Carbachol interactions with nonsteroidal anti-inflammatory drugs

The inhibition of cyclooxygenase enzymes by nonsteroidal anti-inflammatory drugs (NSAIDs) does not completely explain the antinociceptive efficacy of these agents. It is known that cholinergic agonists are antinociceptive, and this study evaluates the interactions between carbachol and some NSAIDs. Antinociceptive activity was evaluated in mice by the acetic acid writhing test. Dose-response curves were constructed for NSAIDs and carbachol, administered either intraperitoneally (i.p.) or intrathecally (i.t.). The interactions of carbachol with NSAIDs were evaluated by isobolographic analysis after the simultaneous administration of fixed proportions of carbachol with each NSAID. All of the drugs were more potent after spinal than after systemic administration. The combinations of NSAIDs and carbachol administered i.p. were supra-additive; however, the i.t. combinations were only additive. Isobolographic analysis of the coadministration of NSAIDs and carbachol and the fact that atropine antagonized the synergistic effect suggest that carbachol may strongly modulate the antinociceptive activity of NSAIDs; thus, