin E2 level, nor did they decrease gastric mucosal blood flow, even when hydrochloric acid was added to the chamber. Furthermore, measurement of vasoconstrictive factors present in the mucosa showed that endothelin-1 levels increased after administration of diclofenac s.c. in the presence of intragastric hydrochloric acid. This indicates that the presence of mucosal hydrochloric acid plays an important role in the NSAID-induced decrease in gastric mucosal blood flow, while the COX-1-derived basal prostaglandin E2, which is unlikely to control gastric mucosal blood flow itself, protects microcirculatory systems from mucosal hydrochloric acid.

  19. Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival.

    PubMed

    Nagle, Christina M; Ibiebele, Torukiri I; DeFazio, Anna; Protani, Melinda M; Webb, Penelope M

    2015-04-01

    Aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease tumor progression in pre-clinical models of ovarian cancer, however the influence of these drugs on survival in women following a diagnosis of ovarian cancer is unknown. We included 1305 Australian women diagnosed with incident invasive epithelial ovarian cancer, recruited into a population-based case-control study. Use of aspirin, nonaspirin NSAIDs and acetaminophen in the 5 years preceding ovarian cancer diagnosis was assessed from self-reports. Deaths were ascertained up to October 2011 via linkage with the Australian National Death Index. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CI). During a mean follow-up time of 4.9 years (SD 2.8 years), there were 834 deaths, of which 779 (93% of deaths) were from ovarian cancer. We found uniformly inverse, but non-significant, HRs for ever use in the last five years of aspirin, nonaspirin NSAIDs and acetaminophen compared with no use (adjusted HRs 0.92 [95% CI 0.81-1.06], 0.91 [95% CI 0.80-1.05] and 0.91 [95% CI 0.69-1.20], respectively). There was no evidence of any dose response trends. The results remained unchanged when we limited the outcome to ovarian cancer mortality. Associations did not differ by histologic subtype, age at diagnosis or stage. Given current interest in the role of aspirin and nonaspirin NSAIDs in cancer survival these results are noteworthy given they are the first to investigate these associations in women with ovarian cancer. Our results provide no strong evidence that pre-diagnostic use of aspirin or nonaspirin NSAIDs are associated with improved survival in women with ovarian cancer.

  20. Synergistic effects of the anti-cholinergic R,R-glycopyrrolate with anti-inflammatory drugs.

    PubMed

    Pahl, Andreas; Bauhofer, Artur; Petzold, Ursula; Cnota, Peter J; Maus, Joachim; Brune, Kay; Szelenyi, Stefan

    2006-12-15

    Currently, much effort is geared towards developing therapies that impact on the inflammation in respiratory diseases such as asthma and COPD, assuming that this will improve disease pathology. R,R-Glycopyrrolate, a quaternary ammonium compound, is a muscarinic receptor antagonist with the potential to be used as a long-acting bronchodilator in patients with asthma and COPD. In this study we evaluated whether the combination of R,R-glycopyrrolate with known anti-inflammatory drugs results in synergistic effects. Human primary monocytes were used as an in vitro model system. M3, M4, M1 and M2 receptors were expressed in these cells in descending order. The combinatory effects of the drugs on the release of TNF-alpha after lipopolysaccharide stimulation were analyzed. R,R-Glycopyrrolate alone did not affect LPS induced TNF-alpha release. The PDE4 inhibitor rolipram dose dependently inhibited the TNF-alpha release. Maximum inhibition was around 70%. The IC(35) for rolipram was 68.9+/-15.2 nM. The simultaneous administration of 10 microM R,R-glycopyrrolate reduced the IC(35) to 1.70+/-1.18 nM. The anti-histamine azelastine inhibited TNF-alpha release dose dependently. The simultaneous administration of R,R-glycopyrrolate did not influence the action of azelastine. The corticosteroid budesonide inhibited the TNF-alpha release dose dependently with an IC(50) of 0.55+/-0.13 nM. The simultaneous administration of 10 microM R,R-glycopyrrolate reduced the IC(50) to 0.13+/-0.03 nM. Finally, R,R-glycopyrrolate was most effective in the triple combination with budesonide and rolipram in the reduction of TNF-alpha release. In conclusion, R,R-glycopyrrolate acts synergistically with the PDE4 inhibitor rolipram and the steroid budesonide in inhibiting inflammatory mediators.

  1. Diclofenac, a nonsteroidal anti-inflammatory drug, is an antagonist of human TRPM3 isoforms.

    PubMed

    Suzuki, Hiroka; Sasaki, Eiji; Nakagawa, Ayumi; Muraki, Yukiko; Hatano, Noriyuki; Muraki, Katsuhiko

    2016-06-01

    The effects of diclofenac (Dic), an acetic acid derivative-type nonsteroidal anti-inflammatory drug, were examined on the function of transient receptor potential (TRP) melastatin (TRPM) 3 (TRPM3) in human embryonic kidney 293 cell-line (HEK293) cells with recombinant human TRPM3 isoforms (TRPM31325, TRPM3-3, TRPM3-9, and TRPM3-S) and in a neuroblastoma cell line human neuroblastoma IMR-32 cells (IMR-32 cells) derived from human peripheral neurons. TRPM3 responses evoked by pregnenolone sulfate (PregS) were effectively inhibited by Dic in a concentration-dependent manner in Ca(2+) measurement and electrophysiological assays. The apparent IC 50 for PregS-induced Ca(2+) response of TRPM31325, TRPM3-3, and TRPM3-9 was calculated to be 18.8, 42.5, and 7.1 μmol/L, respectively. The TRPM3-dependent Ca(2+) responses evoked by nifedipine, another TRPM3 agonist, were also significantly inhibited by Dic. In contrast, aceclofenac, an acetoxymethyl analog of Dic, had no effects on PregS-induced TRPM3 responses. Constitutive channel activity of TRPM3-S without TRPM3 agonists was substantially inhibited by Dic, ruling out the possibility of interaction of Dic against TRPM3 agonists to the channel binding sites. Moreover, Dic reversibly inhibited TRPM3 single-channel activity recorded in excised outside-out patches without affecting the channel conductance. In differentiated neuronal IMR-32 cells with endogenous TRPM3, Dic inhibited PregS-evoked Ca(2+) responses with an apparent IC 50 of 17.1 μmol/L. Taken together, our findings demonstrate that Dic inhibits human TRPM3 without interacting with the channel pore.

  2. The association of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in peptic ulcer disease

    PubMed Central

    Zapata-Colindres, Juan Carlos; Zepeda-Gómez, Sergio; Montaño-Loza, Aldo; Vázquez-Ballesteros, Edgar; de Jesús Villalobos, José; Valdovinos-Andraca, Francisco

    2006-01-01

    BACKGROUND AND AIM: Peptic ulcer disease (PUD) affects 10% of the world population. Helicobacter pylori infection and the use of a nonsteroidal anti-inflammatory drug (NSAID) are the principal factors associated with PUD. The aim of the present study was to evaluate a cohort of patients with PUD and determine the association between H pylori infection and NSAID use. PATIENTS AND METHODS: The medical charts of patients with endoscopic diagnosis of PUD were retrospectively reviewed from September 2002 to August 2003. Patients were divided into three groups according to ulcer etiology: H pylori infection (group 1); NSAID use (group 2); and combined H pylori infection and NSAID use (group 3). RESULTS: One hundred two patients were evaluated: 36 men (35.3%) and 66 women (64.7%). Forty patients had H pylori infection, 43 had used NSAIDs and 15 had combined H pylori infection and NSAID use; four patients with ulcers secondary to malignancy were excluded. The frequency of women was significantly higher in group 2 (P=0.01). The mean age of patients in group 1 was significantly lower than in the other two groups (P=0.003). PUD developed earlier in group 3 than in group 2 (5.0±4.7 months versus 1.4±2.1 months, respectively, P=0.018). Thirty-two patients (32.7%) had bleeding peptic ulcer. Group 2 had a higher risk of bleeding peptic ulcer than the other two groups (P=0.001). CONCLUSIONS: The development of PUD was observed earlier in the combined H pylori and NSAID group than in patients with only NSAID use. This suggests a synergic effect between the two risks factors in the development of PUD. PMID:16609757

  3. Degradation of the anti-inflammatory drug ibuprofen by electro-peroxone process.

    PubMed

    Li, Xiang; Wang, Yujue; Yuan, Shi; Li, Zhaoxin; Wang, Bin; Huang, Jun; Deng, Shubo; Yu, Gang

    2014-10-15

    Electro-peroxone (E-peroxone) treatment of the anti-inflammatory drug ibuprofen aqueous solution was investigated in this study. The E-peroxone process combined conventional ozonation with electrolysis processes, and used a carbon-polytetrafluorethylene cathode to electrochemically generate H2O2 from O2 in the sparged ozone generator effluent (O2 and O3 mixture). The in-situ generated H2O2 then reacted with the sparged O3 to produce aqueous •OH, which can in turn oxidize pollutants effectively in the bulk solution. The E-peroxone process overcomes several intrinsic limitations of conventional ozonation and electrolysis processes for pollutant degradation such as the selective oxidation with O3 and mass transfer limitations of pollutants to the electrodes, and thus significantly enhanced both ibuprofen degradation and total organic carbon (TOC) mineralization. Results show that ibuprofen could be completely degraded much more rapidly in the E-peroxone process (e.g., 5-15 min under all tested reaction conditions) than in ozonation (≥30 min) and electrolysis (several hours) processes. In addition, thanks to the powerful and non-selective oxidation capacity of •OH, toxic intermediates formed during ibuprofen degradation could be completely mineralized in the E-peroxone process. The E-peroxone effluent (2 h) thus exhibited much lower toxicity (5% inhibition of bioluminescence of Vibrio fisheri) than the ozonation and electrolysis effluents (22% and 88% inhibition, respectively). The results of this study indicate that the E-peroxone process may provide a promising technology for pharmaceutical wastewater treatment.

  4. Aspirin and other nonsteroidal anti-inflammatory drugs and risk of non-hodgkin lymphoma.

    PubMed

    Teras, Lauren R; Gapstur, Susan M; Patel, Alpa V; Thun, Michael J; Diver, W Ryan; Zhai, Yusheng; Jacobs, Eric J

    2013-03-01

    Few large prospective studies have examined associations between nonsteroidal anti-inflammatory drug (NSAID) use and non-Hodgkin lymphoma (NHL). We examined the association between NSAID use and NHL incidence among 149,570 participants in the Cancer Prevention Study-II Nutrition cohort. Aspirin and nonaspirin NSAID use were reported at enrollment in 1992 and updated on periodic follow-up questionnaires. During follow-up through 2007, 1,709 incident NHLs were identified. Time-dependent hazard ratios were calculated using extended Cox regression. Compared to no use, current use of 60+ NSAID pills/month (aspirin and nonaspirin NSAIDs combined) was associated with slightly higher NHL incidence (hazard ratio [HR] = 1.26, 95% confidence interval [CI], 1.04-1.53), but no association with frequency of use was observed when NSAID exposure was lagged by approximately 2 years (HR = 1.08, 95% CI, 0.88-1.32). Long duration regular use (current use of 30+ pills/month for ≥5 years) was not associated with NHL incidence (HR = 1.09, 95% CI, 0.91-1.33). In subtype analyses, current use of 60+ NSAID pills/month was associated with follicular lymphoma incidence (HR = 1.87, 95% CI, 1.08-3.24). This association persisted when NSAID exposure was lagged (HR = 1.76, 95% CI, 1.04-2.98) and was similar for aspirin and nonaspirin NSAIDs. The association of current, but not lagged, NSAID use with risk of all NHL could be attributable to use of NSAIDs to relieve symptoms of undiagnosed NHL. However, the association with follicular lymphoma persisted in analyses where NSAID use was lagged and should be investigated further. These findings are particularly important for aspirin as the risks and benefits of prophylactic daily use are weighed.

  5. Nonsteroidal anti-inflammatory drugs and other analgesic use and bladder cancer in northern New England

    PubMed Central

    Baris, Dalsu; Karagas, Margaret R.; Koutros, Stella; Colt, Joanne S.; Johnson, Alison; Schwenn, Molly; Fischer, Alexander H.; Figueroa, Jonine D.; Berndt, Sonja I.; Han, Summer; Beane Freeman, Laura E.; Lubin, Jay H.; Cherala, Sai; Cantor, Kenneth P.; Jacobs, Kevin; Chanock, Stephen; Chatterjee, Nilanjan; Rothman, Nathaniel; Silverman, Debra T.

    2014-01-01

    A few epidemiologic studies have found that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of bladder cancer. However, the effects of specific NSAID use and individual variability in risk have not been well studied. We examined the association between NSAIDs use and bladder cancer risk, and its modification by 39 candidate genes related to NSAID metabolism. A population-based case–control study was conducted in northern New England, enrolling 1,171 newly diagnosed cases and 1,418 controls. Regular use of nonaspirin, nonselective NSAIDs was associated with reduced bladder cancer risk, with a statistically significant inverse trend in risk with duration of use (ORs of 1.0, 0.8, 0.6 and 0.6 for <5, 5–9, 10–19 and 201 years, respectively; ptrend = 0.015). This association was driven mainly by ibuprofen; significant inverse trends in risk with increasing duration and dose of ibuprofen were observed (ptrend = 0.009 and 0.054, respectively). The reduced risk from ibuprofen use was limited to individuals carrying the T allele of a single nucleotide polymorphism (rs4646450) compared to those who did not use ibuprofen and did not carry the T allele in the CYP3A locus, providing new evidence that this association might be modified by polymorphisms in genes that metabolize ibuprofen. Significant positive trends in risk with increasing duration and cumulative dose of selective cyclooxygenase (COX-2) inhibitors were observed. Our results are consistent with those from previous studies linking use of NSAIDs, particularly ibuprofen, with reduced risk. We observed a previously unrecognized risk associated with use of COX-2 inhibitors, which merits further evaluation. PMID:22505343

  6. Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice.

    PubMed

    Kinsey, Steven G; Nomura, Daniel K; O'Neal, Scott T; Long, Jonathan Z; Mahadevan, Anu; Cravatt, Benjamin F; Grider, John R; Lichtman, Aron H

    2011-09-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics, but can cause gastric and esophageal hemorrhages, erosion, and ulceration. The endogenous cannabinoid (endocannabinoid; eCB) system possesses several potential targets to reduce gastric inflammatory states, including cannabinoid receptor type 1 (CB(1)), cannabinoid receptor type 2 (CB(2)), and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184), a selective inhibitor of the primary catabolic enzyme of 2-AG, monoacylglycerol lipase (MAGL), would protect against NSAID-induced gastric damage. Food-deprived mice administered the nonselective cyclooxygenase inhibitor diclofenac sodium displayed gastric hemorrhages and increases in proinflammatory cytokines. JZL184, the proton pump inhibitor omeprazole (positive control), or the primary constituent of marijuana, Δ(9)-tetrahydrocannabinol (THC), significantly prevented diclofenac-induced gastric hemorrhages. JZL184 also increased stomach levels of 2-AG, but had no effect on AEA, arachidonic acid, or the prostaglandins E(2) and D(2). MAGL inhibition fully blocked diclofenac-induced increases in gastric levels of proinflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor α, and granulocyte colony-stimulating factor, as well as IL-10. Pharmacological inhibition or genetic deletion of CB(1) or CB(2) revealed that the gastroprotective effects of JZL184 and THC were mediated via CB(1). The antihemorrhagic effects of JZL184 persisted with repeated administration, indicating a lack of tolerance. These data indicate that increasing 2-AG protects against gastric damage induced by NSAIDs, and its primary catabolic enzyme MAGL offers a promising target for the development of analgesic therapeutics possessing gastroprotective properties.

  7. Transdermal fentanyl combined with nonsteroidal anti-inflammatory drugs for analgesia in horses.

    PubMed

    Thomasy, S M; Slovis, N; Maxwell, L K; Kollias-Baker, C

    2004-01-01

    This study investigated the pharmcokinetics, efficacy, and safety of the fentanyl transdermal therapeutic system (TTS) in horses in which there was an inadequate analgesic response to nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Nine horses with pain that was refractory to therapeutic doses of phenylbutazone (n = 3) or flunixin meglumine (n = 6) subsequently also received between 39 and 110 microg/kg of transdermal fentanyl. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, and 72 hours after patch application, and a radioimmunoassay was used to determine serum fentanyl concentrations. Pharmacokinetic values were determined by noncompartmental analysis. Physical examination findings were recorded in all horses, and pain and lameness grading systems were used to assign scores to 8 and 6 horses, respectively. All horses tolerated the administration of fentanyl TTS, in that no clinically significant adverse effects attributable to fentanyl were observed. Use of the TTS resulted in variable serum concentrations of fentanyl, with a peak serum concentration of 2.2+/-1.1 ng/mL (mean+/-SD) and a time to peak serum concentration of 26+/-13 hours. After transdermal fentanyl administration, mean time to reach serum fentanyl concentrations consistent with analgesia in other species (1 ng/mL) was 14 hours. In addition, serum fentanyl concentrations of 1 ng/mL or greater were maintained in all but one horse for at least 18 hours. Pain scores were significantly decreased after fentanyl TTS and NSAID administration (P < .05), but lameness scores were not significantly different (P > .05). Overall, administration of fentanyl TTS had a favorable pharmacokinetic profile in horses with clinical pain, and the fentanyl TTS in combination with NSAIDs appeared to provide safe and effective analgesia in most of the horses with pain that was refractory to NSAID therapy alone.

  8. Advent of Novel Phosphatidylcholine-Associated Nonsteroidal Anti-Inflammatory Drugs with Improved Gastrointestinal Safety

    PubMed Central

    Lim, Yun Jeong; Dial, Elizabeth J.

    2013-01-01

    The mucosa of the gastrointestinal (GI) tract exhibits hydrophobic, nonwettable properties that protect the underlying epithelium from gastric acid and other luminal toxins. These biophysical characteristics appear to be attributable to the presence of an extracellular lining of surfactant-like phospholipids on the luminal aspects of the mucus gel layer. Phosphatidylcholine (PC) represents the most abundant and surface-active form of gastric phospholipids. PC protected experimental rats from a number of ulcerogenic agents and/or conditions including nonsteroidal anti-inflammatory drugs (NSAIDs), which are chemically associated with PC. Moreover, preassociating a number of the NSAIDs with exogenous PC prevented a decrease in the hydrophobic characteristics of the mucus gel layer and protected rats against the injurious GI side effects of NSAIDs while enhancing and/or maintaining their therapeutic activity. Bile plays an important role in the ability of NSAIDs to induce small intestinal injury. NSAIDs are rapidly absorbed from the GI tract and, in many cases, undergo enterohepatic circulation. Thus, NSAIDs with extensive enterohepatic cycling are more toxic to the GI tract and are capable of attenuating the surface hydrophobic properties of the mucosa of the lower GI tract. Biliary PC plays an essential role in the detoxification of bile salt micelles. NSAIDs that are secreted into the bile injure the intestinal mucosa via their ability to chemically associate with PC, which forms toxic mixed micelles and limits the concentration of biliary PC available to interact with and detoxify bile salts. We have worked to develop a family of PC-associated NSAIDs that appear to have improved GI safety profiles with equivalent or better therapeutic efficacy in both rodent model systems and pilot clinical trials. PMID:23423874

  9. The choleretic effect of nonsteroidal anti-inflammatory drugs in total parenteral nutrition-associated cholestasis.

    PubMed

    Nussinovitch, M; Zahavi, I; Marcus, H; Hackelman, B; Dinari, G

    1996-12-01

    Cholestasis is a frequent problem in patients on total parenteral nutrition (TPN) therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, cause choleresis in animals. We studied the effect of aspirin on bile flow and bile salt secretion in TPN-associated cholestasis in rats. Four groups of 6-10 animals each received either 154 mM NaCl (saline) or 2.5% amino acid solution (TRAVASOL, Travenol, Israel) and 10% glucose i.v. (TPN) for 3 h. During the second and third hours, taurocholate, the main bile salt in rats, was infused at a rate of 10 micromol/min per kg to prevent bile salt pool depletion. Aspirin, one of the main NSAIDs, was infused during the last 2 h into animals with or without TPN treatment at a rate of 100 mg/kg. Bile was directly collected from the common bile duct for 3 h. Rats given TPN showed a significant reduction in bile flow and bile salt secretion rate compared to control groups: 20.89 vs. 29.60 microl/min per kg (P <0.02) and 0.37 vs. 0.65 micromol/min per kg (P <0.0001), respectively. Aspirin had a significant choleretic effect and was able to overcome the bile flow and bile salt secretion rate reduction caused by TPN; 33.07 vs. 20.89 microl/min per kg (P <0.002) and 0.66 vs. 0.37 micromol/min per kg (P <0.0001), respectively. These results may have clinical implications for TPN-associated cholestasis.

  10. Use of nonsteroidal anti-inflammatory drugs and reduced breast cancer risk among overweight women.

    PubMed

    Cui, Yong; Deming-Halverson, Sandra L; Shrubsole, Martha J; Beeghly-Fadiel, Alicia; Cai, Hui; Fair, Alecia M; Shu, Xiao-Ou; Zheng, Wei

    2014-07-01

    Chronic inflammation is associated with increased risk of multiple cancers, including breast cancer. Adipose tissues produce proinflammatory cytokines, and obesity is a risk factor for postmenopausal breast cancer. We evaluated the association of regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk, overall and by body mass index (BMI) and tumor subtypes defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status. We conducted a population-based, case-control study involving 5,078 women aged 25-75 years who were recruited primarily from the Nashville metropolitan area of Tennessee. Multivariate unconditional logistic regression models were used to estimate odds ratios and 95 % confidence intervals for breast cancer risk after adjusting for multiple potential confounding factors. Regular use of any NSAID was associated with significantly reduced breast cancer risk (OR 0.78; 95 % CI 0.69-0.89). This association was observed for regular use of baby aspirin only (OR 0.82, 95 % CI 0.69-0.99), other NSAIDs only (OR 0.81, 95 % CI 0.69-0.95), and both baby aspirin and other NSAIDs (OR 0.52, 95 % CI 0.40-0.69). These significant inverse associations were found among overweight women (BMI ≥25 kg/m(2)) overall and by subtypes of breast cancer, but not among women with BMI <25 kg/m(2) (P for interaction = 0.023). Regular use of NSAIDs was inversely associated with breast cancer risk, particularly among overweight women. Overweight women may benefit more from the protective effects of NSAID use than normal-weight women.

  11. Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug

    PubMed Central

    Dang, Tram T.; Thai, Anh V.; Cohen, Joshua; Slosberg, Jeremy E.; Siniakowicz, Karolina; Doloff, Joshua C.; Ma, Minglin; Hollister-Lock, Jennifer; Tang, Katherine; Gu, Zhen; Cheng, Hao; Weir, Gordon C.; Langer, Robert; Anderson, Daniel G.

    2013-01-01

    Immuno-isolation of islets has the potential to enable the replacement of pancreatic function in diabetic patients. However, host response to the encapsulated islets frequently leads to fibrotic overgrowth with subsequent impairment of the transplanted grafts. Here, we identified and incorporated anti-inflammatory agents into islet-containing microcapsules to address this challenge. In vivo subcutaneous screening of 16 small molecule anti-inflammatory drugs was performed to identify promising compounds that could minimize the formation of fibrotic cell layers. Using parallel non-invasive fluorescent and bioluminescent imaging, we identified dexamethasone and curcumin as the most effective drugs in inhibiting the activities of inflammatory proteases and reactive oxygen species in the host response to subcutaneously injected biomaterials. Next, we demonstrated that co-encapsulating curcumin with pancreatic rat islets in alginate microcapsules reduced fibrotic overgrowth and improved glycemic control in a mouse model of chemically-induced type I diabetes. These results showed that localized administration of anti-inflammatory drug can improve the longevity of encapsulated islets and may facilitate the translation of this technology towards a long-term cure for type I diabetes. PMID:23660251

  12. Pharmacokinetics and Efficacy of Topically Applied Nonsteroidal Anti-Inflammatory Drugs in Retinochoroidal Tissues in Rabbits

    PubMed Central

    Kida, Tetsuo; Kozai, Seiko; Takahashi, Hiroaki; Isaka, Mitsuyoshi; Tokushige, Hideki; Sakamoto, Taiji

    2014-01-01

    Purpose To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits. Methods The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits. Results The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs. Conclusions Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and

  13. Novel 2,5-disubstituted-1,3,4-oxadiazoles as anti-inflammatory drugs

    PubMed Central

    Durgashivaprasad, Ega; Mathew, Geetha; Sebastian, Sarine; Reddy, S.A Manohar; Mudgal, Jayesh; Nampurath, Gopalan Kutty

    2014-01-01

    Objective: 1,3,4-oxadiazole ring is a versatile moiety with a wide range of pharmacological properties. The present work deals with the synthesis and evaluation of the anti-inflammatory activity of two novel 2,5-disubstituted-1,3,4-oxadiazoles (OSD and OPD). Materials and Methods: Carrageenan-induced rat hind paw edema was employed as an acute model of inflammation. For evaluating sub-acute anti-inflammatory activity, carrageenan-induced inflammation in rat air pouch was employed. Complete Freund's adjuvant-induced arthritis in rats was used as a model of chronic inflammation. To evaluate in vitro anti-inflammatory activity, lipopolysaccharide (LPS)-stimulated RAW264.7 cells were used. Results: OSD (100 mg/kg) reduced carrageen-induced paw edema by 60%, and OPD (100 mg/kg) produced a modest 32.5% reduction. OSD also reduced leukocyte influx and myeloperoxidase in carrageenan-induced rat air pouch model. In complete Freund's adjuvant-induced arthritis model, both OSD and OPD (200 mg/kg for 14 days) reduced paw edema and NO levels. In LPS-stimulated RAW264.7 cells, OSD and OPD inhibited formation of nitric oxide and reactive oxygen species, with OPD showing a better activity in comparison to OSD. Conclusions: OSD was the better of the two compounds in in vivo models of inflammation. The o-phenol substitution at position 2 of oxadiazole ring in OSD may be responsible for its better in vivo anti-inflammatory activity. The ability of the compounds to inhibit LPS-induced pro-inflammatory mediator release suggests an anti-inflammatory mechanism targeting LPS-TLR4-NF-κB signalling pathway, which needs to be explored in detail. The disparate efficacy in vitro and in vivo also requires in-depth evaluation of the pharmacokinetics of these novel oxadiazoles. PMID:25298582

  14. Spatiotemporal effects of a controlled-release anti-inflammatory drug on the cellular dynamics of host response

    PubMed Central

    Dang, Tram T.; Bratlie, Kaitlin M.; Bogatyrev, Said R.; Chen, Xiao Y.; Langer, Robert; Anderson, Daniel G.

    2017-01-01

    In general, biomaterials induce a non-specific host response when implanted in the body. This reaction has the potential to interfere with the function of the implanted materials. One method for controlling the host response is through local, controlled release of anti-inflammatory agents. Herein, we investigate the spatial and temporal effects of an anti-inflammatory drug on the cellular dynamics of the innate immune response to subcutaneously implanted poly(lactic-co-glycolic) microparticles. Noninvasive fluorescence imaging was used to investigate the influence of dexamethasone drug loading and release kinetics on the local and systemic inhibition of inflammatory cellular activities. Temporal monitoring of host response showed that inhibition of inflammatory proteases in the early phase was correlated with decreased cellular infiltration in the later phase of the foreign body response. We believe that using controlled-release anti-inflammatory platforms to modulate early cellular dynamics will be useful in reducing the foreign body response to implanted biomaterials and medical devices. PMID:21429573

  15. Maximizing the safety of nonsteroidal anti-inflammatory drug use for postoperative dental pain: an evidence-based approach.

    PubMed Central

    Ong, K. S.; Seymour, R. A.

    2003-01-01

    This article reviews the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for postoperative dental pain. An evidence-based approach is used to evaluate the clinical studies to date on the safe use of these drugs in dental patients. No drugs are without adverse effects or are perfectly safe, but their safe use in clinical practice would entail maximizing the therapeutic efficacy and minimizing the adverse effects. Therapeutic recommendations are made after reviewing the evidence for the safe use of NSAIDs in postoperative dental pain. PMID:12866802

  16. Editorial Commentary: The Efficacy of Nonsteroidal Anti-inflammatory Drugs for Prophylaxis of Heterotopic Ossification in Hip Arthroscopy--Do We Treat Patients or X-rays?

    PubMed

    Miller, G Klaud

    2016-03-01

    A systematic review of 5 series comparing the incidence of heterotopic ossification after hip arthroscopy with and without nonsteroidal anti-inflammatory drug prophylaxis showed a statistically significant improvement with the use of prophylaxis.

  17. Nonsteroidal Anti-Inflammatory Drugs and the Risk of Barrett’s Esophagus

    PubMed Central

    Khalaf, Natalia; Nguyen, Theresa; Ramsey, David; El-Serag, Hashem B.

    2014-01-01

    Objectives Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested to protect against esophageal adenocarcinoma (EAC). This study examined the effect of NSAIDs on the risk of developing Barett’s esophagus (BE), the precursor lesion to EAC. Methods We conducted a case-control study among eligible patients scheduled for either elective esophagogastroduodenoscopy (EGD) or recruited from primary care clinics to undergo a study EGD. We compared 323 patients with BE (296 nondysplastic and 27 dysplastic) with 2 separate control groups: 1347 patients from the elective EGD group ("endoscopy controls") and 502 patients from the primary care group ("primary care controls") with no endoscopic or histopathologic BE. Use of aspirin products and 23 nonaspirin NSAIDs was ascertained from detailed, self-reported questionnaires. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic-regression models. Results There were no significant differences in self-reported NSAID use between all BE cases and all controls (58.2% vs. 54.6%, P=0.33); this was seen for aspirin products (43.0% vs. 37.4%, P=0.08) and nonaspirin NSAIDs (7.7% vs. 8.9%, P=0.46). These findings persisted in the multivariable model for any NSAIDs (adjusted OR 0.89; 95% CI 0.75–1.28), aspirin (adjusted OR 1.16; 95% CI 0.90–1.51), and nonaspirin NSAIDs (adjusted OR 0.88; 95% CI 0.55–1.39). Use of a combination of aspirin and nonaspirin NSAIDs was reported in 7.4% cases and 8.3% controls, and a non-significant inverse association with BE was seen (adjusted OR 0.70; 95% CI 0.44–1.11). There was no significant association between BE and daily NSAID use (adjusted OR 1.03; 95% CI 0.78–1.37). Similar findings were observed for comparisons involving nondysplastic or dysplastic BE cases, and endoscopy or primary care control groups separately or combined. Conclusion The use of NSAIDs was not associated with a reduced risk of BE. It is likely that the protective

  18. Licorice: a possible anti-inflammatory and anti-ulcer drug.

    PubMed

    Aly, Adel M; Al-Alousi, Laith; Salem, Hatem A

    2005-09-20

    The purpose of this investigation was to study the anti-inflammatory activities of both glycerrhitinic acid (GA) and the aqueous licorice extract (ALE) in comparison with diclofenac sodium (DS) (10 mg/kg), using the carrageenan-induced paw edema model in male albino rats. In addition, the anti-ulcer activities of ALE, famotidine (FT), and a combination of ALE and FT using indomethacin-induced ulceration technique in rat stomach were investigated. Conventional DS tablets containing GA, as well as DS chewable tablets containing either GA or ALE with different tastes were prepared. Also, rapidly disintegrating FT tablets were prepared using direct compression and camphor sublimation methods. ALE or GA produced significant anti-inflammatory activity similar to DS, and when taken concomitantly, there is no possible antagonism. The anti-ulcer activity of licorice was found to be similar to that of FT in indomethacin-induced ulceration technique in rat stomach. Combination therapy of both FT and licorice showed higher anti-ulcer activity than either of them alone. Generally, tablets containing the crosslinked sodium carboxymethyl cellulose (AcDisol) showed more rapidly disintegrating effect than those including Sodium starch glycolate (Primojel). The oral disintegration was very rapid for all the tested formulations. Also, the amount of FT absorbed from the oral cavity was nearly 9 from 10 mg theoretically present in each formula. It could be concluded that both GA and ALE have anti-inflammatory activity comparable with DS. It may be recommended to add ALE to either FT or diclofinac for more effective anti-inflammatory or anti-ulcer formulations, respectively.

  19. The Effects of Anti-inflammatory Drug Treatment in Gastric Cancer Prevention: an Update of a Meta-analysis

    PubMed Central

    Kong, Pengfei; Wu, Ruiyan; Liu, Xuechao; Liu, Jianjun; Chen, Shangxiang; Ye, Minting; Yang, Chenlu; Song, Ze; He, Wenzhuo; Yin, Chenxi; Yang, Qiong; Jiang, Chang; Liao, Fangxin; Peng, Roujun; Zhou, Zhiwei; Xu, Dazhi; Xia, Liangping

    2016-01-01

    Gastric cancer has high incidence and fatality rates, making chemoprevention agents necessary. There is an ongoing debate about aspirin/nonsteroidal anti-inflammatory drugs (NSAIDs) use can significant reduce the risk of GC. We conducted a meta-analysis of existing studies evaluating the association of anti-inflammatory drug and GC. We performed a systematic literature search of PubMed, Web of Science, Embase, OVID, Cochrane Library and Clincialtrials.gov up to August 31, 2015. Either a fixed-effects or a random-effects model using was based on the result of homogeneity analysis. Subgroup, sensitivity, meta-regression, and publication bias analyses were evaluated. Forty-seven studies were finally included in this meta-analysis. The overall GC risk reduction benefit associated with anti-inflammatory drug use represented an RR of 0.78 (95% CI 0.71 to 0.85) and an adjusted RR of 0.74 (95% CI 0.71 to 0.77). Besides, the prevention benefit of aspirin/NSAIDs ingestion appeared to be confined to those patients with regiment of short or middle-term (≤5 years), high-frequency (>30 times per month) and low dose (<200 mg per day). Further, our data also suggest that COX-2 inhibitors use is a more effective approach in GC prevention (RR, 0.45; 95% CI, 0.29-0.70). In this meta-analysis, our finding support short or middle-term (≤5 years), high-frequency (>30 times per month) and low dose (<200 mg per day) aspirin/NSAIDs intake is a well method for GC prevention and also confirm the inverse association between aspirin/NSAIDs use and GC risk. Additionally, selective COX-2 inhibitors use probably a more effective approach to reduce GC risk. PMID:27994661

  20. Acute effects of anti-inflammatory drugs on neodymium:yttrium aluminum garnet laser-induced uveitis in dogs.

    PubMed

    Millichamp, N J; Dziezyc, J; Rohde, B H; Chiou, G C; Smith, W B

    1991-08-01

    Dogs were treated with flunixin meglumine, a cyclooxygenase inhibitor; L-651,896, a 5-lipoxygenase inhibitor; and matrine, a herbal anti-inflammatory drug. Acute inflammation was induced in the eyes by disruption of the anterior lens capsule, using a neodymium:yttrium aluminum garnet laser. Intraocular pressure, pupil diameter, and eicosanoid production in the aqueous humor were measured. Statistically significant effects were seen in the eyes of flunixin meglumine-treated dogs where mydriasis was maintained and aqueous prostaglandin E2 concentration was reduced.

  1. Anti-inflammatory drugs as moderators of antidepressant effects, especially those of the selective serotonin-reuptake inhibitor class.

    PubMed

    Kronenberg, Sefi

    2011-09-01

    Large studies examining remission rates obtained by antidepressants have yielded somewhat dismal results. In the well-reported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 36.8% of patients exhibited remission with the selective serotonin-reuptake inhibitor (SSRI) citalopram and the cumulative remission rate was 67% after multiple treatments were attempted. Warner-Schmidt et al. recently published an interesting paper that suggests specific mechanisms by which anti-inflammatory drugs inhibit the antidepressant effects of SSRIs. They employed well-established mouse models of depression: the tail suspension test and the forced swim test. In their experiment, ibuprofen significantly attenuated the antidepressant-like effects of SSRIs in both tests. The authors also presented data from the STAR*D study itself. These data - demonstrating higher remission rates for depressed patients receiving citalopram without concomitant NSAIDs (55.2%) than those receiving citalopram with NSAIDs (44.5%) - serve to illustrate the potential hindering effects of anti-inflammatory drugs.

  2. Evolving guidelines in the use of topical nonsteroidal anti-inflammatory drugs in the treatment of osteoarthritis

    PubMed Central

    2014-01-01

    Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are a standard treatment for osteoarthritis (OA), but the use of oral NSAIDs has been linked to an elevated risk for cardiovascular and gastrointestinal adverse events and renal toxicity. Topical NSAIDs are thought to afford efficacy that is comparable to oral formulations while reducing widespread systemic drug exposure, which may provide a benefit in terms of safety and tolerability. As a result, European treatment guidelines have, for many years, recommended the use of topical NSAIDs as a safe and effective treatment option for OA. Following the recent approval of several topical NSAID formulations by the US Food and Drug Administration, US treatment guidelines are increasingly recommending the use of topical NSAIDs as an alternative therapy and, in some cases, as a first-line option for OA. This commentary summarizes OA treatment guidelines that are currently available and discusses their potential evolution with regard to the increased inclusion of topical NSAIDs. PMID:24444047

  3. Traumeel – an emerging option to nonsteroidal anti-inflammatory drugs in the management of acute musculoskeletal injuries

    PubMed Central

    Schneider, Christian

    2011-01-01

    Musculoskeletal injuries are on the rise. First-line management of such injuries usually employs the RICE (rest, ice, compression, and elevation) approach to limit excessive inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also commonly used to limit inflammation and to control pain. Traumeel®, a preparation with bioregulatory effects is also used to treat the symptoms associated with acute musculoskeletal injuries, including pain and swelling. Traumeel is a fixed combination of biological and mineral extracts, which aims to apply stimuli to multiple targets to restore normal functioning of regulatory mechanisms. This paper presents the accumulating evidence of Traumeel’s action on the inflammatory process, and of its efficacy and tolerability in randomized trials, as well as observational and surveillance studies for the treatment of musculoskeletal injuries. Traumeel has shown comparable effectiveness to NSAIDs in terms of reducing symptoms of inflammation, accelerating recovery, and improving mobility, with a favorable safety profile. While continued research and development is ongoing to broaden the clinical evidence of Traumeel in acute musculoskeletal injury and to further establish its benefits, current information suggests that Traumeel may be considered as an anti-inflammatory agent that is at least as effective and appears to be better tolerated than NSAIDs. PMID:21556350

  4. Is Alzheimer's Disease Autoimmune Inflammation of the Brain That Can be Treated With Nasal Nonsteroidal Anti-Inflammatory Drugs?

    PubMed

    Lehrer, Steven; Rheinstein, Peter H

    2015-05-01

    The Alzheimer's Association recently reported that a woman's estimated lifetime risk of developing Alzheimer's at age 65 is 1 in 6, compared to nearly 1 in 11 for a man (ie, female to male ratio 1.8). Based on female to male ratio, Alzheimer's disease could well be an autoimmune disorder. Like Alzheimer's, multiple sclerosis, an autoimmune inflammation of the central nervous system, has a female to male ratio of 2.3. Also based on female to male ratio, Alzheimer's resembles the autoimmune inflammatory disease rheumatoid arthritis, which has a female to male ratio of 2.7. The reasons for the female preponderance in autoimmune disease are unclear, but nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and successfully employed to treat autoimmune anti-inflammatory disease and dramatically relieve symptoms. Moreover, oral NSAIDs consistently reduce the risk of Alzheimer's disease, although they have been totally ineffective as a treatment in multiple failed clinical trials. A basis for this failure might well be that the brain dose after oral administration is too small and not sufficiently early in the pathogenesis of the disorder. But NSAID brain dose could be significantly increased by delivering the NSAIDs intranasally.

  5. Synthesis and biological evaluation of phenyl-1H-1,2,3-triazole derivatives as anti-inflammatory agents.

    PubMed

    Kim, Tae Woo; Yong, Yeonjoong; Shin, Soon Young; Jung, Hyeryoung; Park, Kwan Ha; Lee, Young Han; Lim, Yoongho; Jung, Kang-Yeoun

    2015-04-01

    Rapid and efficient synthesis of a phenyl-1H-1,2,3-triazole library enabled cost-effective biological testing of a range of novel non-steroidal anti-inflammatory drugs with potential for improved drug efficacy and toxicity profiles. Anti-inflammatory activities of the phenyl-1H-1,2,3-triazole analogs synthesized in this report were assessed using the xylene-induced ear edema model in mice. At least four analogs, 2a, 2b, 2c, and 4a, showed more potent effects than the reference anti-inflammatory drug diclofenac at the same dose of 25 mg/kg. To explore relationships between the structural properties of phenyl-1H-1,2,3-triazole analogs and their anti-inflammatory activities in xylene-induced ear edema, comparative molecular field analysis was performed, and pharmacophores showing good anti-inflammatory activities were identified based on an analysis of contour maps obtained from comparative molecular field analysis. The anti-inflammatory effect on the molecular level was tested by the expression of tumor necrosis factor-alpha induced COX-2 using Western blots. Because the addition of the analog 2c caused the expression change of TNF-α induced COX-2, the molecular binding mode between 2c and COX-2 was elucidated using in silico docking.

  6. Pharmacoinformatics study of Piperolactam A from Piper betle root as new lead for non steroidal anti fertility drug development.

    PubMed

    Amin, Sk Abdul; Bhattacharya, Plaban; Basak, Souvik; Gayen, Shovanlal; Nandy, Ashis; Saha, Achintya

    2017-04-01

    Fertility control is a burning problem all over the world to regulate population overflow and maintain ecological balance. This study is an in-silico approach to explore a non-steroidal lead as contraceptive agent in order to avoid several contraindications generated by steroidal analogues. Piperolactam A, an aristolactam isolated from Piper betle Linn. showed binding affinity towards estrogen and progesterone receptor as -8.9 and -9.0Kcal/mol (inhibition constant Ki=0.294μM and 0.249μM) respectively which is even larger than that of reported antagonists such as Rohitukine and OrgC (binding affinity -8.7 and -8.4Kcal/mol; Ki 0.443μM and 0.685μM respectively). The binding site exploration displayed more hydrogen bonding of Piperolactam A (His 524, Leu 346, Thr 347) than Rohitukine and OrgC (Leu 718) with associated receptors which was further confirmed by molecular dynamics simulations. The drug-likeliness of the compound has been proved from its tally with Lipinsky's Rule of Five and lowered toxicity such as cardiac toxicity, liver toxicity, mutagenicity and ecological toxicity. Endocrine disruptome and later docking guided molecular simulations revealed that Piperolactam A has weaker binding affinity and/or lower probability of binding with nuclear receptors especially hERG and cytochrome P450. The high Caco-2 permeability suggested more bioavailability hence more therapeutic efficacy of the drug.

  7. Computational drug repositioning for peripheral arterial disease: prediction of anti-inflammatory and pro-angiogenic therapeutics

    PubMed Central

    Chu, Liang-Hui; Annex, Brian H.; Popel, Aleksander S.

    2015-01-01

    Peripheral arterial disease (PAD) results from atherosclerosis that leads to blocked arteries and reduced blood flow, most commonly in the arteries of the legs. PAD clinical trials to induce angiogenesis to improve blood flow conducted in the last decade have not succeeded. We have recently constructed PADPIN, protein-protein interaction network (PIN) of PAD, and here we combine it with the drug-target relations to identify potential drug targets for PAD. Specifically, the proteins in the PADPIN were classified as belonging to the angiome, immunome, and arteriome, characterizing the processes of angiogenesis, immune response/inflammation, and arteriogenesis, respectively. Using the network-based approach we predict the candidate drugs for repositioning that have potential applications to PAD. By compiling the drug information in two drug databases DrugBank and PharmGKB, we predict FDA-approved drugs whose targets are the proteins annotated as anti-angiogenic and pro-inflammatory, respectively. Examples of pro-angiogenic drugs are carvedilol and urokinase. Examples of anti-inflammatory drugs are ACE inhibitors and maraviroc. This is the first computational drug repositioning study for PAD. PMID:26379552

  8. Computational drug repositioning for peripheral arterial disease: prediction of anti-inflammatory and pro-angiogenic therapeutics.

    PubMed

    Chu, Liang-Hui; Annex, Brian H; Popel, Aleksander S

    2015-01-01

    Peripheral arterial disease (PAD) results from atherosclerosis that leads to blocked arteries and reduced blood flow, most commonly in the arteries of the legs. PAD clinical trials to induce angiogenesis to improve blood flow conducted in the last decade have not succeeded. We have recently constructed PADPIN, protein-protein interaction network (PIN) of PAD, and here we combine it with the drug-target relations to identify potential drug targets for PAD. Specifically, the proteins in the PADPIN were classified as belonging to the angiome, immunome, and arteriome, characterizing the processes of angiogenesis, immune response/inflammation, and arteriogenesis, respectively. Using the network-based approach we predict the candidate drugs for repositioning that have potential applications to PAD. By compiling the drug information in two drug databases DrugBank and PharmGKB, we predict FDA-approved drugs whose targets are the proteins annotated as anti-angiogenic and pro-inflammatory, respectively. Examples of pro-angiogenic drugs are carvedilol and urokinase. Examples of anti-inflammatory drugs are ACE inhibitors and maraviroc. This is the first computational drug repositioning study for PAD.

  9. Synthesis and evaluation of the anti-inflammatory effects of niflumic acid lipophilic prodrugs in brain edema.

    PubMed

    el Kihel, L; Bourass, J; Richomme, P; Petit, J Y; Letourneux, Y

    1996-11-01

    Five new lipophilic prodrugs of the non-steroidal anti-inflammatory drug, niflumic acid (Nifluril, CAS 4394-00-7), were synthetized and evaluated on the experimental brain edema (injection of phospholipase A2). The effect of these drugs in comparison with dexamethasone which elicits a marked effect on clinical and experimental brain edema was evaluated. Niflumic acid was vectorised by cholesterol, hexadecanol and by three 1,3-diacylglycerols. The anti-inflammatory activity of these compounds on experimental brain edema was evaluated by determination of the prostaglandin E2 (PGE2) brain tissue concentration. Niflumic acid reduced the prostaglandin E2 production more significantly than dexamethasone. Niflumic acid prodrug forms (1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyl] glycerol and 1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyloxybuta noyl] glycerol also showed a marked anti-inflammatory activity at low concentrations.

  10. [Prescribers' awareness about the pharmacology of the non-steroidal drugs in the capital town of Antananarivo].

    PubMed

    Fara, R; Rasoloherimampiononiaina, M R; Rajaonarivony, T; Randriamiarana, J M

    2008-01-01

    In order to assess prescribers' level of knowledge about the pharmacology of the non steroidian anti-inflammatory drugs (NSAIDs), we led a prospective study without randomization among the caregivers of three university teaching hospitals and three private hospitals centres of Antananarivo, capital town of Malagasy Republic. The answers to the questionnaire were coded as known or unknown. Statistical analysis (by SPSS 10.0 software for Windows) displayed Fisher's exact test and p value less than 0.05 was set as cut-off for significance. The response rate was 71% (43 over 60), mainly from physicians (62.8%). The correct posology, the non-digestive adverse effects and the adequate follow-up were the main ignored items. Analysis by logistic regression demonstrated association between medical professionals and ignorance of adequate follow-up (p=0.030), female gender and ignorance of the non-digestive adverse effects (p=0.041). In conclusion, routine prescription hides ignorance about the safe use of the drug and periodical recycling of health professionals is helpful.

  11. Endogenous migration modulators as parent compounds for the development of novel cardiovascular and anti-inflammatory drugs

    PubMed Central

    Poller, Wolfgang; Rother, Madlen; Skurk, Carsten; Scheibenbogen, Carmen

    2012-01-01

    Development of novel cell migration modulators for anti-inflammatory and cardiovascular therapy is a complex task since any modulator will necessarily interfere with a balanced system of physiological regulators directing proper positioning of diverse immune cell types within the body. Whereas this shall serve efficient pathogen elimination, lack of proper control over these processes may result in counterproductive chronic inflammation and progressive tissue injury instead of healing. Prediction of the therapeutic potential or side effects of any migration modulator is not possible based on theoretical considerations alone but needs to be experimentally evaluated in preclinical disease models and by clinical studies. Here, we briefly summarize basic mechanism of cell migration, and groups of synthetic drugs currently in use for migration modulation. We then discuss one fundamental problem encountered with single-target approaches that arises from the complexity of any inflammation, with multiple interacting and often redundant factors being involved. This issue is likely to arise for any class of therapeutic agent (small molecules, peptides, antibodies, regulatory RNAs) addressing a single gene or protein. Against this background of studies on synthetic migration modulators addressing single targets, we then discuss the potential of endogenous proteins as therapeutic migration modulators, or as parent compounds for the development of mimetic drugs. Regulatory proteins of this type commonly address multiple receptors and signalling pathways and act upon the immune response in a phase-specific manner. Based on recent evidence, we suggest investigation of such endogenous migration modulators as novel starting points for anti-inflammatory and cardiovascular drug development. PMID:22035209

  12. Molecular mechanisms of inflammation. Anti-inflammatory benefits of virgin olive oil and the phenolic compound oleocanthal.

    PubMed

    Lucas, Lisa; Russell, Aaron; Keast, Russell

    2011-01-01

    Chronic inflammation is a critical factor in the pathogenesis of many inflammatory disease states including cardiovascular disease, cancer, diabetes, degenerative joint diseases and neurodegenerative diseases. Chronic inflammatory states are poorly understood, however it is known that dietary habits can evoke or attenuate inflammatory responses. Popular methods to deal with inflammation and its associated symptoms involve the use of non steroidal anti-inflammatory drugs, however the use of these drugs are associated with severe side effects. Therefore, investigations concerned with natural methods of inflammatory control are warranted. A traditional Mediterranean diet has been shown to confer some protection against the pathology of chronic diseases through the attenuation of pro-inflammatory mediators and this has been partially attributed to the high intake of virgin olive oil accompanying this dietary regime. Virgin olive oil contains numerous phenolic compounds that exert potent anti-inflammatory actions. Of interest to this paper is the recently discovered phenolic compound oleocanthal. Oleocanthal is contained in virgin olive oil and possesses similar anti-inflammatory properties to ibuprofen. This pharmacological similarity has provoked interest in oleocanthal and the few studies conducted thus far have verified its anti-inflammatory and potential therapeutic actions. A review of the health benefits of the Mediterranean diet and anti-inflammatory properties of virgin olive oil is presented with the additional emphasis on the pharmacological and anti-inflammatory properties of the phenolic compound oleocanthal.

  13. Application of f--f luminescence of terbium ion for determination of non-steroidal anti-inflammatory drug-niflumic acid.

    PubMed

    Egorova, A; Beltyukova, S; Teslyuk, O; Karpinchik, V

    2001-03-01

    A simple, rapid and sensitive luminescence method for determination of niflumic acid (NFA) is described. The method is based on the intramolecular energy transfer from niflumic acid to terbium ion (Tb(3+)) in the presence of trioctylphosphine oxide (TOPO). Optimum conditions for the formation of the NFA-Tb(3+)-TOPO ternary complex have been investigated. The calibration graph is linear over the range 0.002--0.02 microg ml(-1). The relative standard deviation is close to 4%. The recoveries obtained by applying the method to the analysis of urine ranged from 94--102%.

  14. Rapid method for the determination of non-steroidal anti-inflammatory drugs in animal tissue by liquid chromatography-mass spectrometry with ion-trap detector.

    PubMed

    Igualada, Carmen; Moragues, Francisco; Pitarch, Jorge

    2007-03-14

    A rapid and new liquid chromatography-mass spectrometry with ion-trap detection method for the determination of meloxicam (MLX), flunixin meglumine (FLU), carprofen (CPF), and tolfenamic acid (TOLF) in animal tissue is described. MRLs between 10 and 500 microg kg(-1) in muscle and between 65 and 1000 microg kg(-1) in liver, from different animal species have been established in the EU for these compounds. After chemical hydrolysis, an organic extraction from homogenised tissue was performed. Final extract was injected in a liquid chromatograph with an ion-trap mass spectrometer with electrospray interface. Four identification points (one precursor and two product ions) and a minimum of one ion ratio was monitored for each compound. For quantitative purposes flunixin-D3 (FLU-D3) was used as internal standard. The method was validated using fortified blank muscle and liver from different animal species according to the 2002/657/EC European decision criteria. The decision limits (CCalpha) and detection capabilities (CCbeta) were determined and their values were at concentrations near the MRL for each substance.

  15. Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach

    PubMed Central

    Richy, F; Bruyere, O; Ethgen, O; Rabenda, V; Bouvenot, G; Audran, M; Herrero-Beaumont, G; Moore, A; Eliakim, R; Haim, M; Reginster, J

    2004-01-01

    Methods: An exhaustive systematic search was performed. Inclusion criteria were: RCT or controlled study, duration of 5 days at least, inactive control, assessment of minor or major NSAID adverse effects, publication range January 1985 to January 2003. The publications retrieved were assessed during a specifically dedicated WHO meeting including leading experts in all related fields. Statistics were performed conservatively. Meta-regression was performed by regressing NSAID adjusted estimates against study duration categories. Results: Among RCT data, indolic derivates provided a significantly higher risk of GI complications related to NSAID use than for non-users: RR = 2.25 (1.00; 5.08) than did other compounds: naproxen: RR = 1.83 (1.25; 2.68); diclofenac: RR = 1.73 (1.21; 2.46); piroxicam: RR = 1.66 (1.14; 2.44); tenoxicam: RR = 1.43 (0.40; 5.14); meloxicam: RR = 1.24 (0.98; 1.56), and ibuprofen: RR = 1.19 (0.93; 1.54). Indometacin users had a maximum relative risk for complication at 14 days. The other compounds presented a better profile, with a maximum risk at 50 days. Significant additional risk factors included age, dose, and underlying disease. The controlled cohort studies provided higher estimates: RR = 2.22 (1.7; 2.9). Publication bias testing was significant, towards a selective publication of deleterious effects of NSAIDs from small sized studies. Conclusion: This meta-analysis characterised the "compound" and "time" aspects of the GI toxicity of non-selective NSAIDs. The risk/benefit ratio of such compounds should thus be carefully and individually evaluated at the start of long term treatment. PMID:15194568

  16. Label-free optical biosensor for detection and quantification of the non-steroidal anti-inflammatory drug diclofenac in milk without any sample pretreatment.

    PubMed

    Rau, Sabrina; Hilbig, Urs; Gauglitz, Günter

    2014-05-01

    A label-free optical biosensor for detection and quantification of diclofenac in bovine milk has been developed. This was achieved by using reflectometric interference spectroscopy as detection method. In a first step, the immunosensor was developed and optimised in buffer concerning sensitivity, selectivity, stability and reproducibility. By comparing recovery rates—not only the good intra- but also the good inter-chip—reproducibility could be proven. Consequently, the assay was transferred in the more complex matrix milk. By utilising an optimised surface modification and evaluation method, matrix effects could successfully be prevented or circumvented. As a result, the developed immunosensor does not need sample pretreatment at all. By obtaining a limit of detection of 0.112 μg L(−1) (0.108 μg kg(−1)), the capability of the developed biosensor is comparable or better than those of standard detection methods. Moreover, the presented biosensor reaches the range of the maximum residue limit (0.1 μg kg(−1)) set by the European Union. Thus, for the first time, diclofenac was successfully quantified at relevant levels in milk by using an optical biosensor.

  17. Administration of the non-steroidal anti-inflammatory drug ibuprofen increases macrophage concentrations but reduces necrosis during modified muscle use

    NASA Technical Reports Server (NTRS)

    Cheung, E. V.; Tidball, J. G.

    2003-01-01

    OBJECTIVE: To test the hypothesis that ibuprofen administration during modified muscle use reduces muscle necrosis and invasion by select myeloid cell populations. METHODS: Rats were subjected to hindlimb unloading for 10 days, after which they experienced muscle reloading by normal weight-bearing to induce muscle inflammation and necrosis. Some animals received ibuprofen by intraperitoneal injection 8 h prior to the onset of muscle reloading, and then again at 8 and 16 h following the onset of reloading. Other animals received buffer injection at 8 h prior to reloading and then ibuprofen at 8 and 16 h following the onset of reloading. Control animals received buffer only at each time point. Quantitative immunohistochemical analysis was used to assess the presence of necrotic muscle fibers, total inflammatory infiltrate, neutrophils, ED1+ macrophages and ED2+ macrophages at 24 h following the onset of reloading. RESULT: Administration of ibuprofen beginning 8 h prior to reloading caused significant reduction in the concentration of necrotic fibers, but increased the concentration of inflammatory cells in muscle. The increase in inflammatory cells was attributable to a 2.6-fold increase in the concentration of ED2+ macrophages. Animals treated with ibuprofen 8 h following the onset of reloading showed no decrease in muscle necrosis or increase in ED2+ macrophage concentrations. CONCLUSION: Administration of ibuprofen prior to increased muscle loading reduces muscle damage, but increases the concentration of macrophages that express the ED2 antigen. The increase in ED2+ macrophage concentration and decrease in necrosis may be mechanistically related because ED2+ macrophages have been associated with muscle regeneration and repair.

  18. Rapid confirmatory analysis of non-steroidal anti-inflammatory drugs in bovine milk by rapid resolution liquid chromatography tandem mass spectrometry.

    PubMed

    Dowling, Geraldine; Gallo, Pasquale; Malone, Edward; Regan, Liam

    2009-11-13

    A rapid method has been developed to analyse carprofen (CPF), diclofenac (DCF), mefenamic acid (MFN), niflumic acid (NIFLU), naproxen (NAP), oxyphenylbutazone (OXYPHEN), phenylbutazone (PBZ) and suxibuzone (SUXI) residues in bovine milk. Milk samples are extracted with acetonitrile and sample extracts were purified on Evolute ABN solid phase extraction cartridges. Aliquots were analysed by rapid resolution liquid chromatography tandem mass spectrometry (RRLC-MS/MS) with a runtime of 6.5 min. The method was validated in bovine milk, according to the criteria defined in Commission Decision 2002/657/EC. CCalpha values of 0.46, 1.08, 0.92, 1.26, 1.29, 2.12, 0.55 and 2.86 ng mL(-1) were determined for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI, respectively. CCbeta values of 0.79, 1.85, 1.56, 2.15, 2.19, 3.62, 0.94 and 4.87 ng mL(-1) were determined for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI, respectively. The measurement uncertainty of the method was estimated at 9, 28, 28, 45, 46, 45, 10 and 39% for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI. Fortifying bovine milk samples (n=18) in three separate assays, show the accuracy of the method to be between 82 and 108%. The precision of the method, expressed as RSD values for the within-lab reproducibility at the three levels of fortification (5, 7.5 and 10 ng mL(-1)) was less than 16%, respectively. The advantage of the method is that low ng mL(-1) levels can be detected and quantitatively confirmed rapidly in milk and that 3 batches of samples can be analysed within a single day using RRLC-MS/MS with a runtime of 6.5 min.

  19. Photosensitizing properties of 6-methoxy-2-naphthylacetic acid, the major metabolite of the phototoxic non-steroidal anti-inflammatory and analgesic drug nabumetone.

    PubMed

    Canudas, N; Zamora, D; Villamizar, J E; Fuentes, J; Castelli, C; Taddei, A

    2005-08-01

    The photobiological properties of 6-methoxy-2-naphthylacetic acid (6-MNAA) were studied using a variety of in vitro phototoxicity assays: photohemolysis, photoperoxidation of linoleic acid, photosensitized degradation of histidine and thymine and the Candida phototoxicity test. 6-MNAA was phototoxic in vitro. 6-MNAA reduced nitro blue tetrazolium (NBT) when irradiated with lambda > or = 300 nm in deoxygenated aqueous buffer solution (pH 7.4). NBT can be reduced by reaction with the excited state of 6-MNAA subject to interference with molecular oxygen. The photohemolysis rate was inhibited by the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO), sodium azide (NaN3) and reduced glutathione (GSH). Photoperoxidation of linoleic acid and photosensitized degradation of histidine and thymine were significantly inhibited by sodium azide and reduced glutathione. 6-MNAA was phototoxic to C. albicans, C. lipolytica and C. tropicalis. A mechanism involving singlet oxygen, radicals, and electron transfer reactions is suggested for the observed phototoxicity.

  20. Non-steroidal Anti-inflammatory Drug use Not Associated with Erectile Dysfunction Risk: Results from the Prostate Cancer Prevention Trial

    PubMed Central

    Patel, Darshan P; Schenk, Jeannette M; Darke, Amy; Myers, Jeremy B; Brant, William O; Hotaling, James M

    2016-01-01

    Objective ◦ To evaluate associations of NSAID use and risk of ED, considering indications for NSAID use. Patients and Methods ◦ Data are from 4,726 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) without evidence of ED at baseline. ◦ Incident ED was defined as mild/moderate (decrease in normal function) and severe (absence of function). ◦ Proportional hazards models were used to estimate covariate-adjusted associations of NSAID–related medical conditions and time-dependent NSAID use with ED risk. Results ◦ Arthritis (HR: 1.56), chronic musculoskeletal pain (HR: 1.35), general musculoskeletal complaints (HR:1.36), headaches (HR:1.44), sciatica (HR:1.50), and atherosclerotic disease (HR:1.60) were all significantly associated with increased risk of, mild/moderate ED, while only general musculoskeletal complaints (HR:1.22), headaches (HR:1.47) and atherosclerotic disease (HR:1.60) were associated with increased risk of severe ED. ◦ Non-aspirin NSAID use was associated with an increased risk of mild/moderate ED (HR: 1.16, p=0.02) and Aspirin use was associated with an increased risk of severe ED (HR: 1.16, p=0.03, respectively). ◦ Associations of NSAID use with ED risk were attenuated after controlling for indications of NSAID use. Conclusions ◦ The modest associations of NSAID use with ED risk in this cohort were likely due to confounding indications of NSAID use. NSAID use was not associated with ED risk. PMID:26305866

  1. Preoperative treatment with a non-steroidal anti-inflammatory drug (NSAID) increases tumor tissue infiltration of seemingly activated immune cells in colorectal cancer

    PubMed Central

    Andersson, Marianne; Arvidsson, Annette; Nordgren, Svante; Brevinge, Hans; Lagerstedt, Kristina; Lundholm, Kent

    2008-01-01

    This study evaluates HLA gene expression and tumor infiltration by B-cells, macrophages, dendritic cells, T-helper and cytotoxic T-lymphocytes in response to short-term preoperative treatment with cyclooxygenase inhibitors. Patients with colorectal carcinoma were randomized to receive oral NSAID (indomethacin or celebrex) for three days preoperatively; controls received esomeprazol. Peroperative tumor biopsies and normal colon tissue were analyzed by microarray, quantitative PCR and immunohistochemistry. Efficacy of short-term systemic NSAID treatment was confirmed by measurement of PGE2 production in blood monocytes from healthy volunteers. NSAID treatment upregulated genes at the MHC locus on chromosome 6p21 in tumor tissue, but not in normal colon tissue, from the same patient. 23 of the 100 most upregulated genes belonged to MHC class II. HLA-DM, -DO (peptide loading), HLA-DP, -DQ, -DR (antigen presentation), granzyme B, H, perforin and FCGR3A (CD16) (cytotoxicity) displayed increased expression, as did CD8, a marker of cytotoxic T-lymphocytes, while HLA-A and -C expression were not increased by NSAID treatment. MHC II protein (HLA-DP, -DQ, -DR) levels and infiltration by CD4+ T-helper cells of tumor stroma increased upon NSAID treatment, while CD8+ cytotoxic T-lymphocytes increased in both tumor stroma and epithelium. Molecules associated with immunosuppressive T regulatory cells (FOXP3, IL-10) were significantly decreased in indomethacin-exposed tumors. Standard oral administration of NSAID three days preoperatively was enough to increase tumor infiltration by seemingly activated immune cells. These findings agree with previous information that high prostanoid activities in colorectal cancer increase the risk for reduced disease-specific survival following tumor resection. PMID:18307280

  2. Necrotizing Sialometaplasia of the Hard Palate in a Patient Treated with Topical Nonsteroidal Anti-Inflammatory Drug

    PubMed Central

    2016-01-01

    Necrotizing sialometaplasia is a rare, benign, self-limiting, necrotizing process involving the minor salivary glands, mainly the mucoserous glands of the hard palate. It is thought to be the result of an ischemic event of the vasculature supplying the salivary gland lobules. Some predisposing factors such as smoking, use of alcohol, denture wearing, recent surgery, traumatic injuries, respiratory infections, systemic diseases bulimia, and anorexia have been described. Herein we present a case of necrotizing sialometaplasia of the hard palate in a patient without known predisposing factors, in our opinion, resulting from the use of topical anti-inflammatory drug. After diagnosis, the patient underwent treatment with chlorhexidine gluconate and a full palatal acrylic guard to protect the exposed bone from food residues during meals. After the sixth week the lesion regressed. PMID:27833767

  3. Basophil activation after nonsteroidal anti-inflammatory drugs stimulation in patients with immediate hypersensitivity reactions to these drugs.

    PubMed

    Ariza, Adriana; Fernandez, Tahia D; Doña, Inmaculada; Aranda, Ana; Blanca-Lopez, Natalia; Melendez, Lidia; Canto, Gabriela; Blanca, Miguel; Torres, Maria J; Mayorga, Cristobalina

    2014-05-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in allergic reactions of which two main types exist: IgE-mediated and crossintolerance. The diagnosis of crossintolerance reactions is often based on the drug provocation test. The potential value of the basophil activation test (BAT) was evaluated using different basophil markers in the diagnosis of patients with crossintolerance to NSAIDs and cutaneous symptoms. We studied 46 patients with crossintolerance to NSAIDs and 45 tolerant controls. BAT was performed with acetyl salicylic acid, paracetamol, diclofenac, dipyrone, naproxen, and ibuprofen at four different concentrations using CD193 and CD203c as basophil markers and CD63 as activation marker. We compared BAT results using CD193⁺ or CD193⁺ CD203c⁺ for basophil selection and found a significant increase in the stimulation index when using CD193⁺ CD203c⁺ in both patients and controls (P = 0.004 and P = 0.017, respectively). Selection of living cells only produced an increase in basophil stimulation in patients for both CD193⁺ and CD193⁺ CD203c⁺ (P < 0.001 for both), whereas in controls there was no change with CD193⁺ and a decrease with CD193⁺ CD203c⁺ (P = 0.001). We found that CD193⁺ CD203c⁺ increased the percentage of positive cases in patients and controls when compared with CD193⁺. When excluding dead cells, there was an increase of 21.7% in patients and 10% in controls. These results indicate that using CD193⁺ CD203⁺, excluding dead cells, is the best approach for BAT although this test is not recommended for the diagnosis of patients with crossintolerance to NSAIDs owing to its low sensitivity and specificity.

  4. Optimization and Pharmacological Validation of a Leukocyte Migration Assay in Zebrafish Larvae for the Rapid In Vivo Bioactivity Analysis of Anti-Inflammatory Secondary Metabolites

    PubMed Central

    Vicet-Muro, Liliana; Wilches-Arizábala, Isabel María; Esguerra, Camila V.; de Witte, Peter A. M.; Crawford, Alexander D.

    2013-01-01

    Over the past decade, zebrafish (Danio rerio) have emerged as an attractive model for in vivo drug discovery. In this study, we explore the suitability of zebrafish larvae to rapidly evaluate the anti-inflammatory activity of natural products (NPs) and medicinal plants used in traditional medicine for the treatment of inflammatory disorders. First, we optimized a zebrafish assay for leukocyte migration. Inflammation was induced in four days post-fertilization (dpf) zebrafish larvae by tail transection and co-incubation with bacterial lipopolysaccharides (LPS), resulting in a robust recruitment of leukocytes to the zone of injury. Migrating zebrafish leukocytes were detected in situ by myeloperoxidase (MPO) staining, and anti-inflammatory activity was semi-quantitatively scored using a standardized scale of relative leukocyte migration (RLM). Pharmacological validation of this optimized assay was performed with a panel of anti-inflammatory drugs, demonstrating a concentration-responsive inhibition of leukocyte migration for both steroidal and non-steroidal anti-inflammatory drugs (SAIDs and NSAIDs). Subsequently, we evaluated the bioactivity of structurally diverse NPs with well-documented anti-inflammatory properties. Finally, we further used this zebrafish-based assay to quantify the anti-inflammatory activity in the aqueous and methanolic extracts of several medicinal plants. Our results indicate the suitability of this LPS-enhanced leukocyte migration assay in zebrafish larvae as a front-line screening platform in NP discovery, including for the bioassay-guided isolation of anti-inflammatory secondary metabolites from complex NP extracts. PMID:24124487

  5. Nonsteroidal anti-inflammatory drug flufenamic acid is a potent activator of AMP-activated protein kinase.

    PubMed

    Chi, Yuan; Li, Kai; Yan, Qiaojing; Koizumi, Schuichi; Shi, Liye; Takahashi, Shuhei; Zhu, Ying; Matsue, Hiroyuki; Takeda, Masayuki; Kitamura, Masanori; Yao, Jian

    2011-10-01

    Flufenamic acid (FFA) is a nonsteroidal anti-inflammatory drug (NSAID). It has anti-inflammatory and antipyretic properties. In addition, it modulates multiple channel activities. The mechanisms underlying the pharmacological actions of FFA are presently unclear. Given that AMP-activated protein kinase (AMPK) has both anti-inflammatory and channel-regulating functions, we examined whether FFA induces AMPK activation. 1) Exposure of several different types of cells to FFA resulted in an elevation of AMPKα phosphorylation at Thr172. This effect of FFA was reproduced by functionally and structurally similar mefenamic acid, tolfenamic acid, niflumic acid, and meclofenamic acid. 2) FFA-induced activation of AMPK was largely abolished by the treatment of cells with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (an intracellular Ca(2+) chelator) or depletion of extracellular Ca(2+), whereas it was mimicked by stimulation of cells with the Ca(2+) ionophore 5-(methylamino)-2-({(2R,3R,6S,8S,9R,11R)-3,9,11-trimethyl-8-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7-dioxaspiro[5.5]undec-2-yl}methyl)-1,3-benzoxazole-4-carboxylic acid (A23187) or ionomycin. 3) FFA triggered a rise in intracellular Ca(2+), which was abolished by cyclosporine, a blocker of mitochondrial permeability transition pore. Cyclosporine also abolished FFA-induced activation of AMPK. 4) Inhibition of Ca(2+)/calmodulin-dependent kinase kinase β (CaMKKβ) with 7-oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic acid acetate (STO-609) or down-regulation of CaMKKβ with short interfering RNA largely abrogated FFA-induced activation of AMPK. 5) FFA significantly suppressed nuclear factor-κB activity and inducible nitric-oxide synthase expression triggered by interleukin-1β and tumor necrosis factor α. This suppression was also largely abrogated by STO-609. Taken together, we conclude that FFA induces AMPK activation through the Ca(2+)-CaMKKβ pathway

  6. Non-Steroid Anti-Infflamatory Drugs in Municipal Wastewater and Surface Waters/ Niesteroidowe Leki Przeciwzaplane W Ściekach Mieskich I Wodach Powierzchniowych

    NASA Astrophysics Data System (ADS)

    Płuciennik-Koropczuk, Ewelina

    2014-09-01

    Increased production and consumption of drugs influences the pollution pharmaceuticals. Recent years have seen a significant increase in the consumption of non-prescription medicines, among which, are a large group of non-steroidal anti-inflammatory drugs (NSAIDs). Research conducted in Poland and abroad showed the presence of NSAIDs, both in treated wastewater in surface waters and drinking waters. One of the most frequently detected drugs in the environment is diclofenac, belongs to NSAID. Its concentration in surface waters range from 9 to 3363 ng/L. Traditional wastewater treatment plants are not specialized enough in removing the pharmaceuticals and their metabolites, and with purified wastewater are introduced into surface waters. Diclofenac concentrations in treated wastewater range from 0.29 to 2.5 μg/L, the average removal efficiency is about 40%. Wzrost produkcji i spożycia leków wpływa na zanieczyszczenie środowiska farmaceutykami. W ostatnich latach zaobserwowano zdecydowany wzrost spożycia leków dostępnych bez recepty, wśród których znaczną grupę stanowią niesteroidowe leki przeciwzapalne (NLPZ). Badania prowadzone na świecie i w Polsce wykazały obecność niesteroidowych leków przeciwzapalnych zarówno w ściekach oczyszczonych, w wodach powierzchniowych oraz w wodach pitnych. Jednym z najczęściej wykrywanych leków w środowisku jest diklofenak należący NLPZ. Jego stężenia w wodach powierzchniowych wynoszą od 9 do 3633 ng/dm3. Tradycyjne układy technologiczne oczyszczania nie eliminują zupełnie farmaceutyków i ich metabolitów i wraz ze ściekami oczyszczonymi są one wprowadzane do wód powierzchniowych. Stężenia diklofenaku w ściekach oczyszczonych wynoszą od 0,29 do 2,5 μg/dm3, a średnia skuteczność usuwania jest na poziomie ok 40%. Należy zaznaczyć, że dane te nie odzwierciedlają stanu rzeczywistego, gdyż badania są prowadzone wyrywkowo. W 2013 r. Komisja Europejska w dyrektywie Parlamentu Europejskiego i

  7. Synthetic Zeolites as Controlled-Release Delivery Systems for Anti-Inflammatory Drugs.

    PubMed

    Khodaverdi, Elham; Soleimani, Hossein Ali; Mohammadpour, Fatemeh; Hadizadeh, Farzin

    2016-06-01

    Scientists have always been trying to use artificial zeolites to make modified-release drug delivery systems in the gastrointestinal tract. An ideal carrier should have the capability to release the drug in the intestine, which is the main area of absorption. Zeolites are mineral aluminosilicate compounds with regular structure and huge porosity, which are available in natural and artificial forms. In this study, soaking, filtration and solvent evaporation methods were used to load the drugs after activation of the zeolites. Weight measurement, spectroscopy FTIR, thermogravimetry and scanning electronic microscope were used to determine drug loading on the systems. Finally, consideration of drug release was made in a simulated gastric fluid and a simulated intestinal fluid for all matrixes (zeolites containing drugs) and drugs without zeolites. Diclofenac sodium (D) and piroxicam (P) were used as the drug models, and zeolites X and Y as the carriers. Drug loading percentage showed that over 90% of drugs were loaded on zeolites. Dissolution tests in stomach pH environment showed that the control samples (drug without zeolite) released considerable amount of drugs (about 90%) within first 15 min when it was about 10-20% for the matrixes. These results are favorable as NSAIDs irritate the stomach wall and it is ideal not to release much drugs in the stomach. Furthermore, release rate of drugs from matrixes has shown slower rate in comparison with control samples in intestine pH environment.

  8. Do the pharmacodynamics of the nonsteroidal anti-inflammatory drugs suggest a role in the management of postoperative pain?

    PubMed

    Mather, L E

    1992-01-01

    Until recently, nonsteroidal anti-inflammatory drugs (NSAIDs) were regarded as weak analgesic agents with a potent antiplatelet effect that severely limited their perioperative usefulness. However, the recent development of injectable NSAIDs has stimulated a re-evaluation of the potential role of this class of drugs in postoperative pain management. In general surgery, NSAIDs have been shown to be effective analgesics when administered after surgery, as judged by either a reduction in pain scores and/or by an opioid sparing effect. Parenteral NSAIDs alone, notably ketorolac and diclofenac, may be adequate or even preferred analgesic agents after minor surgery. In dental surgery, NSAIDs produce greater initial analgesia than steroids, although the latter produce greater suppression of swelling and less functional loss. NSAID pretreatment results in only modest suppression of swelling compared with placebo. These data suggest that the acute analgesic effects of NSAIDs in oral surgery and probably other models result from suppression of a nociceptive process, rather than a generalised anti-inflammatory effect. This view challenges the traditional association between inhibition of prostaglandin synthesis and the therapeutic effects of these drugs. The variety of NSAIDs leads to a range in half-lives from short, e.g. diclofenac (1 h), intermediate, e.g. ketorolac (5h), to long, e.g. tenoxicam (60h), which has implications for both convenience of the dosage regimen and drug accumulation. For some racemic NSAIDs (e.g. ibuprofen), metabolic 'activation' of the inactive R-enantiomer to the active S-enantiomer occurs. Renal dysfunction may increase both the plasma concentration and body residence time of NSAIDs, thereby increasing the risk of adverse effects. The concomitant effects of anaesthesia have not yet been studied. The principal concern regarding the use of perioperative NSAIDs is the risk of decreased haemostasis and wound healing. Although it has been found that

  9. Pharmacological interactions of anti-inflammatory-analgesics in odontology.

    PubMed

    Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis

    2009-02-01

    In this second article we describe the more interesting pharmacological interactions in dental practice based on the prescription of analgesic narcotics, paracetamol and non-selective non-steroid anti-inflammatory drugs (NSAI) (which inhibit cyclooxigenase 1 -COX 1- and cyclooxigenase 2 -COX 2-) and selective NSAIs (COX 2 inhibitors). The importance of preventing the appearance of these pharmacological interactions is because these are medicaments prescribed daily in odontology for moderate pain treatment and inflammation in the oral cavity. Paracetamol can interact with warfarin and therefore care should be taken with chronic alcoholic patients. All NSAIs reduce renal blood flow and consequently are capable of reducing the efficacy of medicaments used for treating arterial hypertension, which act via a renal mechanism. Especial attention should be taken considering the risk of interaction between the antagonists of AT1 receptors of angiostensin II (ARAII) and the NSAIs.

  10. Modulating the Innate Immune Response to Influenza A Virus: Potential Therapeutic Use of Anti-Inflammatory Drugs

    PubMed Central

    Ramos, Irene; Fernandez-Sesma, Ana

    2015-01-01

    Infection by influenza A viruses (IAV) is frequently characterized by robust inflammation that is usually more pronounced in the case of avian influenza. It is becoming clearer that the morbidity and pathogenesis caused by IAV are consequences of this inflammatory response, with several components of the innate immune system acting as the main players. It has been postulated that using a therapeutic approach to limit the innate immune response in combination with antiviral drugs has the potential to diminish symptoms and tissue damage caused by IAV infection. Indeed, some anti-inflammatory agents have been shown to be effective in animal models in reducing IAV pathology as a proof of principle. The main challenge in developing such therapies is to selectively modulate signaling pathways that contribute to lung injury while maintaining the ability of the host cells to mount an antiviral response to control virus replication. However, the dissection of those pathways is very complex given the numerous components regulated by the same factors (i.e., NF kappa B transcription factors) and the large number of players involved in this regulation, some of which may be undescribed or unknown. This article provides a comprehensive review of the current knowledge regarding the innate immune responses associated with tissue damage by IAV infection, the understanding of which is essential for the development of effective immunomodulatory drugs. Furthermore, we summarize the recent advances on the development and evaluation of such drugs as well as the lessons learned from those studies. PMID:26257731

  11. Nonsteroidal anti-inflammatory drugs and 5-HT₃ serotonin receptor antagonists as innovative antipsychotic augmentation treatments for schizophrenia.

    PubMed

    Andrade, Chittaranjan

    2014-07-01

    Antipsychotic treatment is the mainstay in the management of schizophrenia. However, despite optimum use of antipsychotic drugs, many schizophrenia patients continue to exhibit residual positive, negative, cognitive, and other symptoms. Various antipsychotic augmentation strategies have been studied using non-antipsychotic augmenting agents; 2 innovative classes of drugs examined have been nonsteroidal anti-inflammatory drugs (NSAIDs) and 5-HT₃ serotonin receptor antagonists. Meta-analysis of the NSAID studies in schizophrenia patients with positive symptoms (8 randomized controlled trials [RCTs], pooled N = 774) shows that NSAID augmentation is associated with a significant decrease in positive symptom ratings (standardized mean difference [SMD] = 0.19), with no significant change in negative or total symptom ratings. Meta-analysis of the 5-HT₃ antagonist studies in stable schizophrenia patients (6 RCTs, pooled N = 311) shows that 5-HT₃ antagonist augmentation is associated with significant reduction in negative symptom (SMD = 1.10), general psychopathology (SMD = 0.70), and total symptom (SMD = 1.03) ratings without reduction in positive symptom ratings. Neither NSAID nor 5-HT₃ antagonist augmentation increases the dropout rate. Whereas the benefits with NSAID augmentation are, perhaps, too small to be clinically meaningful, antipsychotic augmentation with 5-HT₃ antagonists may be a possible strategy to reduce persistent negative symptoms in schizophrenia. Both fields of inquiry require further investigation.

  12. Gastroprotective Effects of Grape Seed Proanthocyanidin Extracts against Nonsteroid Anti-Inflammatory Drug-Induced Gastric Injury in Rats

    PubMed Central

    Kim, Tae Ho; Jeon, Eun Jeong; Cheung, Dae Young; Kim, Chang Whan; Kim, Sung Soo; Park, Soo-Heon; Han, Sok Won; Kim, Myung Jun; Lee, Youn Soo; Cho, Mi-La; Chang, Jae Hyuck

    2013-01-01

    Background/Aims To investigate the gastroprotective effects of grape seed proanthocyanidin extracts (GSPEs) against nonsteroid anti-inflammatory drug (NSAID)-induced gastric mucosal injury in rats. Methods Sprague-Dawley rats were randomly allocated to the normal control, indomethacin, low-dose GSPE, high-dose GSPE and misoprostol groups. All groups except the normal control group received pretreatment drugs for 6 consecutive days. On the 5th and 6th day, indomethacin was administered orally to all groups except for normal control group. The microscopic features of injury were analyzed. The levels of gastric mucosal glutathione, gastric mucosal prostaglandin E2 (PGE2), and proinflammatory cytokines were investigated. Results The total areas of ulceration in the GSPE and misoprostol groups were significantly decreased compared with the indomethacin group (p<0.05). However, a difference in ulcer formation among the drug treatment groups was not observed. Meanwhile, the glutathione levels in the high-dose GSPE group were higher than those of both the indomethacin and misoprostol groups (p<0.05) and were similar to those of the normal control group. Additionally, there was no difference among the groups in the levels of gastric mucosal PGE2 and proinflammatory cytokines. Conclusions High-dose GSPE has a strong protective effect against NSAID-induced gastric mucosal injury, which may be associated with the antioxidant effects of GSPE. PMID:23710308

  13. Ginger--an herbal medicinal product with broad anti-inflammatory actions.

    PubMed

    Grzanna, Reinhard; Lindmark, Lars; Frondoza, Carmelita G

    2005-01-01

    The anti-inflammatory properties of ginger have been known and valued for centuries. During the past 25 years, many laboratories have provided scientific support for the long-held belief that ginger contains constituents with antiinflammatory properties. The original discovery of ginger's inhibitory effects on prostaglandin biosynthesis in the early 1970s has been repeatedly confirmed. This discovery identified ginger as an herbal medicinal product that shares pharmacological properties with non-steroidal anti-inflammatory drugs. Ginger suppresses prostaglandin synthesis through inhibition of cyclooxygenase-1 and cyclooxygenase-2. An important extension of this early work was the observation that ginger also suppresses leukotriene biosynthesis by inhibiting 5-lipoxygenase. This pharmacological property distinguishes ginger from nonsteroidal anti-inflammatory drugs. This discovery preceded the observation that dual inhibitors of cyclooxygenase and 5-lipoxygenase may have a better therapeutic profile and have fewer side effects than non-steroidal anti-inflammatory drugs. The characterization of the pharmacological properties of ginger entered a new phase with the discovery that a ginger extract (EV.EXT.77) derived from Zingiber officinale (family Zingiberaceae) and Alpina galanga (family Zingiberaceae) inhibits the induction of several genes involved in the inflammatory response. These include genes encoding cytokines, chemokines, and the inducible enzyme cyclooxygenase-2. This discovery provided the first evidence that ginger modulates biochemical pathways activated in chronic inflammation. Identification of the molecular targets of individual ginger constituents provides an opportunity to optimize and standardize ginger products with respect to their effects on specific biomarkers of inflammation. Such preparations will be useful for studies in experimental animals and humans.

  14. Underlying mechanism for NMDA receptor antagonism by the anti-inflammatory drug, sulfasalazine, in mouse cortical neurons.

    PubMed

    Noh, Ji-Hyun; Gwag, Byoung-Joo; Chung, Jun-Mo

    2006-01-01

    Sulfasalazine (SULFA), of anti-inflammatory drugs, shows a protective action against NMDA-induced neuronal toxicity. Here, we used an electrophysiological study of the pharmacological effects of SULFA on NMDA receptors to examine the molecular mechanisms underlying the neuroprotective role of SULFA. The drug acted as a typical noncompetitive inhibitor with neither agonist- nor use-dependency, and antagonized NMDA-evoked responses in a voltage-independent manner, suggesting that SULFA is not an open channel blocker. Noise and single channel analyses showed that SULFA-blocked NMDA responses by reducing the number of NMDA channels available for activation, and also reduced the channel open probability without changing single channel conductance. Moreover, SULFA accelerated NMDA desensitization without affecting the affinity of the receptor for NMDA or glutamate. Taken together, these data indicate that SULFA blocks the NMDA response by reducing the number of NMDA channels available for activation. This appears to occur via a SULFA-induced decrease in the channel open probability, and a concomitant acceleration of the desensitization response, which is likely associated with a reduced affinity for glycine. SULFA indeed decreased the glycine-potentiated NMDA response without binding directly to the glycine site. Our results suggest that SULFA acts as a noncompetitive NMDA receptor antagonist with an allosteric glycine modulation.

  15. Effects of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion

    SciTech Connect

    Cheng, Huiwen; Mollica, Molly Y.; Lee, Shin Hee; Wang, Lei; Velázquez-Martínez, Carlos A.; Wu, Shiyong

    2012-10-15

    A new class of nitric oxide (NO•)-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) were developed in recent years and have shown promising potential as NSAID substitutes due to their gentle nature on cardiovascular and gastrointestinal systems. Since nitric oxide plays a role in regulation of cell adhesion, we assessed the potential use of NONO-NSAIDs as anti-metastasis drugs. In this regard, we compared the effects of NONO-aspirin and a novel NONO-naproxen to those exerted by their respective parent NSAIDs on avidities of human melanoma M624 cells. Both NONO-NSAIDs, but not the corresponding parent NSAIDs, reduced M624 adhesion on vascular cellular adhesion molecule-1 (VCAM-1) by 20–30% and fibronectin by 25–44% under fluid flow conditions and static conditions, respectively. Only NONO-naproxen reduced (∼ 56%) the activity of β1 integrin, which binds to α4 integrin to form very late antigen-4 (VLA-4), the ligand of VCAM-1. These results indicate that the diazeniumdiolate (NO•)-donor moiety is critical for reducing the adhesion between VLA-4 and its ligands, while the NSAID moiety can impact the regulation mechanism of melanoma cell adhesion. -- Highlights: ► NONO-naproxen, a novel nitric oxide-releasing NSAID, was synthesized. ► NONO-NSAIDs, but not their parent NSAIDs, reduced melanoma adhesion. ► NONO-naproxen, but not NONO-aspirin and NSAIDs, reduced activity of β1 integrin.

  16. Effects of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion.

    PubMed

    Cheng, Huiwen; Mollica, Molly Y; Lee, Shin Hee; Wang, Lei; Velázquez-Martínez, Carlos A; Wu, Shiyong

    2012-10-15

    A new class of nitric oxide (NO•)-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) were developed in recent years and have shown promising potential as NSAID substitutes due to their gentle nature on cardiovascular and gastrointestinal systems. Since nitric oxide plays a role in regulation of cell adhesion, we assessed the potential use of NONO-NSAIDs as anti-metastasis drugs. In this regard, we compared the effects of NONO-aspirin and a novel NONO-naproxen to those exerted by their respective parent NSAIDs on avidities of human melanoma M624 cells. Both NONO-NSAIDs, but not the corresponding parent NSAIDs, reduced M624 adhesion on vascular cellular adhesion molecule-1 (VCAM-1) by 20-30% and fibronectin by 25-44% under fluid flow conditions and static conditions, respectively. Only NONO-naproxen reduced (~56%) the activity of β1 integrin, which binds to α4 integrin to form very late antigen-4 (VLA-4), the ligand of VCAM-1. These results indicate that the diazeniumdiolate (NO•)-donor moiety is critical for reducing the adhesion between VLA-4 and its ligands, while the NSAID moiety can impact the regulation mechanism of melanoma cell adhesion.

  17. The Influence of Different Nonsteroidal Anti-Inflammatory Drugs on Alveolar Bone in Rats: An Experimental Study

    PubMed Central

    Inal, Sermet; Kabay, Sahin; Cayci, Muhammet Kasim; Deger, Ayşenur; Kuru, Halil Isa; Altikat, Sayit; Akkas, Gizem

    2015-01-01

    The aim The aim of this study was to investigate the effect of dexketoprofen trometamol, meloxicam, diclofenac sodium on any untreated alveolar bone when they are used as drugs for another indication. Materials and Methods Twenty eight male Spraque-Dawley rats were randomized into four groups as dexketoprofen trometamol (Group I), meloxicam (Group II), diclofenac sodium (Group III) and control group. Nonsteroidal anti-inflammatory drugs (NSAID) were administered after a fibula fracture for 10 days. Untreated alveolar bone was histopathologically examined for spongious bone density, osteoclastic density and osteoblastic density. Results Spongious bone density was lower in study groups (Group I, group II and group III) than the control group (p<0.05). In contrast, the increase in osteoclastic density was observed in other groups apart from the control group (p<0.05). Osteoblastic density was evaluated and it was determined that group II and group III had lower results than the control group (p<0.05) but group I was equal to the control group. Conclusion This study showed that systemically administrated NSAIDs have the potential to affect untreated alveolar bone. This should also be considered in long term use of NSAIDs. PMID:27688417

  18. Nonsteroidal anti-inflammatory drugs (NSAIDs) in older people: prescribing patterns according to pain prevalence and adherence to clinical guidelines.

    PubMed

    Gnjidic, Danijela; Blyth, Fiona M; Le Couteur, David G; Cumming, Robert G; McLachlan, Andrew J; Handelsman, David J; Seibel, Markus; Waite, Louise; Naganathan, Vasi

    2014-09-01

    The evidence on the patterns of nonsteroidal anti-inflammatory drug (NSAID) use according to pain prevalence and clinical guidelines in older people is sparse. This cross-sectional study examined the patterns of NSAID use according to pain prevalence and concordance with clinical guideline recommendations for safe NSAID use in older people, in relation to duration of use, patterns of use, concomitant use of proton pump inhibitors (PPIs), and prevalence of specific drug interactions. Community-dwelling men (n=1696) age ≥ 70 years living in Sydney were studied. 8.2% (n=139) of participants reported regular NSAID use compared with 2.9% (n=50) reporting as-needed use. The mean treatment duration for regular NSAID use was 4.9 years, suggesting long-term rather than short-term use as recommended by the guidelines. Although guidelines recommend use of PPIs together with an NSAID, only 25.2% of regular NSAID users reported PPI use. Regular NSAID users were significantly more likely to report use of opioid analgesics (P<.0001) compared with nonregular users. In relation to pain prevalence, regular NSAID users were significantly more likely to report chronic pain (P<.0001), recent pain (P=.0001), and chronic intrusive pain (P<.0001) compared with nonregular users. The findings of this study indicate that NSAID prescribing practices do not align with clinical guidelines for safe use in older people. This difference between the guideline recommendations and what is happening in the real world should be explored further.

  19. Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis

    PubMed Central

    Hendrix, Andrew S.; Spoonmore, Thomas J.; Wilde, Aimee D.; Putnam, Nicole E.; Hammer, Neal D.; Snyder, Daniel J.; Guelcher, Scott A.; Skaar, Eric P.

    2016-01-01

    Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro. Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo. Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis. PMID:27324764

  20. The Diverse Roles of Nonsteroidal Anti-inflammatory Drug Activated Gene (NAG-1/GDF15) in Cancer

    PubMed Central

    Wang, Xingya; Baek, Seung Joon; Eling, Thomas E.

    2013-01-01

    Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1, NAG-1, is a divergent member of the transforming growth factor-beta (TGF-β) superfamily that plays a complex but poorly understood role in several human diseases including cancer. NAG-1 expression is substantially increased during cancer development and progression especially in gastrointestinal, prostate, pancreatic, colorectal, breast, melanoma, and glioblastoma brain tumors. Aberrant increases in the serum levels of secreted NAG-1 correlate with poor prognosis and patient survival rates in some cancers. In contrast, the expression of NAG-1 is up-regulated by several tumor suppressor pathways including p53, GSK-3β, and EGR-1. NAG-1 expression is also induced by many drugs and dietary compounds which are documented to prevent the development and progression of cancer in mouse models. Studies with transgenic mice expressing human NAG-1 demonstrated that the expression of NAG-1 inhibits the development of intestinal tumors and prostate tumors in animal models. Laboratory and clinical evidence suggest that NAG-1, like other TGF-β family members, may have different or pleiotropic functions in the early and late stages of carcinogenesis. Upon understanding the molecular mechanism and function of NAG-1 during carcinogenesis, NAG-1 may serve as a potential biomarker for the diagnosis and prognosis of cancer and a therapeutic target for the inhibition and treatment of cancer development and progression. PMID:23220538

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

    PubMed

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

    2015-10-01

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

  2. Provocation tests with the offending nonsteroidal anti-inflammatory drugs in patients with urticaria/angioedema reactions.

    PubMed

    Zisa, Giuliana; Riccobono, Francesca; Bommarito, Luisa; D'Antonio, Cristian; Calamari, Ambra Marianna; Poppa, Mariangela; Moschella, Maria Adele; Di Pietrantonj, Carlo; Galimberti, Maurizio

    2012-01-01

    The provocation test (PT) with the suspected drug represents the gold standard in the diagnosis of non-IgE hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). Nevertheless, there is no consensus regarding the clinical management of suspected NSAID-sensitive patients. This study assessed if a PT with the suspected drug is a reliable and safe proceeding to confirm NSAID hypersensitivity in patients with a clinical history of urticaria/angioedema (Urt/AE). It also analyzed different patient characteristics (such as gender, age, atopy, dermographism, time interval between the last drug reaction, and number of previous NSAID reactions) in relation to PT positivity. One hundred fifty-nine patients with Urt/AE apparently related to assumption of one or more NSAIDs underwent PT with the suspected drugs. Moreover, to distinguish single/multiple NSAID reactivity in patients who did not tolerate the offending NSAID, another strong cyclooxygenase-1 inhibitor PT was performed. PT was negative in 142/159 patients (89.31%), ruling out a diagnosis of NSAIDs hypersensitivity; 17/159 patients (10.69%) experienced a reaction of Urt/AE during the PT: 8 patients were diagnosed as single reactors to NSAIDs and 4 as multiple reactors to NSAIDs. Those with a history of multiple NSAID reactions and male patients were both more likely to have a positive PT. Our results suggest that in all patients with history of NSAID cutaneous reactions, the NSAID hypersensitivity should be confirmed by an oral PT and that the diagnostic proceeding can safely start with the offending NSAID.

  3. Evaluation of synthetic zeolites as oral delivery vehicle for anti-inflammatory drugs

    PubMed Central

    Khodaverdi, Elham; Honarmandi, Reza; Alibolandi, Mona; Baygi, Roxana Rafatpanah; Hadizadeh, Farzin; Zohuri, Gholamhossein

    2014-01-01

    Objective(s): In this research, zeolite X and zeolite Y were used as vehicle to prepare intestine targeted oral delivery systems of indomethacin and ibuprofen. Materials and Methods: A soaking procedure was implemented to encapsulate indomethacin or ibuprofen within synthetic zeolites. Gravimetric methods and IR spectra of prepared formulations were used to assess drug loading efficiencies into zeolite structures. Scanning Electron Microscopy (SEM) was also utilized to determine morphologies changes in synthetic zeolites after drug loading. At the next stage, dissolution studies were used to predict the in vivo performance of prepared formulations at HCl 0.1 N and PBS pH 6.5 as simulated gastric fluid (SGF) and simulated intestine fluid (SIF), respectively. Results: Drug loadings of prepared formulations was determined between 24-26 % w/w. Dissolution tests at SGF were shown that zeolites could retain acidic model drugs in their porous structures and can be able to limit their release into the stomach. On the other hand, all prepared formulations completely released model drugs during 3 hr in simulated intestine fluid. Conclusion: Obtained results indicated zeolites could potentially be able to release indomethacin and ibuprofen in a sustained and controlled manner and reduced adverse effects commonly accompanying oral administrations of NSAIDs. PMID:24967062

  4. Selected mucolytic, anti-inflammatory and cardiovascular drugs change the ability of neutrophils to form extracellular traps (NETs).

    PubMed

    Zawrotniak, Marcin; Kozik, Andrzej; Rapala-Kozik, Maria

    2015-01-01

    Neutrophils form the first line of host defense against infections that combat pathogens using two major mechanisms, the phagocytosis or the release of neutrophil extracellular traps (NETs). The netosis (NET formation) exerts additional, unfavorable effects on the fitness of host cells and is also involved at the sites of lung infection, increasing the mucus viscosity and in the circulatory system where it can influence the intravascular clot formation. Although molecular mechanisms underlying the netosis are still incompletely understood, a role of NADPH oxidase that activates the production of reactive oxygen species (ROS) during the initiation of NETs has been well documented. Since several commonly used drugs can affects the netosis, our current study was aimed to determine the effects of selected mucolytic, anti-inflammatory and cardiovascular drugs on NET formation, with a special emphasis on ROS production and NADPH oxidase activity. The treatment of neutrophils with N-acetylcysteine, ketoprofen and ethamsylate reduced the production of ROS by these cells in a dose-dependent manner. NET formation was also modulated by selected drugs. N-acetylcysteine inhibited the netosis but in the presence of H2O2 this neutrophil ability was restored, indicating that N-acetylcysteine may influence the NET formation by modulating ROS productivity. The administration of ethamsylate led to a significant reduction in NET formation and this effect was not restored by H2O2 or S. aureus, suggesting the unexpected additional side effects of this drug. Ketoprofen seemed to promote ROS-independent NET release, simultaneously inhibiting ROS production. The results, obtained in this study strongly suggest that the therapeutic strategies applied in many neutrophil-mediated diseases should take into account the NET-associated effects.

  5. Topical anti-inflammatory activity of Eupatilin, a lipophilic flavonoid from mountain wormwood ( Artemisia umbelliformis Lam.).

    PubMed

    Giangaspero, Anna; Ponti, Cristina; Pollastro, Federica; Del Favero, Giorgia; Della Loggia, Roberto; Tubaro, Aurelia; Appendino, Giovanni; Sosa, Silvio

    2009-09-09

    Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) is the major lipophilic flavonoid from Artemisia umbelliformis Lam. and Artemisia genipi Weber, two mountain wormwoods used for the production of the celebrated alpine liqueur genepy. The topical anti-inflammatory activity of eupatilin was investigated using the inhibition of the Croton-oil-induced dermatitis in the mouse ear as the end point. The oedematous response and the leukocyte infiltration were evaluated up to 48 h after the induction of phlogosis, comparing eupatilin with hydrocortisone and indomethacin as representatives of steroid and non-steroid anti-inflammatory drugs, respectively. At maximum development, eupatilin significantly reduced edema in a dose-dependent manner (ID(50) = 0.28 micromol/cm(2)), showing an anti-inflammatory potency comparable to that of indomethacin (ID(50) = 0.26 micromol/cm(2)) and only 1 order of magnitude lower than that of hydrocortisone (ID(50) = 0.03 micromol/cm(2)). Within 48 h, eupatilin (0.30 micromol/cm(2)) caused a global inhibition of the oedematous response (42%) higher than that of an equimolar dose of indomethacin (18%) and fully comparable to that of 0.03 micromol/cm(2) of hydrocortisone (55%). Moreover, the effect of eupatilin on the granulocytes infiltrate (32% inhibition) was similar to that of indomethacin (35% inhibition) and comparable to that of hydrocortisone (42% reduction), as confirmed by histological analysis. When our results are taken together, they show that eupatilin is endowed with potent in vivo topical anti-inflammatory activity, qualitatively similar to that of hydrocortisone and intermediate in terms of potency between those of steroid and non-steroid drugs.

  6. Aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, and pancreatic cancer risk: a clinic-based case-control study.

    PubMed

    Tan, Xiang-Lin; Reid Lombardo, Kaye M; Bamlet, William R; Oberg, Ann L; Robinson, Dennis P; Anderson, Kristin E; Petersen, Gloria M

    2011-11-01

    Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case-control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60-0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49-0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer.

  7. Regulation of the Stem Cell–Host Immune System Interplay Using Hydrogel Coencapsulation System with an Anti-Inflammatory Drug

    PubMed Central

    Chen, Chider; Xu, Xingtian; Ansari, Sahar; Zadeh, Homayoun H.; Schricker, Scott R.; Paine, Michael L.; Moradian-Oldak, Janet; Khademhosseini, Ali; Snead, Malcolm L.

    2015-01-01

    The host immune system is known to influence mesenchymal stem cell (MSC)-mediated bone tissue regeneration. However, the therapeutic capacity of hydrogel biomaterial to modulate the interplay between MSCs and T-lymphocytes is unknown. Here it is shown that encapsulating hydrogel affects this interplay when used to encapsulate MSCs for implantation by hindering the penetration of pro-inflammatory cells and/or cytokines, leading to improved viability of the encapsulated MSCs. This combats the effects of the host pro-inflammatory T-lymphocyte-induced nuclear factor kappaB pathway, which can reduce MSC viability through the CASPASE-3 and CAS-PASE-8 associated proapoptotic cascade, resulting in the apoptosis of MSCs. To corroborate rescue of engrafted MSCs from the insult of the host immune system, the incorporation of the anti-inflammatory drug indomethacin into the encapsulating alginate hydrogel further regulates the local microenvironment and prevents pro-inflammatory cytokine-induced apoptosis. These findings suggest that the encapsulating hydrogel can regulate the MSC-host immune cell interplay and direct the fate of the implanted MSCs, leading to enhanced tissue regeneration. PMID:26120294

  8. A Novel Allosteric Mechanism of NF-κB Dimerization and DNA Binding Targeted by an Anti-Inflammatory Drug

    PubMed Central

    Ashkenazi, Shaked; Plotnikov, Alexander; Bahat, Anat; Ben-Zeev, Efrat; Warszawski, Shira

    2016-01-01

    The NF-κB family plays key roles in immune and stress responses, and its deregulation contributes to several diseases. Therefore its modulation has become an important therapeutic target. Here, we used a high-throughput screen for small molecules that directly inhibit dimerization of the NF-κB protein p65. One of the identified inhibitors is withaferin A (WFA), a documented anticancer and anti-inflammatory compound. Computational modeling suggests that WFA contacts the dimerization interface on one subunit and surface residues E285 and Q287 on the other. Despite their locations far from the dimerization site, E285 and Q287 substitutions diminished both dimerization and the WFA effect. Further investigation revealed that their effects on dimerization are associated with their proximity to a conserved hydrophobic core domain (HCD) that is crucial for dimerization and DNA binding. Our findings established NF-κB dimerization as a drug target and uncovered an allosteric domain as a target of WFA action. PMID:26830231

  9. Comparative Impact on Prostanoid Biosynthesis of Celecoxib and the Novel Nonsteroidal Anti-Inflammatory Drug CG100649

    PubMed Central

    Skarke, C; Alamuddin, N; Lawson, JA; Cen, L; Propert, KJ; FitzGerald, GA

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase-2 (COX-2)-dependent biosynthesis of prostacyclin (PGI2). CG100649 is a novel NSAID proposed to inhibit both COX-2 and carbonic anhydrase (CA)-I/-II. We compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX-2. In a controlled, double-blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3-dinor-6-keto-PGF1α (PGI-M); the effect of CG100649 was dose-dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX-1-dependent prostanoid formation. CA inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX-2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined. PMID:22278334

  10. New potential nonsteroidal anti-inflammatory drugs with antileukotrienic effects: influence on model proteins with catalytic activity.

    PubMed

    Netopilová, Miloslava; Drsata, Jaroslav; Beránek, Martin; Palicka, Vladimír

    2002-01-01

    Unspecific and side effects caused by interaction with proteins belong to common problems of many structures synthesized as potential medicaments. Possible in vitro interactions with proteins of a group of phenylsulfonyl benzoic acid derivatives (VUFB 19363, 19369, 19370, 19371, and 19760) as new potential anti-inflammatory compounds with anti-leukotrienic activities were studied in the present work. Three purified enzymes were used as model proteins with catalytic activities: Pig heart aspartate aminotransferase (AST, EC 2.6.1.1), alanine aminotransferase (ALT, EC 2.6.1.2), and glutamate decarboxylase (GAD, EC 4.1.1.15) from E. coli. Catalytic activities during incubation of individual compounds (6 x 10(-5) M solution to 5 x 10(-2) M suspension) at 37 degrees C with enzymes served as criteria of stability and function of the proteins. No immediate influence of any compound studied on enzyme activities was found. Aminotransferase activities were not affected even during incubation up to 20 d. In the case of GAD, the compounds VUFB 19369, 19370, 19371, and 19760 had stabilizing influence on GAD activity during incubation at enzyme concentrations of 11.25 and 5.62 mg prot/l. The lack of an immediate effect of compounds and the stability of enzymes during incubation them are favorable and support the prospective of the compounds as potential drugs.

  11. Role of dietary fiber in formation and prevention of small intestinal ulcers induced by nonsteroidal anti-inflammatory drug.

    PubMed

    Satoh, Hiroshi

    2010-01-01

    Recent advances in endoscopic techniques such as capsule endoscopy have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) often cause ulcers in the small intestine in humans, but there are few effective agents for treatment of small intestinal ulcers. Although the pathogenesis of NSAID-induced intestinal ulcer has been widely studied, dietary factors have seldom been considered. In the present review, the role of dietary fiber (DF) in the formation of NSAID-induced intestinal ulcers is discussed. In previous studies, small intestinal lesions were not observed when NSAIDs were administered to fasted rats, dogs, and cats, but were observed in conventionally-fed animals, suggesting the importance of feeding in the formation of intestinal lesions induced by NSAIDs. However, in animals fed diets containing low or no DF, indomethacin (IND) did not produce lesions in the small intestine, but did produce lesions in animals fed diets supplemented with insoluble dietary fiber (IDF, cellulose). The results suggest that IDF in the diet plays an important role in the formation of NSAID-induced intestinal lesions. On the other hand, addition of soluble dietary fibers (SDFs) such as pectin or mucin to regular diet markedly decreased NSAID-induced intestinal lesions. Thus, IDF and SDF have opposing effects on IND-induced intestinal lesions, i.e., IDF is harmful while SDF is protective. SDFs potentially represent a novel and safe means for protecting the small intestine against NSAID-induced intestinal lesions.

  12. Repositioning of 2,4-dichlorophenoxy acetic acid as a potential anti-inflammatory agent: in silico and pharmaceutical formulation study.

    PubMed

    Khedr, Mohammed A; Shehata, Tamer M; Mohamed, Maged E

    2014-12-18

    2,4-Dichlorophenoxy acetic acid (2,4-D) is a well-known plant auxin which is widely used in plant tissue culture experiments as well as a weed killer and a herbicide. In this study, 2,4-D was rediscovered as a new anti-inflammatory agent through an in silico molecular modeling and docking studies along with drug formulation and in vivo anti-inflammatory inspection. The molecular modeling and docking studies indicated high affinity of 2,4-D toward COX-2 enzyme in a way similar to Ibuprofen, suggesting a higher anti-inflammatory activity. Molecular docking by both MOE 2013.08 and Leadit 2.1.2 revealed excellent binding pattern compared to some of well-known non-steroidal anti-inflammatory drugs. 2,4-D was formulated in different gel bases. In vitro drug release experiments were used to examine the best 2,4-D formula for in vivo studies. In vivo carrageenan-induced hind paw edema inflammatory model in rats was used to test the in silico finding. 2,4-D showed potential in vivo anti-inflammatory activity and significantly reduced the concentration of prostaglandin E2 in hind paw tissues in a way similar to Ibuprofen. These results may open the door to introduce a new anti-inflammatory molecule; especially that 2,4-D is a well-investigated regarding its toxicity and side effect.

  13. Avoidance of nonsteroidal anti-inflammatory drugs after negative provocation tests in urticaria/angioedema reactions: Real-world experience.

    PubMed

    Bommarito, Luisa; Zisa, Giuliana; Riccobono, Francesca; Villa, Elisa; D'Antonio, Cristian; Calamari, Ambra M; Poppa, Mariangela; Moschella, Adele; Di Pietrantonj, Carlo; Galimberti, Maurizio

    2014-01-01

    Drug provocation tests (DPTs) are the gold standard in diagnosing nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity; however, only few data about follow-up of patients with negative DPTs are actually available. The aim of this study was to assess patients' behavior in taking NSAIDs again and to evaluate NSAID tolerability after negative allergological workup. This is a follow-up study involving patients evaluated for history of cutaneous reactions (urticaria and or angioedema) after NSAID intake and with negative DPTs with the suspected NSAID. Patients were asked during a phone interview about the intake of NSAIDs, tolerance, or reasons of avoidance. The negative predictive value (NPV) of NSAIDs DPTs was calculated. One hundred eleven of 142 patients were successfully contacted; 46/111 (41.44%) took the same NSAID previously tested with two adverse reactions reported (4.34%). Fifty-three of 111 (47.74%) patients did not take the same NSAID, but 34 of them took at least another strong cyclooxygenase (COX) 1 inhibitor, with 1 adverse reaction (2.94%) and 19 of them took only weak COX-1 inhibitors. Twelve of 111 patients (10.8%) did not take any NSAID. Reasons for drug avoidance were mainly fear of reactions (70.8%) and no need (29.2%). NPV, overall, was 96.97% (95% confidence interval, 91-99%). Although NSAID hypersensitivity diagnosis was ruled out by oral provocation test, the majority of patients with a history of urticaria/angioedema avoided the intake of the tested NSAIDs for fear of new reactions, particularly when strong COX-1 inhibitor NSAIDs were involved. The high NPV value of DPT resulting from this study should reassure NSAID intake.

  14. Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug.

    PubMed

    Ranjbar, Mohammad Mehdi; Assadolahi, Vahideh; Yazdani, Mohsen; Nikaein, Donya; Rashidieh, Behnam

    2016-01-01

    Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse model. Previous studies suggested significant anti-inflammatory activities as well as potential anticancer agent of α-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in cancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is shown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This study was conducted based on Cordia species' α-amyrins as a safer natural anti-cancer compound for inhibition of COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes and α-amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes were detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA). Finally drug likeness, molecular pharmacokinetic properties and toxicity of α-amyrins was calculated. Molecular Docking revealed hydrogen and hydrophobic interactions between α-amyrins with both active sites of COX-2 and 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule. Base on binding energies (∆G) α-amyrin has more inhibitory effects on 5-LOX (-10.45 Kcal/mol) than COX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that α-amyrins complied with most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity score showed α-amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR and protease inhibitor ligand. These results clearly demonstrate that α-amyrins could act as potential highly selective COX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal anti-inflammatory drugs (NSAIDs

  15. Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug

    PubMed Central

    Ranjbar, Mohammad Mehdi; Assadolahi, Vahideh; Yazdani, Mohsen; Nikaein, Donya; Rashidieh, Behnam

    2016-01-01

    Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse model. Previous studies suggested significant anti-inflammatory activities as well as potential anticancer agent of α-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in cancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is shown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This study was conducted based on Cordia species' α-amyrins as a safer natural anti-cancer compound for inhibition of COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes and α-amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes were detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA). Finally drug likeness, molecular pharmacokinetic properties and toxicity of α-amyrins was calculated. Molecular Docking revealed hydrogen and hydrophobic interactions between α-amyrins with both active sites of COX-2 and 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule. Base on binding energies (∆G) α-amyrin has more inhibitory effects on 5-LOX (-10.45 Kcal/mol) than COX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that α-amyrins complied with most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity score showed α-amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR and protease inhibitor ligand. These results clearly demonstrate that α-amyrins could act as potential highly selective COX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal anti-inflammatory drugs (NSAIDs

  16. [Non-Helicobacter pylori, Non-nonsteroidal Anti-inflammatory Drug Peptic Ulcer Disease].

    PubMed

    Chang, Young Woon

    2016-06-25

    Non-Helicobacter pylori, non-NSAID peptic ulcer disease (PUD), termed idiopathic PUD, is increasing in Korea. Diagnosis is based on exclusion of common causes such as H. pylori infection, infection with other pathogens, surreptitious ulcerogenic drugs, malignancy, and uncommon systemic diseases with upper gastrointestinal manifestations. The clinical course of idiopathic PUD is delayed ulcer healing, higher recurrence, higher re-bleeding after initial ulcer healing, and higher mortality than the other types of PUD. Genetic predisposition, older age, chronic mesenteric ischemia, cigarette smoking, concomitant systemic diseases, and psychological stress are considered risk factors for idiopathic PUD. Diagnosis of idiopathic PUD should systematically explore all possible causes. Management of this disease is to treat underlying disease followed by regular endoscopic surveillance to confirm ulcer healing. Continuous proton pump inhibitor therapy is an option for patients who respond poorly to the standard ulcer regimen.

  17. Anti-Inflammatory and Pro-Resolving Lipid Mediators

    PubMed Central

    Serhan, Charles N.; Yacoubian, Stephanie; Yang, Rong

    2009-01-01

    The popular view that all lipid mediators are pro-inflammatory arises largely from the finding that non-steroidal anti-inflammatory drugs block the biosynthesis of prostaglandins. The resolution of inflammation was widely held to be a passive event until recently, with the characterization of novel biochemical pathways and lipid-derived mediators that are actively turned on in resolution possessing potent anti-inflammatory and pro-resolving actions. A lipid mediator informatics approach was employed to systematically identify new families of endogenous local-acting mediators from omega-3-polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) in resolving exudates in addition to the lipoxins and aspirin-triggered lipoxins generated from arachidonic acid. These new chemical mediator families were coined resolvins and protectins, given their potent bioactions. In this annual review, we present recent advances on the biosynthesis and stereospecific actions of these new pro-resolving mediators, which have also proven to be organ protective and anti-fibrotic. PMID:18233953

  18. Structural basis of the anti-inflammatory activity of melatonin.

    PubMed

    de la Rocha, Nadir; Rotelli, Alejandra; Aguilar, Carlos F; Pelzer, Lilian

    2007-01-01

    The anti-inflammatory activity of melatonin (CAS 73-31-4) was examined, using the rat paw edema model, and compared with the non-steroidal anti-inflammatory drug (NSAID) indometacin (CAS 53-86-1) which exerts its effects by inhibition of prostaglandin production on acute inflammation. The experiments showed that melatonin has an important effect on acute inflammatory processes acting as an inhibitor in a similar manner to indometacin. The structural interactions of melatonin with cyclooxygenase (COX), the pharmacological target of NSAIDs, were investigated using computer graphics applications. The results indicated that melatonin has an excellent steric and electronic complementarity with COX. It was found, similarly to previously studied crystal structures of protein-inhibitor complexes, that almost all interactions were of the hydrophobic type but for the typical carboxylate or electronegative group interaction, at the mouth of the active site channel, with Arg 120 and Tyr 355. Therefore, it seems possible that melatonin might bind to the active site of COX-1 and COX-2 suggesting that it may act as a natural inhibitor of the functions of cyclooxygenase modulating in a natural manner the activity of this enzyme.

  19. Full factorial design optimization of anti-inflammatory drug release by PCL-PEG-PCL microspheres.

    PubMed

    Azouz, L'Hachemi; Dahmoune, Farid; Rezgui, Farouk; G'Sell, Christian

    2016-01-01

    A biodegradable triblock poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) copolymer was successfully synthesized by ring-opening polymerization of ε-caprolactone, and was characterized by intrinsic viscosimetry, (1)H nuclear magnetic resonance, infrared spectroscopy and X-ray diffraction. Copolymer microparticles loaded with ibuprofen were prepared by an oil-in-water (o/w) emulsion solvent evaporation process. They were carefully weighted and characterized through their zeta potential. In this work, 4 selected process parameters (shaking speed X1, time of contact X2, poly(vinyl alcohol) concentration X3, and ibuprofen concentration X4) were adjusted at 2 different values. For each of the 16 experimental conditions, repeated twice, the drug encapsulation efficiency of the microspheres was determined, according to the following definition: EE (X1, X2, X3, X4)=mass of encapsulated ibuprofen/total weight of ibuprofen. A "full factorial design method" was applied to analyze the results statistically according to a polynomial fit and to determine the optimal conditions for the microencapsulation of the ibuprofen through an accurate statistical protocol. The microparticles obtained exhibit a spherical shape as shown by electron microscopy.

  20. Cost-effectiveness of Strategies for Primary Prevention of Nonsteroidal Anti-inflammatory Drug-induced Peptic Ulcer Disease

    PubMed Central

    Ko, Cynthia W; Deyo, Richard A

    2000-01-01

    OBJECTIVE Nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of peptic ulcer disease by 5- to 7-fold in the first 3 months of treatment. This study examined the relative cost-effectiveness of different strategies for the primary prevention of NSAID-induced ulcers in patients that are starting NSAID treatment. MEASUREMENTS AND MAIN RESULTS A decision analysis model was developed to compare the cost-effectiveness of 6 prophylactic strategies relative to no prophylaxis for patients 65 years of age starting a 3-month course of NSAIDs: (1) testing for Helicobacter pylori infection and treating those with positive tests; (2) empiric treatment of all patients for Helicobacter pylori; (3) conventional-dose histamine2receptor antagonists; (4) high-dose histamine2receptor antagonists; (5) misoprostol; and (6) omeprazole. Costs were estimated from 1997 Medicare reimbursement schedules and the Drug Topics Red Book. Empiric treatment of Helicobacter pylori with bismuth, metronidazole, and tetracycline was cost-saving in the baseline analysis. Selective treatment of Helicobacter pylori, misoprostol, omeprazole, and conventional-dose or high-dose histamine2receptor antagonists cost $23,800, $46,100, $34,400, and $15,600 or $21,500 per year of life saved, respectively, relative to prophylaxis. The results were sensitive to the probability of an ulcer, the probability and mortality of ulcer complications, and the cost of, efficacy of, and compliance with prophylaxis. The cost-effectiveness estimates did not change substantially when costs associated with antibiotic resistance of Helicobacter pylori were incorporated. CONCLUSIONS Several strategies for primary prevention of NSAID-induced ulcers in patients starting NSAIDs were estimated to have acceptable cost-effectiveness relative to prophylaxis. Empirically treating all patients for Helicobacter pylori with bismuth, metronidazole, and tetracycline was projected to be cost-saving in older patients. PMID:10886475

  1. Comparison of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 (COX-2) inhibitors use in Australia and Nova Scotia (Canada)

    PubMed Central

    Barozzi, Nadia; Sketris, Ingrid; Cooke, Charmaine; Tett, Susan

    2009-01-01

    AIMS Cyclooxygenase-2 (COX-2) inhibitors were marketed aggressively and their rapid uptake caused safety concerns and budgetary challenges in Canada and Australia. The objectives of this study were to compare and contrast COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drug (ns-NSAID) use in Nova Scotia (Canada) and Australia and to identify lessons learned from the two jurisdictions. METHODS Ns-NSAID and COX-2 inhibitor Australian prescription data (concession beneficiaries) were downloaded from the Medicare Australia website (2001–2006). Similar Pharmacare data were obtained for Nova Scotia (seniors and those receiving Community services). Defined daily doses per 1000 beneficiaries day−1 were calculated. COX-2 inhibitors/all NSAIDs ratios were calculated for Australia and Nova Scotia. Ns-NSAIDs were divided into low, moderate and high risk for gastrointestinal side-effects and the proportions of use in each group were determined. Which drugs accounted for 90% of use was also calculated. RESULTS Overall NSAID use was different in Australia and Nova Scotia. However, ns-NSAID use was similar. COX-2 inhibitor dispensing was higher in Australia. The percentage of COX-2 inhibitor prescriptions over the total NSAID use was different in the two countries. High-risk NSAID use was much higher in Australia. Low-risk NSAID prescribing increased in Nova Scotia over time. The low-risk/high-risk ratio was constant throughout over the period in Australia and increased in Nova Scotia. CONCLUSIONS There are significant differences in Australia and Nova Scotia in use of NSAIDs, mainly due to COX-2 prescribing. Nova Scotia has a higher proportion of low-risk NSAID use. Interventions to provide physicians with information on relative benefits and risks of prescribing specific NSAIDs are needed, including determining their impact. PMID:19660008

  2. Topical nonsteroidal anti-inflammatory drugs for the treatment of pain due to soft tissue injury: diclofenac epolamine topical patch

    PubMed Central

    Lionberger, David R; Brennan, Michael J

    2010-01-01

    The objective of this article is to review published clinical data on diclofenac epolamine topical patch 1.3% (DETP) in the treatment of acute soft tissue injuries, such as strains, sprains, and contusions. Review of published literature on topical nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac, and DETP in patients with acute soft tissue injuries was included. Relevant literature was identified on MEDLINE using the search terms topical NSAIDs, diclofenac, diclofenac epolamine, acute pain, sports injury, soft tissue injury, strain, sprain, and contusion, and from citations in retrieved articles covering the years 1978–2008. Review of published, randomized clinical trials and meta-analyses shows that topical NSAIDs are significantly more effective than placebo in relieving acute pain; the pooled average relative benefit was 1.7 (95% confidence interval, 1.5–1.9). In a limited number of comparisons, topical and oral NSAIDs provided comparable pain relief, but the use of topical agents produced lower plasma drug concentrations and fewer systemic adverse events (AEs). The physical–chemical properties of diclofenac epolamine make it well suited for topical use. In patients with acute soft tissue injuries treated with DETP, clinical data report an analgesic benefit within hours of the first application, and significant pain relief relative to placebo within 3 days. Moreover, DETP displayed tolerability comparable with placebo; the most common AEs were pruritus and other application site reactions. Review of published literature suggests that DETP is generally safe and well tolerated, clinically efficacious, and a rational treatment option for patients experiencing acute pain associated with strains, sprains, and contusions, and other localized painful conditions. PMID:21197326

  3. Usage patterns of ‘over-the-counter’ vs. prescription-strength nonsteroidal anti-inflammatory drugs in France

    PubMed Central

    Duong, Mai; Salvo, Francesco; Pariente, Antoine; Abouelfath, Abdelilah; Lassalle, Regis; Droz, Cecile; Blin, Patrick; Moore, Nicholas

    2014-01-01

    Aims Most risks of nonsteroidal anti-inflammatory drugs (NSAIDs) are pharmacological, dose and duration dependent. Usage patterns of prescription-only (POM) or ‘over-the-counter (OTC)’ NSAIDs may influence risks, but are not commonly described. Methods The Echantillon Généraliste de Bénéficiaires database, the permanent 1/97 representative sample from the French national healthcare insurance systems, was queried over 2009–2010 to identify usage patterns, concomitant chronic diseases and cardiovascular medication in OTC and POM NSAID users. Results Over 2 years, 229 477 of 526 108 patients had at least one NSAID dispensation; 44 484 patients (19%) were dispensed only OTC NSAIDs (93% ibuprofen) and 121 208 (53%) only POM NSAIDs. The OTC users were younger (39.9 vs. 47.4 years old) and more often female (57 vs. 53%); 69% of OTC users and 49% of POM users had only one dispensation. A mean of 14.6 defined daily doses (DDD) were dispensed over 2 years for OTC vs. 53 for POM; 93% OTC vs. 60% POM patients bought ≤ 30 DDD over 2 years, and 1.5 vs. 12% bought ≥ 90 DDD. Chronic comorbidities were found in 19% of OTC users vs. 28% of POM users; 24 vs. 37% had at least one dispensation of a cardiovascular drug over the 2 years. Conclusions Most of the use of NSAIDs appears to be short term, especially for OTC-type NSAIDs, such as ibuprofen. The validity of risk estimates for NSAIDs extrapolated from clinical trials or from observational studies not including OTC-type usage may need to be revised. PMID:24102791

  4. Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug.

    PubMed

    Agrawal, D K

    2001-03-01

    Desloratadine is a biologically active metabolite of the second-generation antihistamine loratadine. Desloratadine is a highly selective peripheral H1 receptor antagonist that is significantly more potent than loratadine. Results of in vitro and in vivo studies have suggested that desloratadine has anti-allergic effects that are unrelated to its ability to antagonise the effects of histamine. Desloratadine inhibits the expression of cell adhesion molecules, inhibits the generation and release of inflammatory mediators and cytokines, attenuates eosinophil chemotaxis, adhesion and superoxide generation. Studies in animals indicate that desloratadine does not cross the blood-brain barrier and therefore does not cause sedation and does not impair cognition or psychomotor performance. Desloratadine has an excellent overall safety profile. It has no effect on QRS and QTc intervals and does not cause arrhythmias. Desloratadine is not associated with any significant changes in gastrointestinal function. In clinical studies, oral desloratadine is rapidly absorbed and bioavailability is not affected by ingestion with food or grapefruit juice. The half-life of desloratadine in humans is 27 h; the linear kinetic profile is unaltered by race or gender. Desloratadine is not a substrate for P-glycoprotein or organic anion transport polypeptide and the drug does not appear to be metabolised to a significant extent by the cytochrome P450 CYP3A4 pathway. It therefore may be safely administered with ketoconazole, erythromycin, fluoxetine, or azithromycin. Clinically, desloratadine effectively controls both nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR), including nasal congestion. Desloratadine also provides significant relief of SAR symptoms in patients with co-existing asthma and is effective in the treatment of chronic idiopathic urticaria. Desloratadine improves quality of life and is well-tolerated.

  5. Comparative anti-inflammatory effects of anti-arthritic herbal medicines and ibuprofen.

    PubMed

    Kang, Joshua J; Samad, Mohammed A; Kim, Kye S; Bae, Soochan

    2014-09-01

    Non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, are widely used over-the-counter drugs to treat arthritis, but they are often associated with side effects. Herbal medicines have been used to treat various diseases such as arthritis, but the scientific profiles are not well understood. In this study, we examined, in comparison with ibuprofen, the inhibitory effects on various inflammatory markers of the most commonly used herbal medicines to treat arthritis, boswellia (Boswellia sapindales), licorice (Glycyrrhiza glabra), guggul (Commiphora wightii), and neem (Azadirachta indica). To elicit inflammatory response, we exposed mouse myoblast C2C12 cells to lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-α) and monocyte chemotactic protein-1 (MCP-1), which are cytokines activated during an inflammatory response, were determined. The optimal non-toxic concentration was determined by exposing different concentrations of drugs (from 0.01 to 10 mg/mL). Cell death measurement revealed that the drug concentrations lower than 0.05 mg/mL were non-toxic concentrations for each drug, and these doses were used for the main experiments. We found that neem and licorice showed robust anti-inflammatory responses compared with ibuprofen. However, boswellia and guggul did not demonstrate significant anti-inflammatory responses. We concluded that neem and licorice are more effective than ibuprofen in suppressing LPS-induced inflammation in C2C12 cells.

  6. Acute Δ(9)-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice.

    PubMed

    Kinsey, Steven G; Cole, Erica C

    2013-09-05

    Nonsteroidal anti-inflammatory drugs (NSAIDs), which are among the most widely used analgesics in the world, cause gastrointestinal inflammation that is potentially life-threatening. Although inhibitors of endocannabinoid catabolic enzymes protect against gastropathy in fasted NSAID-treated mice, the gastroprotective effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, have yet to be investigated. Male C57BL/6J mice were fasted, administered vehicle or Δ(9)-THC (.01-50mg/kg; oral or intraperitoneal), and then treated with the NSAID diclofenac sodium (100mg/kg, p.o.) to induce gastric lesions. In separate groups of mice, the cannabimimetic behavioral effects of Δ(9)-THC given via each route of administration were compared using a battery of tests, consisting of assessment of locomotor activity, nociception in the tail withdrawal test, catalepsy in the bar test, and hypothermia. Δ(9)-THC dose-dependently attenuated diclofenac-induced gastric hemorrhagic streaks through both p.o. and i.p. routes of administration (ED50 (95% confidence interval)=0.64 (0.26-1.55)mg/kg and 0.06 (0.01-0.34) mg/kg, respectively). Δ(9)-THC given i.p. was 2-3 orders of magnitude more potent in reducing diclofenac-induced gastric ulcers than in producing locomotor immobility, antinociception, hypothermia, and catalepsy, while the potency of ratio of p.o. Δ(9)-THC between each behavior measure was 7-18. These data indicate that the phytocannabinoid Δ(9)-THC protects against diclofenac-induced gastric inflammatory tissue damage at doses insufficient to cause common cannabinoid side effects.

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

    PubMed Central

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

    2016-01-01

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

  8. Safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs in juvenile idiopathic arthritis: results of the phase 4 registry

    PubMed Central

    2014-01-01

    Background This study aimed to assess long-term safety and developmental data on juvenile idiopathic arthritis (JIA) patients treated in routine clinical practice with celecoxib or nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs). Methods Children aged ≥2 to <18 years with rheumatoid-factor–positive or –negative polyarthritis, persistent or extended oligoarthritis, or systemic arthritis were enrolled into this prospective, observational, multicenter standard-of-care registry. Eligible patients were newly or recently prescribed (≤6 months) an nsNSAID or celecoxib. Enrolled patients were followed to the end of the study, whether they remained on the original NSAID, switched, or discontinued therapy altogether. All adverse events (AEs) regardless of severity were captured in the database. Results A total of 274 patients (nsNSAID, n = 219; celecoxib, n = 55) were observed for 410 patient-years of observation. Naproxen, meloxicam, and nabumetone were the most frequently used nsNSAIDs. At baseline, the celecoxib group was older, had a numerically longer median time since diagnosis, and a numerically higher proportion of patients with a history of gastrointestinal-related NSAID intolerance. AEs reported were those frequently observed with NSAID treatment and were similar across groups (nsNSAIDs: 52.0%; celecoxib: 52.9%). Twelve unique patients experienced a total of 18 serious AEs; the most frequent were infections, and none was attributed to NSAID use. Conclusions The safety profile of celecoxib and nsNSAIDs appears similar overall. The results from this registry, ongoing pharmacovigilance, and the phase 3 trial that led to the approval of celecoxib for children with JIA provide evidence that the benefit-risk for celecoxib treatment in JIA remains positive. Trial registration ClinicalTrials.gov identifier NCT00688545. PMID:25057265

  9. Cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal anti-inflammatory drugs and gastric mucosal responses.

    PubMed

    Takeuchi, K; Suzuki, K; Yamamoto, H; Araki, H; Mizoguchi, H; Ukawa, H

    1998-12-01

    Occurrence of gastrointestinal damage and delayed healing of pre-existing ulcer are commonly observed in association with clinical use of nonsteroidal antiinflammatory drugs (NSAIDs). We examined the effects of NS-398, the cyclooxygenase (COX)-2 selective inhibitor, and nitric oxide (NO)- releasing aspirin (NCX-4016) on gastric mucosal ulcerogenic and healing responses in experimental animals, in comparison with those of nonselective COX inhibitors such as indomethacin and aspirin. Indomethacin and aspirin given orally were ulcerogenic by themselves in rat stomachs, while either NS-398 or NCX-4016 was not ulcerogenic at the doses which exert the equipotent antiinflammatory action with indomethacin or aspirin. Among these NSAIDs, only NCX-4016 showed a dose-dependent protection against gastric lesions induced by HCl/ethanol in rats. On the other hand, the healing of gastric ulcers induced in mice by thermal-cauterization was significantly delayed by repeated administration of these NSAIDs for more than 7 days, except NCX-4016. Gastric mucosal prostaglandin contents were reduced by indomethacin, aspirin and NCX-4016 in both normal and ulcerated mucosa, while NS-398 significantly decreased prostaglandin generation only in the ulcerated mucosa. Oral administration of NCX-4016 in pylorus-ligated rats and mice increased the levels of NO metabolites in the gastric contents. In addition, both NS-398 and NCX-4016 showed an equipotent anti-inflammatory effect against carrageenan-induced paw edema in rats as compared with indomethacin and aspirin. These results suggest that both indomethacin and aspirin are ulcerogenic by themselves and impair the healing of pre-existing gastric ulcers as well. The former action is due to inhibition of COX-1, while the latter effect may be accounted for by inhibition of COX-2 and mimicked by NS-398, the COX-2 selective NSAID. NCX-4016, despite inhibiting both COX-1 and COX-2, protects the stomach against damage and preserves the healing

  10. Acute Δ9-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice

    PubMed Central

    Kinsey, Steven G.; Cole, Erica C.

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs), which are among the most widely used analgesics in the world, cause gastrointestinal inflammation that is potentially life-threatening. Although inhibitors of endocannabinoid catabolic enzymes protect against gastropathy in fasted NSAID-treated mice, the gastroprotective effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, have yet to be investigated. Male C57BL/6J mice were fasted, administered vehicle or Δ9-THC (.01–50 mg/kg; oral or intraperitoneal), and then treated with the NSAID diclofenac sodium (100 mg/kg, p.o.) to induce gastric lesions. In separate groups of mice, the cannabimimetic behavioral effects of Δ9-THC given via each route of administration were compared using a battery of tests, consisting of assessment of locomotor activity, nociception in the tail withdrawal test, catalepsy in the bar test, and hypothermia. Δ9-THC dose-dependently attenuated diclofenac-induced gastric hemorrhagic streaks through both p.o. and i.p. routes of administration (ED50 (95% confidence interval) = 0.64 (0.26 – 1.55) mg/kg and 0.06 (0.01 – 0.34) mg/kg, respectively). Δ9-THC given i.p. was 2–3 orders of magnitude more potent in reducing diclofenac-induced gastric ulcers than in producing locomotor immobility, antinociception, hypothermia, and catalepsy, while the potency of ratio of p.o. Δ9-THC between each behavior measure was 7–18. These data indicate that the phytocannabinoid Δ9-THC protects against diclofenac-induced gastric inflammatory tissue damage at doses insufficient to cause common cannabinoid side effects. PMID:23769745

  11. Safe full-dose one-step nabumetone challenge in patients with nonsteroidal anti-inflammatory drug hypersensitivity.

    PubMed

    Confino-Cohen, Ronit; Goldberg, Arnon

    2003-01-01

    Aspirin and all nonsteroidal anti-inflammatory drugs (NSAIDs) are a chemically heterogeneous group of compounds that share the ability to inhibit the enzyme cyclooxygenase (COX). This inhibitory effect, especially of COX-1, is suggested as the mechanism underlying NSAID-induced hypersensitivity reactions. In this study, we evaluated the safety and convenience of a single full-dose challenge with nabumetone, a selective COX-2 inhibitor, in patients with hypersensitivity to nonselective NSAIDs (ns-NSAIDs). Twenty-four subjects with a history of hypersensitivity reactions to at least two different ns-NSAIDs on two different occasions were enrolled in the study. The patients were otherwise healthy and did not suffer from NSAID- or aspirin-induced asthma or urticaria. All subjects were orally challenged by a single full dose (1000 mg) of nabumetone, monitored closely in the hospital for the next 4 hours and contacted by telephone the next morning and 3-12 months afterward. Twenty-two patients tolerated nabumetone without any reaction during and after the challenge. One patient had a single urticarial lesion and one patient reported mild pruritus without objective signs, both of which resolved spontaneously. Thirteen patients, including the patient who responded with pruritus to the challenge, used nabumetone on several occasions during the follow-up period without any adverse reaction. Our study shows that in patients with a history of aspirin- and ns-NSAID-induced hypersensitivity reaction, a rapid one-step challenge with nabumetone was well tolerated. These initial data support the possibility that a single full dose of nabumetone can be tried as a safe alternative in most patients with a hypersensitivity reaction to ns-NSAIDs.

  12. Chemoprevention of Colon Cancer through Inhibition of Angiogenesis and Induction of Apoptosis by Nonsteroidal Anti-Inflammatory Drugs.

    PubMed

    Ghanghas, Preety; Jain, Shelly; Rana, Chandan; Sanyal, Sankar Nath

    2016-01-01

    Cancer cells require nourishment for the growth of the primary tumor mass and spread of the metastatic colony. These needs are fulfilled by tumor-associated neovasculature known as angiogenesis, which also favors the transition from hyperplasia to neoplasia, that is, from a state of cellular multiplication to uncontrolled proliferation. Therefore, targeting angiogenesis is profitable as a mechanism to inhibit tumor growth. Furthermore, it is important to understand the cross-communication between vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in the neoplastic and proinflammatory milieu. We studied the role of two important chemokines (monocyte chemoattractant protein-1 [MCP-1] and macrophage inflammatory protein-1β [MIP-1β]) along with VEGF and MMPs in nonsteroidal anti-inflammatory drug (NSAID)-induced chemopreventive effects in experimental colon cancer in rats. 1,2-Dimethylhydrazine dihydrochloride (DMH) was used as cancer-inducing agent and three NSAIDs (celecoxib, etoricoxib, and diclofenac) were given orally as chemopreventive agents. Analysis by immunofluorescence and western blotting shows that the expression of VEGF, MMP-2, and MMP-9 was found to be significantly elevated in the DMH- treated group and notably lowered by NSAID coadministration. The expression of MCP-1 was found to be markedly decreased, whereas that of MIP-1β increased after NSAID coadministration. NSAID coadministration was also able to induce apoptosis, confirmed using studies by Hoechst/propidium iodide (PI) costaining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results from the present study indicate the potential role of these chemokines along with VEGF and MMPs against angiogenesis in DMH-induced cancer. The inhibition of angiogenesis and induction of apoptosis by NSAIDs were found to be possible mechanisms in the chemoprevention of colon cancer.

  13. Nonsteroidal anti-inflammatory drugs attenuate proliferation of colonic carcinoma cells by blocking epidermal growth factor-induced Ca++ mobilization.

    PubMed

    Kokoska, E R; Smith, G S; Miller, T A

    2000-01-01

    Numerous studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis. We have previously reported that NSAIDs, in human colonic carcinoma cells (Caco-2), attenuate epidermal growth factor (EGF)-induced cellular proliferation through a process independent of their inhibitory effects on prostaglandin synthesis. Furthermore, separate studies have also suggested that NSAIDs inhibit EGF-induced store-operated Ca++ influx. Thus we developed the hypothesis that NSAIDs may limit the activity of EGF by altering intracellular Ca++ ([Ca++]i) mobilization. Serum-deprived Caco-2 cells were employed for all experimentation. [Ca++]i was measured with Fluo-3 and extracellular Ca++ influx was monitored by quenching Fluo-3 fluorescence with Mn++. Proliferation was quantitated with two assays: cellular nucleic acid and total protein content. Caco-2 cells exposed to EGF demonstrated an initial increase in [Ca++]i which was blocked by neomycin, an inhibitor of IPsubscript 3 generation, and the phospholipase C inhibitor U73122 but not U73343 (inactive control). This was followed by sustained extracellular Ca++ influx, which was attenuated with calcium-free buffer (-Ca++), the store- operated Ca++ channel blocker lanthanum, indomethacin, ibuprofen, and aspirin. In subsequent studies, cells were treated with either serum-free media or EGF +/- the aforementioned inhibitors, and again serum starved. Cells exposed to EGF +/- the inactive phospholipase C inhibitor U73343 demonstrated a significant increase in nucleic acid and protein. However, proliferation induced by EGF was not observed when [Ca++]i elevation was prevented by blocking either internal Ca++ store release via phospholipase C/IPsubscript 3 or sustained Ca++ influx through store-operated Ca++ channels. Sustained [Ca++]i elevation, as induced by EGF, appears to be required for mitogenesis. These data support our premise that one mechanism whereby NSAIDs may attenuate colonic neoplasia is

  14. The anti-inflammatory drug carprofen improves long-term outcome and induces gliogenesis after traumatic brain injury.

    PubMed

    Thau-Zuchman, Orli; Shohami, Esther; Alexandrovich, Alexander G; Trembovler, Victoria; Leker, Ronen R

    2012-01-20

    Traumatic brain injury (TBI) initiates acute and chronic inflammatory processes involving cyclooxygenase-2 (COX-2), which may have detrimental effects on outcome and especially on brain regeneration. Therefore we aimed to study whether carprofen, a COX-2 inhibitor, would improve outcome and increase neurogenesis after TBI. TBI was induced in Sabra mice that were then treated with vehicle or carprofen for 7 days. Functional outcome was evaluated with the Neurological Severity Score (NSS).Cytokine levels were assessed 4 h post-TBI and water content was measured 24 h post TBI. Mice were given BrdU to label newborn cells for 10 days. The animals were killed 90 days post-TBI and the lesion size as well as newborn cell fate were assessed. Carprofen significantly reduced lesion size (p=0.002), decreased water content in the lesioned cortex (p=0.03), reduced the number of microglia in the lesioned cortex (p<0.0001), and lowered the levels of proinflammatory cytokines (IL-1β, p=0.03; IL-6, p=0.02). Carprofen led to significantly larger improvements in functional outcome (p≤0.008) which were durable over 90 days. Carprofen also induced a threefold increase in the proliferation of new cells in the peri-lesion area (p≤0.002), but newborn cells differentiated mainly into glia in both groups. Carprofen is neuroprotective and induces cell proliferation and gliogenesis after TBI. Treatment with carprofen is consistently associated with better functional outcome. Our results imply that anti-inflammatory drugs may represent novel therapeutic options for TBI.

  15. Is there an association between prior anti-inflammatory drug exposure and occurrence of peritonsillar abscess (PTA)? A national multicenter prospective observational case-control study.

    PubMed

    Lepelletier, D; Pinaud, V; Le Conte, P; Bourigault, C; Asseray, N; Ballereau, F; Caillon, J; Ferron, C; Righini, C; Batard, E; Potel, G

    2017-01-01

    The aim of this study was to evaluate whether recent systemic anti-inflammatory agents (AIAs) exposure in patients with sore throat managed with or without antibiotic therapy influenced the risk of peritonsillar abscess (PTA). We conducted a multicenter case-control study in 13 French university hospitals in 2009-2012 comparing patients admitted with PTA to matched controls: patients with sore throat but without PTA who were followed up for 10 days after visiting their primary-care physician. In the multivariate stepwise logistic regression model comparing 120 cases with PTA to 143 controls, factors significantly associated with PTA were male gender (odds ratio [OR], 2.0; p = 0.03), smoking (OR, 2.0; p = 0.03), and prior self-medication with systemic AIAs (OR, 3.5; p = 0.01). Topical treatment was associated with significant protection against PTA (OR, 0.3; p < 0.001). In conclusion, self-medication with systemic AIAs appears to be an independent factor associated with the occurrence of PTA. This is an important message as non-steroidal AIAs access is favored by their over-counter availability in pharmacies. This finding must be interpreted with caution due to the study design and a prospective, randomized study is needed to substantiate these possible causal risk factors.

  16. Pharmacological treatment of spondyloarthritis: exploring the effectiveness of nonsteroidal anti-inflammatory drugs, traditional disease-modifying antirheumatic drugs and biological therapies

    PubMed Central

    Caso, Francesco; Costa, Luisa; Del Puente, Antonio; Di Minno, Matteo Nicola Dario; Lupoli, Gelsy; Scarpa, Raffaele; Peluso, Rosario

    2015-01-01

    Spondyloarthritis represents a heterogeneous group of articular inflammatory diseases that share common genetic, clinical and radiological features. The therapy target of spondyloarthritis relies mainly in improving patients’ quality of life, controlling articular inflammation, preventing the structural joints damage and preserving the functional abilities, autonomy and social participation of patients. Among these, traditional disease-modifying antirheumatic drugs have been demonstrated to be effective in the management of peripheral arthritis; moreover, in the last decade, biological therapies have improved the approach to spondyloarthritis. In patients with axial spondyloarthritis, tumor necrosis factor α inhibitors are currently the only effective therapy in patients for whom conventional therapy with nonsteroidal anti-inflammatory drugs has failed. The aim of this review is to summarize the current experience and evidence about the pharmacological approach in spondyloarthritis patients. PMID:26568809

  17. Utilization of gastroprotective strategies for nonsteroidal anti-inflammatory drug-induced gastrointestinal events in a major teaching hospital

    PubMed Central

    Lee, Hooi Leng; Chua, Siew Siang; Mahadeva, Sanjiv

    2016-01-01

    Background and purpose Clinical guidelines recommend the prescribing of gastroprotective strategies in nonsteroidal anti-inflammatory drug (NSAID) users with risk factors for gastrointestinal (GI) ulcer or ulcer complications. However, these guidelines are not often translated into clinical practice. Therefore, the aim of this study was to investigate the utilization of gastroprotective strategies for NSAID-induced upper GI events in at-risk users in a major teaching hospital. Patients and methods A cross-sectional, observational, pharmacy-based study was conducted in a major Asian institution with both primary and secondary health care services. This study involved the screening of prescriptions for regular NSAIDs, and patients who met the inclusion criteria were recruited and interviewed using a questionnaire. Results Of the 409 participants recruited, 83.1% had at least one GI risk factor, of whom 70.3% did not receive appropriate gastroprotection. The most common GI risk factor was the use of high-dose NSAIDs (69.2%), followed by participants aged 65 years and older (22%) and concomitant use of low-dose aspirin (11.7%). Appropriate gastroprotective strategies utilized consisted of the use of a cyclooxygenase (COX)-2 inhibitor alone or a nonselective NSAID plus a proton pump inhibitor (PPI) in the moderate-risk group and a COX-2 inhibitor plus a PPI in the high-risk group. Gastroprotective strategies were underutilized in 67.1% of at-risk participants and overutilized in 59.4% of those without risk factors. Co-prescription of a histamine-2 receptor antagonist at lower-than-recommended doses constituted 59% of the inappropriate gastroprotective agents used. Logistic regression analysis revealed patients aged 65 years and older (odds ratio, 1.89; 95% CI =1.15–3.09) as a predictor for the prescribing of gastroprotection by the clinicians. Conclusion Approximately 70% of at-risk NSAID users, mainly on high-dose NSAIDs, were not prescribed appropriate

  18. Copper(II) complexes of a nonsteroidal anti-inflammatory drug niflumic acid. Synthesis, crystal structure of tetrakis-mu-(2-[3-(trifluoromethyl) phenyl]aminonicotinato)bis(dimethylsulfoxide)-dicopper(II) complex at 190 K. Anti-inflammatory properties.

    PubMed

    Greenaway, F T; Riviere, E; Girerd, J J; Labouze, X; Morgant, G; Viossat, B; Daran, J C; Roch Arveiller, M; Dung, N H

    1999-07-30

    The synthesis and characterization of three complexes with a potent nonsteroidal anti-inflammatory drug niflumic acid {2-[3-(trifluoromethyl)phenyl]aminonicotinic acid} with formula [Cu(niflumato)2L] (L = H2O, DMSO = dimethylsulfoxide, DMF = N,N-dimethylformamide) were investigated. The crystal and molecular structure of the {Cu(niflumato)2(DMSO)}2 was reported. Crystallographic data are as follows: monoclinic system, space group P2(1)/n, Z = 2, a = 11.1318(8), b = 17.513(2), c = 15.336(1) A, beta = 103.316(8) degrees, V = 2909.4(4) A3. The structure was refined to R = 0.030 and wR = 0.037 for 3702 reflections with I > sigma (I). It consists of centrosymmetric binuclear units with the Cu-Cui (symmetry code i: 1-x, -y, 1-z) distance between two centrosymmetrically related ions of 2.6272(5) A. Each Cu(II) ion in [Cu2(DMSO)2(mu-niflumato)4] is coordinated to an apical dimethylsulfoxide O atom on the one hand and to the equatorial carbonyl and carboxylic O atoms of two crystallographically independent niflumate moieties and their centrosymmetric counterparts on the other hand. In spite of the low-temperature (190 K) crystal measurements, one L-CF3 grouping exhibits some disorder. The biological activities of these complexes were compared to that of niflumic acid. Niflumic acid and its various copper complexes significantly inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism, as assessed by chemiluminescence and O2- generation measurement. This effect was dose-dependent. All copper complexes exerted a similar inhibiting effect which was always significantly higher than that exerted by the parent drug.

  19. Evaluation of anti-inflammatory and analgesic effects of synthesized derivatives of ibuprofen.

    PubMed

    Wang, Jingjie; Dai, Dongyan; Qiu, Qianqian; Deng, Xin; Lin, Haiyan; Qian, Hai; Huang, Wenlong

    2015-05-01

    Inflammatory and pain are major areas for drug discovery. Current analgesic drugs often cause a number of side-effects. In the present study, we modified carboxylic acid group of ibuprofen, one of non-steroidal anti-inflammatory drugs, based on the common structure of transient receptor potential vanilloid type 1 antagonists which are considered as new candidates for analgesic drugs, and synthesized several derivatives of ibuprofen. Comprehensive evaluations of the pharmacological properties of these compounds were investigated. Compound 17 showed weak cyclooxygenase inhibition and exhibited strong transient receptor potential vanilloid type 1 antagonistic activity. It was found to be capable of blocking noxious thermal nociception and capsaicin-induced nociception in mice. Besides, 17 showed less ulcerogenic action than ibuprofen did and had no hyperthermia side-effect compared with common transient receptor potential vanilloid type 1 antagonists. Therefore, it suggested that 17 could be used as a safe alternative analgesic candidate for pain treatment.

  20. Effect of farrowing duration, parity number and the type of anti-inflammatory drug on postparturient disorders in sows: a clinical study.

    PubMed

    Tummaruk, Padet; Sang-Gassanee, Kridtasak

    2013-04-01

    The aim of the present study was to investigate the effects of farrowing duration, parity number, and type of anti-inflammatory drug used postpartum on the incidence of postparturient disorders in sows. The duration of farrowing and postparturient disorders were examined in 64 sows at Days 0, 1, 2, and 3 after farrowing. The sows were classified according to parity number (1, 2-4, and 5-7), duration of farrowing (<2, 2-2.9, 3-3.9, and 4-8 h), and the type of anti-inflammatory drugs (flunixin méglumine and dipyrone). The farrowing duration was 178.0 ± 73.5 min (2.96 h). The percentage of sows with fever increased from 40 to 100 % when the farrowing duration increased from <2 to 4-8 h. On Day 1 of the postpartum, 93.7 % of primiparous sows had fever, while 52.6 and 47.6 % of sows parity 2-4 and 5-7 had a fever (P<0.05). The presence of vaginal discharge on Day 1 of the postpartum was higher in sows of parity 5-7 than sows of parity 2-4 (85.7 and 52.6 %, P=0.029). The use of flunixin méglumine after parturition in sows reduced the percentage of sows with a fever from 61.3 to 22.6 % within 2 days (P=0.002), while, the percentage of sows with a fever was not decreased in sows treated with dipyrone. It can be concluded that the incidence of postparturient disorders in sows was affected by sow parity, farrowing duration and the type of anti-inflammatory drug used. Sows with a farrowing duration of ≥ 4 h were at a high risk of having fever at Day 1 after parturition.

  1. Comparative assessment of the cytotoxicity of six anti-inflammatory eyedrops in four cultured ocular surface cell lines, as determined by cell viability scores

    PubMed Central

    Ayaki, Masahiko; Iwasawa, Atsuo; Niwano, Yoshimi

    2012-01-01

    Purpose Anti-inflammatory eyedrops are often used in the treatment of corneal epithelial disorders. In the present study, we evaluated the cytotoxicity of six anti-inflammatory eyedrops in four ocular surface cell lines. Methods The cytotoxicity of six commercially available anti-inflammatory ophthalmic solutions (ie, diclofenac, bromfenac, pranoprofen, betamethasone, and fluoromethorone) was assessed in three corneal cell lines and one conjunctival cell line. Cell viability was determined by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide and neutral red assays after exposing the cells to 10, 30, and 60 minutes of onefold, twofold, and tenfold dilutions of the drugs. Cytotoxicity was compared using the cell viability score (CVS), an integrated cytotoxic parameter that takes various factors into account, such as dilution by tear fluid or concentration by evaporation, drug exposure time, and ocular surface cell type. Results Based on the CVS scores, the order of the anti-inflammatory eyedrops tested from least to most cytotoxic, with the active ingredient %CVS50, and %CVS40/80 for each solution given in parentheses, was as follows: Rinderon® (betamethasone, 100%, 100%) >0.02% Flumethoron® (fluoromethorone, 68%, 22%) = 0.1% Flumethoron® (fluoromethorone, 76%, 22%) >Bronuck® (0.1% bromfenac, 53%, −8%) = Diclod® (0.1% diclofenac, 44%, −15%) = Niflan® (pranoprofen, 50%, −19%). Rinderon® exhibited the least toxicity of all the anti-inflammatory eyedrops tested. Eyedrops containing non-steroidal anti-inflammatory drugs exhibited greater cytotoxicity than those containing steroids with benzalkonium at comparable concentrations. Concentration was the most significant factor affecting cell viability. Conclusion The cytotoxicity of the anti-inflammatory eyedrops evaluated in the present study depended on both the pharmaceutical components and preservatives. The CVS is a concise indicator of drug cytotoxicity. PMID:23185116

  2. Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug-related urticaria and angioedema.

    PubMed

    Kowalski, Marek L; Woessner, Katharine; Sanak, Marek

    2015-08-01

    Nonsteroidal anti-inflammatory drug (NSAID)-induced urticarial and angioedema reactions are among the most commonly encountered drug hypersensitivity reactions in clinical practice. Three major clinical phenotypes of NSAID-induced acute skin reactions manifesting with angioedema, urticaria, or both have been distinguished: NSAID-exacerbated cutaneous disease, nonsteroidal anti-inflammatory drug-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria and angioedema. In some patients clinical history alone might be sufficient to establish the diagnosis of a specific type of NSAID hypersensitivity, whereas in other cases oral provocation challenges are necessary to confirm the diagnosis. Moreover, classification of the type of cutaneous reaction is critical for proper management. For example, in patients with single NSAID-induced reactions, chemically nonrelated COX-1 inhibitors can be safely used. However, there is cross-reactivity between the NSAIDs in patients with NSAID-exacerbated cutaneous disease and NIUA, and thus only use of selective COX-2 inhibitors can replace the culprit drug if the chronic treatment is necessary, although aspirin desensitization will allow for chronic treatment with NSAIDs in some patients with NIUA. In this review we present a practical clinical approach to the patient with NSAID-induced urticaria and angioedema.

  3. Anti-inflammatory and ulcerogenic effects of indomethacin and tenoxicam in combination with cimetidine.

    PubMed

    Maciel, Hermelinda P F; Cardoso, Luiz G V; Ferreira, Luciano R; Perazzo, Fábio F; Carvalho, José Carlos T

    2004-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for the modulation of the inflammatory response. However, a number of facts involving the occurrence of gastrointestinal lesions have limited the chronic use of NSAIDs. In order to diminish the occurrence of gastrointestinal damage caused by NSAIDs, the combination of NSAIDs with the H2 receptor blocker, cimetidine, has been evaluated. The anti-inflammatory and ulcerogenic effects of indomethacin and tenoxicam in association with or without cimetidine were determined at pre-clinical levels. It was observed that the group of animals treated with indomethacin and cimetidine, or tenoxicam and cimetidine (10 mg/kg, p.o.) demonstrated a significant reduction (P < 0.05, ANOVA followed by Tukey-Kramer multiple comparison test) of type-III gastric ulcers. Furthermore, indomethacin or tenoxicam (10 mg/kg, p.o.) in association with cimetidine increased the anti-inflammatory activity. The group, which received indomethacin and cimetidine presented the best performance in decreasing the inflammatory process (P < 0.05, ANOVA followed by Tukey-Kramer multiple comparison test).

  4. Some Important Dietary Polyphenolic Compounds: An Anti-inflammatory and Immunoregulatory Perspective.

    PubMed

    Kinger, Mayank; Kumar, Sushil; Kumar, Vinod

    2017-02-08

    Inflammation plays an important role in maintaining the body's homeostasis. It repairs the damaged tissues of the body resulting from injury or infection. In addition, a diverse array of diseases like hepatitis, arthritis and colitis has been reported and described to be associated with inflammatory processes. Some autoimmune diseases like inflammatory bowel disease (IBD) emerge by the influence of numerous genes in complex environmental situations belongs to inflammation. The currently available processes for curing inflammation and related disorders facilitate the use of non steroidal anti-inflammatory drugs (NSAIDs). Moreover, intolerable side effects are also associated with the consumption of these medications. It is well known that phenolic compounds, largely present in vegetables and fruits, serve as an integral part of normal human diet besides having great medicinal value. These are considered to reflect a variety of anti-inflammatory properties, and can be used as an alternate natural source for the prevention of chronic inflammatory disorders. This mini-review summarized the anti-inflammatory benefits of plants derived very prominent dietary polyphenolic compounds particularly, Oleocanthal, Curcumin, Resveratrol and Quercetin.

  5. Inhibitory Effect of Herbal Remedy PERVIVO and Anti-Inflammatory Drug Sulindac on L-1 Sarcoma Tumor Growth and Tumor Angiogenesis in Balb/c Mice

    PubMed Central

    Skopiński, P.; Bałan, B. J.; Kocik, J.; Zdanowski, R.; Lewicki, S.; Niemcewicz, M.; Gawrychowski, K.; Skopińska-Różewska, E.; Stankiewicz, W.

    2013-01-01

    Anticancer activity of many herbs was observed for hundreds of years. They act as modifiers of biologic response, and their effectiveness may be increased by combining multiple herbal extracts . PERVIVO, traditional digestive herbal remedy, contains some of them, and we previously described its antiangiogenic activity. Numerous studies documented anticancer effects of nonsteroidal anti-inflammatory drugs. We were the first to show that sulindac and its metabolites inhibit angiogenesis. In the present paper the combined in vivo effect of multicomponent herbal remedy PERVIVO and nonsteroidal anti-inflammatory drug sulindac on tumor growth, tumor angiogenesis, and tumor volume in Balb/c mice was studied. These effects were checked after grafting cells collected from syngeneic sarcoma L-1 tumors into mice skin. The strongest inhibitory effect was observed in experimental groups treated with PERVIVO and sulindac together. The results of our investigation showed that combined effect of examined drugs may be the best way to get the strongest antiangiogenic and antitumor effect. PMID:23935247

  6. Anti-inflammatory drugs and tumor necrosis factor-alpha production from monocytes: role of transcription factor NF-kappa B and implication for rheumatoid arthritis therapy.

    PubMed

    Lavagno, Luisa; Gunella, Gabriele; Bardelli, Claudio; Spina, Simona; Fresu, Luigia Grazia; Viano, Ilario; Brunelleschi, Sandra

    2004-10-06

    Inhibition of tumor necrosis factor-alpha (TNF-alpha) represents a relevant target in rheumatoid arthritis therapy. Besides inhibiting cyclooxygenase, anti-inflammatory drugs can affect the activation of transcription factors. We investigated the ability of dexamethasone, indomethacin, and rofecoxib to modulate nuclear factor-kappaB (NF-kappaB) activation and TNF-alpha release from human monocytes challenged with lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA). Both stimuli induced NF-kappaB nuclear translocation and TNF-alpha secretion. Dexamethasone potently inhibited TNF-alpha release, indomethacin inhibited only PMA-evoked release, while rofecoxib had no effect. In the electrophoretic mobility shift assay, dexamethasone and rofecoxib dose-dependently inhibited the DNA binding activity of NF-kappaB in stimulated monocytes, whereas indomethacin failed to inhibit the LPS-evoked one. These results were further confirmed by evaluating the drugs' ability to reduce nuclear NF-kappaB subunits, as well as the amount of phosphorylated IkappaBalpha in cytosolic fractions. In conclusion, these results indicate that anti-inflammatory drugs differ largely in their ability to inhibit NF-kappaB activity and/or TNF-alpha release from human monocytes. These effects can be relevant to rheumatoid arthritis therapy.

  7. Exacerbation of nonsteroidal anti-inflammatory drug-induced small intestinal lesions by antisecretory drugs in rats: the role of intestinal motility.

    PubMed

    Satoh, Hiroshi; Amagase, Kikuko; Takeuchi, Koji

    2012-11-01

    Antisecretory drugs such as histamine H2-receptor antagonists (H2-RAs) and proton pump inhibitors (PPIs) are commonly used for the treatment of gastric and duodenal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, the effects of these drugs on NSAID-induced small intestinal ulcers are not fully understood. The effects of H2-RAs and PPIs on NSAID-induced gastrointestinal lesions and small intestinal motility were examined in rats. Male Wistar rats (180-220 g) were used. Indomethacin (10 mg/kg) was administered orally in fasted or fed rats, and gastrointestinal lesions were examined 24 h after indomethacin administration. Intestinal motility was measured by using a balloon method under urethane anesthesia. Indomethacin produced multiple lesions in the gastric corpus in fasted rats and in the small intestine in fed rats: 1) H2-RAs (cimetidine, ranitidine, and famotidine) and PPIs (omeprazole, lansoprazole, and rabeprazole) markedly inhibited the formation of gastric lesions. 2) The drugs, except for lansoprazole, increased intestinal lesions. 3) H2-RAs augmented the increase in intestinal motility caused by indomethacin, and the effects of H2-RAs on motility and intestinal lesions were markedly inhibited by atropine. 4) Lansoprazole inhibited the formation of intestinal lesions, and the effect was prevented by both pharmacological ablation of capsaicin-sensitive sensory neurons and pretreatment with N-nitro-l-arginine methyl ester, a selective inhibitor of nitric-oxide synthesis. The results suggest that: 1) inhibition of acid secretion by antisecretory drugs may exacerbate NSAID-induced intestinal lesions, 2) H2-RAs further aggravate lesions by increasing intestinal motility via the activation of cholinergic pathways, and 3) lansoprazole protects the intestinal mucosa against NSAID-related ulcerative stimuli.

  8. Aspirin and some other nonsteroidal anti-inflammatory drugs inhibit cystic fibrosis transmembrane conductance regulator protein gene expression in T-84 cells.

    PubMed

    Tondelier, D; Brouillard, F; Lipecka, J; Labarthe, R; Bali, M; Costa de Beauregard, M A; Torossi, T; Cougnon, M; Edelman, A; Baudouin-Legros, M

    1999-01-01

    Cystic fibrosis (CF) is caused by mutations in the CF gene, which encodes CF transmembrane conductance regulator protein (CFTR), a transmembrane protein that acts as a cAMP-regulated chloride channel The disease is characterized by inflammation but the relationship between inflammation, abnormal transepithelial ion transport, and the clinical manifestations of CF are uncertain. The present study was undertaken to determine whether three nonsteroidal anti-inflammatory drugs (NSAIDs) (aspirin, ibuprofen, and indomethacin) modulate CFTR gene expression in T-84 cells. Treatment with NSAIDs reduced CFTR transcripts, and decreased cAMP-stimulated anion fluxes, an index of CFTR function. However, the two phenomena occurred at different concentrations of both drugs. The results indicate that NSAIDs can regulate both CFTR gene expression and the function of CFTR-related chloride transport, and suggest that NSAIDs act via multiple transduction pathways.

  9. Anti-inflammatory effects of fibrates: an overview.

    PubMed

    Tziomalos, Konstantinos; Athyros, Vasilios G; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2009-01-01

    Inflammation plays an important role in the pathogenesis of atherosclerosis. Several cardiovascular drugs exert anti-inflammatory effects and accumulating data suggest that fibrates also share this property. This review summarizes the mechanisms implicated in the anti-inflammatory actions of fibrates. We also provide an overview of the existing clinical studies addressing the effects of fibrates on markers of inflammation. Several, but not all, studies reported that fibrates exert anti-inflammatory actions. The small number of patients included in some studies, as well as differences in diagnoses and duration of follow up might partly explain this discrepancy. It is also possible that fibrates differ substantially in terms of anti-inflammatory effects. It is not clear whether an anti-inflammatory action of fibrates is clinically relevant. Future studies should assess whether the anti-inflammatory actions of fibrates (or for that matter, other drugs) will translate into a reduced risk of vascular disease.

  10. Utilization of spray drying technique for improvement of dissolution and anti-inflammatory effect of Meloxicam.

    PubMed

    Shazly, Gamal; Badran, Mohamed; Zoheir, Khairy; Alomrani, Abdullah

    2015-01-01

    Meloxicam (MLX) is a poorly water-soluble non steroidal anti-inflammatory drug (NSAID). The main objective of the present work was to enhance the dissolution of MLX and thus its bioavailability by the aid of additives. The novelty of this work rises from the utilization of spray drying technology to produce micro particulates solid dispersion systems containing MLX in the presence of small amount of additives. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and Scan Electron Microscope (SEM) were used for studying the physico-chemical and morphological properties of MLX samples. The dissolution of MLX samples was investigated in two different pH media. The morphology of MLX solid dispersion micro-particles was spherical in shape according to SEM. FT-IR profiles indicated that a complex was formed between MLX and the additives. DSC patterns of the MLX micro-particles suggested a reduction in the crystallinity of MLX and probability of presence of an interaction between MLX and the additives. The rate of dissolution of the spray-dried MLX enhanced as compared with the unprocessed MLX in both acidic and neutral media. It was found that 100% of the added MLX released within 5 min in phosphate buffer dissolution medium (pH 7.4) compared to that of the unprocessed MLX (15% in 60 min). Such increase rate in the dissolution of the spray dried MLX could be attributed to the increase in wettability of MLX particles and the hydrophilic nature of the additives. The anti-inflammatory effect of the spray dried MLX was explored using formalin induced rat paw edema model. The spray-dried samples showed an increase in the anti-inflammatory activity of MLX as compared to the unprocessed MLX. This work reveals that the spray drying technique is suitable for preparation of micro-particles with improved dissolution and anti-inflammatory effect of MLX.

  11. Antibacterial and anti-inflammatory drug delivery properties on cotton fabric using betamethasone-loaded mesoporous silica particles stabilized with chitosan and silicone softener.

    PubMed

    Hashemikia, Samaneh; Hemmatinejad, Nahid; Ahmadi, Ebrahim; Montazer, Majid

    2016-10-01

    In this study, mesoporous silica particles with a hexagonal structure (SBA-15) were synthesized and modified with (3-aminopropyl) triethoxysilane, and used as a carrier for anti-inflammatory drug, betamethasone sodium phosphate. Drug-loaded silica particles were grafted on the cotton fabric surface using chitosan and polysiloxane reactive softener as a soft and safe fixing agent to develop an antibacterial cotton fabric with drug delivery properties. Cytometry assays revealed that synthesized silica have no cytotoxicity against human peripheral blood mononuclear cells. Accordingly, the produced drug-loaded nanostructures can be applied via different routes, such as wound dressing. Drug delivery profile of the treated fabrics were investigated and compared. The drug release rate followed the conventional Higuchi model. The treated cotton fabrics were tested and evaluated using scanning electron microscope images, bending length, air permeability, washing durability and anti-bacterial properties. It was found that the chitosan-/softener-treated fabrics compounded with drug-loaded silica particles have a good drug delivery performance and exhibited a powerful antibacterial activity against both Escherichia coli and Staphylococcus aureus even after five washing cycles. The produced antibacterial cotton fabric with drug delivery properties could be proposed as a suitable material for many medical and hygienic applications.

  12. Standardization of the finished product: Habbe Irqun Nisa - A Unani anti-inflammatory formulation

    PubMed Central

    Husain, S. Farhan; Ahmad, Irshad; Shamsi, Shariq

    2012-01-01

    Background: Habb (Pill) is one of the important dosage forms of Unani system of medicine. A number of effective formulations are manufactured in form of Habb because of its various advantages. Out of these, Habbe Irqun Nisa (HI) is a popular anti-inflammatory formulation used in the treatment of Warame Mafasil (arthritis) and Irqun Nisa (sciatica). Nowadays, with increased incidence of these diseases many non-steroidal anti-inflammatory drugs (NSAIDs) are being used in their treatment. Owing to the adverse effects of these drugs, the use of herbal medicines is seen as a better alternative. The basic requirement for the development of Unani system of Medicine is the standardization of single and compound drugs. HI is mentioned in National Formulary of Unani Medicne and selected for the present study. Materials and Methods: HI was prepared manually with the powder of crude drugs, passed through sieve no. 100 and mixed with 1% w/w of gum acacia in mucilage form. It was then dried at 60°C for 90 min and then tested for its standardization on different physicochemical parameters, e.g. organoleptic properties, pH values, moisture content, ash values, friability, hardness, weight variation, disintegration time, and thin layer chromatography (TLC). Results and Conclusion: The data evolved from this study will make it a validated product and will help in the quality control of other finished products in future research. PMID:23929993

  13. Rational design, synthesis and evaluation of chromone-indole and chromone-pyrazole based conjugates: identification of a lead for anti-inflammatory drug.

    PubMed

    Shaveta; Singh, Amrinder; Kaur, Matinder; Sharma, Surbhi; Bhatti, Rajbir; Singh, Palwinder

    2014-04-22

    Conjugates of chromone-indole and chromone-pyrazole were screened for cyclooxygenase-2 (COX-2), cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitory activities. Compounds 8 and 9 were identified as preferred inhibitors of COX-2 over the other two enzymes. Their IC50 for COX-2 was 29 nM and 20 nM, respectively and selectivity indices (SI) for COX-2 over COX-1 was 46 and 337. NMR, mass spectral studies and molecular modelling also indicated preferential interactions of compounds 8 and 9 with COX-2. Tested on albino mice against capsaicin induced algesia, compound 8 exhibited analgesic potential comparable to diclofenac. In addition to the biological profile, the desirable physico-chemical properties of these compounds make them promising leads for anti-inflammatory drugs.

  14. (1)H-Nuclear magnetic resonance-based metabolic profiling of nonsteroidal anti-inflammatory drug-induced adverse effects in rats.

    PubMed

    Um, So Young; Park, Jung Hyun; Chung, Myeon Woo; Choi, Ki Hwan; Lee, Hwa Jeong

    2016-09-10

    Nonsteroidal anti-inflammatory drugs (NSAIDs), which are globally prescribed, exhibit mainly anti-inflammatory and analgesic effects but also can cause adverse effects including gastrointestinal erosions, ulceration, bleeding, and perforation. The purpose of this study was to investigate surrogate biomarkers associated with the gastrointestinal (GI) damage caused by NSAID treatment using pattern recognition analysis of (1)H-nuclear magnetic resonance ((1)H NMR) spectra of rat urine. Urine was collected for 5h after oral administration of the following NSAIDs at low or high doses: acetylsalicylic acid (10 or 200mgkg(-1)), diclofenac (0.5 or 15mgkg(-1)), piroxicam (1 or 10mgkg(-1)), indomethacin (1 or 25mgkg(-1)), or ibuprofen (10, or 150mgkg(-1)) as nonselective COX inhibitors and celecoxib (10 or 100mgkg(-1)) as a COX-2 selective inhibitor. The urine was analyzed using 500MHz (1)H NMR for spectral binning and targeted profiling and the level of gastric damage was examined. The nonselective COX inhibitors caused severe gastric damage while no lesions were observed in the celecoxib-treated rats. The (1)H NMR urine spectra were divided into spectral bins (0.04ppm) for global profiling, and a total of 44 endogenous metabolites were assigned for targeted profiling. Multivariate data analyses were performed to recognize the spectral pattern of endogenous metabolites related to NSAIDs using partial least square-discrimination analysis (PLS-DA). The (1)H NMR spectra clustered differently according to gastric damage score in global profiling. In targeted profiling, the endogenous metabolites of citrate, allantoin, 2-oxoglutarate, acetate, benzoate, glycine, and trimethylamine N-oxide were selected as putative biomarkers for gastric damage caused by NSAIDs. These putative biomarkers might be useful for predicting the risk of adverse effects caused by NSAIDs in the early stage of drug development process.

  15. Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein

    PubMed Central

    2010-01-01

    The limitations of steroidal and non steroidal anti-inflammatory drugs have prompted investigation into other biologically based therapeutics, and identification of immune selective anti-inflammatory agents of salivary origin. The traditional view of salivary glands as accessory digestive structures is changing as their importance as sources of systemically active immunoregulatory and anti-inflammatory factors is recognized. Salivary gland involvement in maintenance of whole body homeostasis is regulated by the nervous system and thus constitutes a "neuroendocrine axis". The potent anti-inflammatory activities, both in vivo and in vitro, of the tripeptide Phe-Glu-Gly (FEG) are reviewed. FEG is a carboxyl terminal peptide of the prohormone SMR1 identified in the rat submandibular salivary gland, The D-isomeric form (feG) mimics the activity of its L-isomer FEG. Macropharmacologically, feG attenuates the cardiovascular and inflammatory effects of endotoxemia and anaphylaxis, by inhibition of hypotension, leukocyte migration, vascular leak, and disruption of pulmonary function and intestinal motility. Mechanistically, feG affects activated inflammatory cells, especially neutrophils, by regulating integrins and inhibiting intracellular production of reactive oxygen species. Pharmacodynamically, feG is active at low doses (100 μg/kg) and has a long (9-12 hour) biological half life. As a therapeutic agent, feG shows promise in diseases characterized by over exuberant inflammatory responses such as systemic inflammatory response syndrome and other acute inflammatory diseases. Arthritis, sepsis, acute pancreatitis, asthma, acute respiratory inflammation, inflammatory bowel disease, and equine laminitis are potential targets for this promising therapeutic peptide. The term "Immune Selective Anti-Inflammatory Derivatives" (ImSAIDs) is proposed for salivary-derived peptides to distinguish this class of agents from corticosteroids and nonsteroidal anti-inflammatory drugs

  16. Association of terpinolene and diclofenac presents antinociceptive and anti-inflammatory synergistic effects in a model of chronic inflammation

    PubMed Central

    Macedo, E.M.A.; Santos, W.C.; Sousa, B.P.; Lopes, E.M.; Piauilino, C.A.; Cunha, F.V.M.; Sousa, D.P.; Oliveira, F.A.; Almeida, F.R.C.

    2016-01-01

    Pharmacological treatment of inflammatory pain is usually done by administration of non-steroidal anti-inflammatory drugs (NSAIDs). These drugs present high efficacy, although side effects are common, especially gastrointestinal lesions. One of the pharmacological strategies to minimize such effects is the combination of drugs and natural products with synergistic analgesic effect. The monoterpene terpinolene (TPL) is a chemical constituent of essential oils present in many plant species, which have pharmacological activities, such as analgesic and anti-inflammatory. The association of ineffective doses of TPL and diclofenac (DCF) (3.125 and 1.25 mg/kg po, respectively) presented antinociceptive and anti-inflammatory effects in the acute (0, 1, 2, 3, 4, 5 and 6 h, after treatment) and chronic (10 days) inflammatory hyperalgesia induced by Freund's complete adjuvant (CFA) in the right hind paw of female Wistar rats (170-230 g, n=6-8). The mechanical hyperalgesia was assessed by the Randall Selitto paw pressure test, which determines the paw withdrawal thresholds. The development of edema was quantified by measuring the volume of the hind paw by plethismography. The TPL/DCF association reduced neutrophils, macrophages and lymphocytes in the histological analysis of the paw, following a standard staining protocol with hematoxylin and eosin and the counts were performed with the aid of optical microscopy after chronic oral administration of these drugs. Moreover, the TPL/DCF association did not induce macroscopic gastric lesions. A possible mechanism of action of the analgesic effect is the involvement of 5-HT2A serotonin receptors, because ketanserin completely reversed the antinociceptive effect of the TPL/DCF association. These results suggest that the TPL/DCF association had a synergistic anti-inflammatory and analgesic effect without causing apparent gastric injury, and that the serotonergic system may be involved in the antinociceptive effect of this association

  17. Association of terpinolene and diclofenac presents antinociceptive and anti-inflammatory synergistic effects in a model of chronic inflammation.

    PubMed

    Macedo, E M A; Santos, W C; Sousa, B P; Lopes, E M; Piauilino, C A; Cunha, F V M; Sousa, D P; Oliveira, F A; Almeida, F R C

    2016-06-20

    Pharmacological treatment of inflammatory pain is usually done by administration of non-steroidal anti-inflammatory drugs (NSAIDs). These drugs present high efficacy, although side effects are common, especially gastrointestinal lesions. One of the pharmacological strategies to minimize such effects is the combination of drugs and natural products with synergistic analgesic effect. The monoterpene terpinolene (TPL) is a chemical constituent of essential oils present in many plant species, which have pharmacological activities, such as analgesic and anti-inflammatory. The association of ineffective doses of TPL and diclofenac (DCF) (3.125 and 1.25 mg/kg po, respectively) presented antinociceptive and anti-inflammatory effects in the acute (0, 1, 2, 3, 4, 5 and 6 h, after treatment) and chronic (10 days) inflammatory hyperalgesia induced by Freund's complete adjuvant (CFA) in the right hind paw of female Wistar rats (170-230 g, n=6-8). The mechanical hyperalgesia was assessed by the Randall Selitto paw pressure test, which determines the paw withdrawal thresholds. The development of edema was quantified by measuring the volume of the hind paw by plethismography. The TPL/DCF association reduced neutrophils, macrophages and lymphocytes in the histological analysis of the paw, following a standard staining protocol with hematoxylin and eosin and the counts were performed with the aid of optical microscopy after chronic oral administration of these drugs. Moreover, the TPL/DCF association did not induce macroscopic gastric lesions. A possible mechanism of action of the analgesic effect is the involvement of 5-HT2A serotonin receptors, because ketanserin completely reversed the antinociceptive effect of the TPL/DCF association. These results suggest that the TPL/DCF association had a synergistic anti-inflammatory and analgesic effect without causing apparent gastric injury, and that the serotonergic system may be involved in the antinociceptive effect of this association.

  18. Anti-inflammatory properties of new bioisosteres of indomethacin synthesized from safrole which are sulindac analogues.

    PubMed

    Pereira, E F; Pereira, N A; Lima, M E; Coelho, F A; Barreiro, E J

    1989-01-01

    The anti-inflammatory activities of new compounds (I, II, III and IV) synthesized in 30% overall yield from the abundant natural product safrole, the principal chemical constituent of the oil of sassafras (Ocotea pretiosa, Lauraceae), were determined in mice. The synthesis of these new indenyl-acetic acids (I and II) and indenyl-propionic acids (III and IV) was based on the minimal structural features of non-steroid anti-inflammatory agents of the aryl- or heteroarylcarboxylic acid group. The compounds exhibited potencies 4- to 10-fold less than that of indomethacin in inhibiting carrageenan-induced hindpaw edema. In contrast, like sulindac, all the new compounds were more potent than indomethacin in antagonizing writhing pain and increased vascular permeability caused by acetic acid. The results confirm the anticipated bioisosteric relationship between these synthetic derivatives, designed as sulindac analogues, and the classical non-steroidal anti-inflammatory agent, indomethacin.

  19. Microextraction by packed sorbent and HPLC-PDA quantification of multiple anti-inflammatory drugs and fluoroquinolones in human plasma and urine.

    PubMed

    D'Angelo, Veronica; Tessari, Francesco; Bellagamba, Giuseppe; De Luca, Elisa; Cifelli, Roberta; Celia, Christian; Primavera, Rosita; Di Francesco, Martina; Paolino, Donatella; Di Marzio, Luisa; Locatelli, Marcello

    2016-01-01

    We developed and validated an analytical method based on microextraction packed sorbent (MEPS) and high-performance liquid chromatography (HPLC) coupled to photodiode array (PDA) detector to simultaneously quantify multiple nonsteroidal anti-inflammatory drugs (NSAIDs) and fluoroquinolones (FLQs), which may provide as combination several adverse reactions in nephrology and neurology. The linearity range from LOQs (0.1 μg/mL) to 10 μg/mL, and LODs values were 0.03 μg/mL for both NSAIDs and FLQs. The validation was performed according to international guidelines and the accuracy was tested measuring the precision, intermediate precision and trueness. The drugs stability was tested under different storage conditions (+4 °C and -20 °C) and after three different cycles of freezing and thawing. The method can be a suitable tool to simultaneously detect a possible association of drugs in human biological samples and provide several potentialities for clinical applications, bioequivalence studies, pharmacodynamics and toxicodynamics of different pharmaceutical dosage forms showing NSAIDs and FLQs.

  20. Copper(II) interacting with the non-steroidal antiinflammatory drug flufenamic acid: structure, antioxidant activity and binding to DNA and albumins.

    PubMed

    Tolia, Charikleia; Papadopoulos, Athanassios N; Raptopoulou, Catherine P; Psycharis, Vassilis; Garino, Claudio; Salassa, Luca; Psomas, George

    2013-06-01

    Copper(II) complexes with the non-steroidal antiinflammatory drug flufenamic acid (Hfluf) in the presence of N,N-dimethylformamide (DMF) or nitrogen donor heterocyclic ligands (2,2'-bipyridylamine (bipyam), 1,10-phenanthroline (phen), 2,2'-bipyridine (bipy) or pyridine (py)) have been synthesized and characterized. The crystal structures of [Cu2(fluf)4(DMF)2], 1, and [Cu(fluf)(bipyam)Cl], 2, have been determined by X-ray crystallography. Density functional theory (DFT) (CAM-B3LYP/LANL2DZ/6-31G**) was employed to determine the structure of complex 2 and its analogues (complexes [Cu(fluf)(phen)Cl], 3, [Cu(fluf)(bipy)Cl], 4 and [Cu(fluf)2(py)2], 5). Time-dependent DFT calculations of doublet-doublet transitions show that the lowest-energy band in the absorption spectrum of 2-5 has a mixed d-d/LMCT character. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA with [Cu(fluf)(bipy)Cl] exhibiting the highest binding constant to CT DNA. The complexes can bind to CT DNA via intercalation as concluded by studying the cyclic voltammograms of the complexes in the presence of CT DNA solution and by DNA solution viscosity measurements. Competitive studies with ethidium bromide (EB) have shown that the complexes can displace the DNA-bound EB suggesting strong competition with EB. Flufenamic acid and its Cu(II) complexes exhibit good binding affinity to human or bovine serum albumin protein with high binding constant values. All compounds have been tested for their antioxidant and free radical scavenging activity as well as for their in vitro inhibitory activity against soybean lipoxygenase showing significant activity with [Cu(fluf)(phen)Cl] being the most active.

  1. Anti-inflammatory and anti-oxidant properties of Curcuma longa (turmeric) versus Zingiber officinale (ginger) rhizomes in rat adjuvant-induced arthritis.

    PubMed

    Ramadan, Gamal; Al-Kahtani, Mohammed Ali; El-Sayed, Wael Mohamed

    2011-08-01

    Turmeric (rich in curcuminoids) and ginger (rich in gingerols and shogaols) rhizomes have been widely used as dietary spices and to treat different diseases in Ayurveda/Chinese medicine since antiquity. Here, we compared the anti-inflammatory/anti-oxidant activity of these two plants in rat adjuvant-induced arthritis (AIA). Both plants (at dose 200 mg/kg body weight) significantly suppressed (but with different degrees) the incidence and severity of arthritis by increasing/decreasing the production of anti-inflammatory/pro-inflammatory cytokines, respectively, and activating the anti-oxidant defence system. The anti-arthritic activity of turmeric exceeded that of ginger and indomethacin (a non-steroidal anti-inflammatory drug), especially when the treatment started from the day of arthritis induction. The percentage of disease recovery was 4.6-8.3% and 10.2% more in turmeric compared with ginger and indomethacin (P < 0.05), respectively. The present study proves the anti-inflammatory/anti-oxidant activity of turmeric over ginger and indomethacin, which may have beneficial effects against rheumatoid arthritis onset/progression as shown in AIA rat model.

  2. Partitioning of anti-inflammatory steroid drugs into phosphatidylcholine and phosphatidylcholine-cholesterol small unilamellar vesicles as studied by second-derivative spectrophotometry.

    PubMed

    Takegami, Shigehiko; Kitamura, Keisuke; Funakoshi, Takako; Kitade, Tatsuya

    2008-05-01

    The partition coefficients (Kps) of six anti-inflammatory steroid drugs, dexamethasone (DMS), betamethasone (BMS), triamcinolone acetonide (TCLA), fluocinolone acetonide (FCLA), betamethasone 17,21-dipropionate (BMSDP), and clobetasole propionate (CBSP), for phosphatidylcholine (PC), and PC-cholesterol small unilamellar vesicles (SUVs) were determined by a second-derivative spectrophotometric method. The Kp values were obtained with a relative standard deviation of below 10% and the following order was observed: BMS< or =DMSdrugs examined, i.e., the Kp value of CBSP was 1.2 times that of BMSDP. The presence of 30 mol% cholesterol in the SUV bilayers reduced these Kp values to approximately 35-50% of those values for the PC SUVs, although the order of the Kp values remained unchanged. The order of the Kp values agreed with that of the reported dermatological therapeutic potency of these drugs, although the order of their log P values for n-octanol/water systems showed a discrepancy. Our results indicate that the potency of steroid drugs in dermatological treatments depends to some extent on the Kp values of the drug, that is, the affinity of steroid drugs for PC bilayers influences their clinical potency, since potency is related to transdermal absorption.

  3. Polyox and carrageenan based composite film dressing containing anti-microbial and anti-inflammatory drugs for effective wound healing.

    PubMed

    Boateng, Joshua S; Pawar, Harshavardhan V; Tetteh, John

    2013-01-30

    Polyethylene oxide (Polyox) and carrageenan based solvent cast films have been formulated as dressings for drug delivery to wounds. Films plasticised with glycerol were loaded with streptomycin (30%, w/w) and diclofenac (10%, w/w) for enhanced healing effects in chronic wounds. Blank and drug loaded films were characterised by texture analysis (for mechanical and mucoadhesive properties), scanning electron microscopy, differential scanning calorimetry, X-ray diffraction and Fourier transform infrared spectroscopy. In addition, swelling, in vitro drug release and antibacterial studies were conducted to further characterise the films. Both blank and drug loaded films showed a smooth, homogeneous surface morphology, excellent transparency, high elasticity and acceptable tensile (mechanical) properties. The drug loaded films showed a high capacity to absorb simulated wound fluid and significant mucoadhesion force which is expected to allow effective adherence to and protection of the wound. The films showed controlled release of both streptomycin and diclofenac for 72 h. These drug loaded films produced higher zones of inhibition against Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli compared to the individual drugs zones of inhibition. Incorporation of streptomycin can prevent and treat chronic wound infections whereas diclofenac can target the inflammatory phase of wound healing to relieve pain and swelling.

  4. Anti-inflammatory and immunomodulatory properties of Carica papaya.

    PubMed

    Pandey, Saurabh; Cabot, Peter J; Shaw, P Nicholas; Hewavitharana, Amitha K

    2016-07-01

    Chronic inflammation is linked with the generation and progression of various diseases such as cancer, diabetes and atherosclerosis, and anti-inflammatory drugs therefore have the potential to assist in the treatment of these conditions. Carica papaya is a tropical plant that is traditionally used in the treatment of various ailments including inflammatory conditions. A literature search was conducted by using the keywords "papaya", "anti-inflammatory and inflammation" and "immunomodulation and immune" along with cross-referencing. Both in vitro and in vivo investigation studies were included. This is a review of all studies published since 2000 on the anti-inflammatory activity of papaya extracts and their effects on various immune-inflammatory mediators. Studies on the anti-inflammatory activities of recognized phytochemicals present in papaya are also included. Although in vitro and in vivo studies have shown that papaya extracts and papaya-associated phytochemicals possess anti-inflammatory and immunomodulatory properties, clinical studies are lacking.

  5. Pectin/zein hydrogels for the delivery of drugs and nutrients

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two pectin/zein coacervates were prepared with either calcium ions or zinc ions. Piroxicam, a non-steroidal anti-inflammatory drug, was encapsulated. It was found that at lower solution pH the release of piroxicam displayed a near zero order kinetics, whether the coacervates were cross-linked with c...

  6. Combined Anti-Inflammatory and Anti-AGE Drug Treatments Have a Protective Effect on Intervertebral Discs in Mice with Diabetes

    PubMed Central

    Illien-Junger, Svenja; Grosjean, Fabrizio; Laudier, Damien M.; Vlassara, Helen; Striker, Gary E.; Iatridis, James C.

    2013-01-01

    Objective Diabetes and low back pain are debilitating diseases and modern epidemics. Diabetes and obesity are also highly correlated with intervertebral disc (IVD) degeneration and back pain. Advanced-glycation-end-products (AGEs) increase reactive-oxygen-species (ROS) and inflammation, and are one cause for early development of diabetes mellitus. We hypothesize that diabetes results in accumulation of AGEs in spines and associated spinal pathology via increased catabolism. We present a mouse model showing that: 1) diabetes induces pathological changes to structure and composition of IVDs and vertebrae; 2) diabetes is associated with accumulation of AGEs, TNFα, and increased catabolism spinal structures; and 3) oral-treatments with a combination of anti-inflammatory and anti-AGE drugs mitigate these diabetes-induced degenerative changes to the spine. Methods Three age-matched groups of ROP-Os mice were compared: non-diabetic, diabetic (streptozotocin (STZ)-induced), or diabetic mice treated with pentosan-polysulfate (anti-inflammatory) and pyridoxamine (AGE-inhibitor). Mice were euthanized and vertebra-IVD segments were analyzed by μCT, histology and Immunohistochemistry. Results Diabetic mice exhibited several pathological changes including loss in IVD height, decreased vertebral bone mass, decreased glycosaminoglycan content and morphologically altered IVDs with focal deposition of tissues highly expressing TNFα, MMP-13 and ADAMTS-5. Accumulation of larger amounts of methylglyoxal suggested that AGE accumulation was associated with these diabetic degenerative changes. However, treatment prevented or reduced these pathological effects on vertebrae and IVD. Conclusion This is the first study to demonstrate specific degenerative changes to nucleus pulposus (NP) morphology and their association with AGE accumulation in a diabetic mouse model. Furthermore, this is the first study to demonstrate that oral-treatments can inhibit AGE-induced ROS and inflammation in

  7. Determination of Residual Nonsteroidal Anti-Inflammatory Drugs in Aqueous Sample Using Magnetic Nanoparticles Modified with Cetyltrimethylammonium Bromide by High Performance Liquid Chromatography

    PubMed Central

    Khoeini Sharifabadi, Malihe; Saber-Tehrani, Mohammad; Waqif Husain, Syed; Mehdinia, Ali; Aberoomand-Azar, Parviz

    2014-01-01

    A simple and sensitive solid-phase extraction method for separation and preconcentration of trace amount of four nonsteroidal anti-inflammatory drugs (naproxen, indomethacin, diclofenac, and ibuprofen) using Fe3O4 magnetic nanoparticles modified with cetyltrimethylammonium bromide has been developed. For this purpose, the surface of MNPs was modified with cetyltrimethylammonium bromide (CTAB) as a cationic surfactant. Effects of different parameters influencing the extraction efficiency of drugs including the pH, amount of salt, shaking time, eluent type, the volume of solvent, amount of adsorbent, sample volume, and the time of desorption were investigated and optimized. Methanol has been used as desorption solvent and the extracts were analysed on a reversed-phase octadecyl silica column using 0.02 M phosphate-buffer (pH = 6.02) acetonitrile (65 : 35 v/v) as the mobile phase and the effluents were measured at 202 nm with ultraviolet detector. The relative standard deviation (RSD%) of the method was investigated at three concentrations (25, 50, and 200 ng/mL) and was in the range of 3.98–9.83% (n = 6) for 50 ng/mL. The calibration curves obtained for studied drugs show reasonable linearity (R2 > 0.99) and the limit of detection (LODs) ranged between 2 and 7 ng/mL. Finally, the proposed method has been effectively employed in extraction and determination of the drugs in biological and environmental samples. PMID:24982923

  8. Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes

    SciTech Connect

    Nadanaciva, Sashi; Aleo, Michael D.; Strock, Christopher J.; Stedman, Donald B.; Wang, Huijun; Will, Yvonne

    2013-10-15

    To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors. Eleven NSAIDs, flufenamic acid, tolfenamic acid, mefenamic acid, diclofenac, meloxicam, sudoxicam, piroxicam, diflunisal, acetylsalicylic acid, nimesulide, and sulindac (and its two metabolites, sulindac sulfide and sulindac sulfone), were tested for their effects on (a) the respiration of rat liver mitochondria, (b) a panel of mechanistic endpoints in rat hepatocytes, and (c) the viability and organ morphology of zebrafish. We show good concordance for distinguishing among/between NSAID chemical classes in the observations among the three approaches. Furthermore, the assays were complementary and able to correctly identify “toxic” and “non-toxic” drugs in accordance with their human safety profile, with emphasis on hepatic and gastrointestinal safety. We recommend implementing our multi-assay approach in the drug discovery process to reduce compound attrition. - Highlights: • NSAIDS cause liver and GI toxicity. • Mitochondrial uncoupling contributes to NSAID liver toxicity. • ER stress is a mechanism that contributes to liver toxicity. • Zebrafish and cell based assays are complimentary.

  9. Isolated and combined effects of photobiomodulation therapy, topical nonsteroidal anti-inflammatory drugs, and physical activity in the treatment of osteoarthritis induced by papain

    NASA Astrophysics Data System (ADS)

    Tomazoni, Shaiane Silva; Leal-Junior, Ernesto Cesar Pinto; Frigo, Lúcio; Pallotta, Rodney Capp; Teixeira, Simone; de Almeida, Patricia; Bjordal, Jan Magnus; Lopes-Martins, Rodrigo Álvaro Brandão

    2016-10-01

    Osteoarthritis (OA) is a chronic inflammatory disease and is characterized as a degenerative process. This study aimed to evaluate and compare the effects of a topical nonsteroidal anti-inflammatory drug (NSAID), physical activity, and photobiomodulation therapy (PBMT) applied alone and/or in combination between them in an experimental model of knee OA. OA was induced by injection of papain in the knees of rats. After 21 days, the animals started to be treated with the above treatment. Histological analysis shows that the experimental model of OA induction causes morphological changes consistent with the disease, and among treatments, the PBMT is the most effective for reducing these changes. Moreover, the results demonstrate that PBMT and NSAID reduce the total number of cells in the inflammatory infiltrate (p<0.05) and PBMT was the most effective for reducing the activity of myeloperoxidase (p<0.05). Finally, we observed that both NSAID and PBMT were effective for reducing the gene expression of MMP-3 (p<0.05), but in relation to the gene expression of MMP-13, PBMT was the most effective treatment (p<0.05). The results of this study indicate that PBMT is the most effective therapy in stopping disease progression, and improving inflammatory conditions observed in OA.

  10. Multi-spectroscopic method study the interaction of anti-inflammatory drug ketoprofen and calf thymus DNA and its analytical application

    NASA Astrophysics Data System (ADS)

    Guo, Hongqin; Cai, Changqun; Gong, Hang; Chen, Xiaoming

    2011-06-01

    Interactions of the anti-inflammatory drug ketoprofen with calf thymus DNA (ctDNA) in aqueous solution have been studied by multi-spectroscopic method including resonance light scattering (RLS) technique, ultraviolet spectra (UV), 1H NMR, etc. The characteristics of RLS spectra, the effective factors and optimum conditions of the reaction have been unequivocally investigated. Mechanism investigations have shown that ketoprofen can bind to ctDNA by groove binding and form large particles, which resulted in the enhancement of RLS intensity. In Critic acid-Na 2HPO 4 buffer (pH = 6.5), ketoprofen has a maximum peak 451.5 nm and the RLS intensity is remarkably enhanced by trace amount of ctDNA due to the interaction between ketoprofen and ctDNA. The enhancement of RLS signal is directly proportional to the concentration of ctDNA in the range of 1.20 × 10 -6-1.0 × 10 -5 mol/L, and its detection limit (3 σ) is 1.33 × 10 -9 mol/L. The method is simple, rapid, practical and relatively free from interference generated by coexisting substance, and was applied to the determination of trace amounts of nucleic acid in synthetic samples with satisfactory results.

  11. Electromembrane-surrounded solid-phase microextraction coupled to ion mobility spectrometry for the determination of nonsteroidal anti-inflammatory drugs: A rapid screening method in complicated matrices.

    PubMed

    Abedi, Hamid; Ebrahimzadeh, Homeira

    2015-05-01

    A new robust method of electromembrane-surrounded solid-phase microextraction coupled to ion mobility mass spectrometry was applied for nonsteroidal anti-inflammatory drugs determination in complex matrices. This is the first time that a graphene/polyaniline composite coating is applied in electromembrane-surrounded solid-phase microextraction method. The homemade graphene/polyaniline composite is characterized by a high electrical conductivity and thermal stability. The variables affecting electromembrane-surrounded solid-phase microextraction, including extraction time; applied voltage and pH were optimized through chemometric methods, central composite design, and response surface methodology. Under the optimized conditions, limits of detection of 0.04 and 0.05 ng/mL were obtained for mefenamic acid and ibuprofen, respectively. The feasibility of electromembrane-surrounded solid-phase microextraction followed by ion mobility mass spectrometry was successfully confirmed by the extraction and determination of low levels of ibuprofen and mefenamic acid in human urine and plasma samples and satisfactory results were obtained.

  12. Effect of substrate concentration on inhibition of prostaglandin synthetase of bull seminal vesicles by anti-inflammatory drugs and fenamic acid analogs.

    PubMed

    Cushman, D W; Cheung, H S

    1976-03-26

    Although microsomes of bull seminal vesicle synthesize prostaglandins F2alpha, E2 and D2 from arachidonic acid under suitable assay conditions, prostaglandin E2 is the only significant product at either low concentration of arachidonic acid or high concentration of microsomes. Studies of inhibition of prostaglandin synthesis in vitro by anti-inflammatory drugs at both high (1 mM) and low (1 muM) concentrations of arachidonic acid, suggest three distinct mechanisms of inhibition. Benzydamine and flazalone are non-competitive or weakly competitive with arachidonic acid and, at high concentrations of arachidonic acid, they augment sythesis of prostaglandin E2 while inhibiting production of prostaglandins F2alpha and D2. Niflumic acid and the arylacetic acids naproxen and ibuprofen are competitive inhibiting all products equally, but with 100-500-fold greater potency at the low substrate concentration. The fenamic acids, indomethacin, aspirin, and phenylbutazone also inhibit equally all prostaglandin products, but are only 20--50 times more potent at the low substrate concentration. Studies with analogs of the fenamic acids indicate that the diphenylamine protion of their structure is essential for inhibition of prostaglandin synthesis, whereas the o-carboxyl and m-alkul substitutents greatly enhance inhibitory potency.

  13. Nonsteroidal Anti-Inflammatory Drug and Aspirin Use, and Mortality among Critically Ill Pandemic H1N1 Influenza Patients: an Exploratory Analysis.

    PubMed

    Epperly, Holly; Vaughn, Frances L; Mosholder, Andrew D; Maloney, Elizabeth M; Rubinson, Lewis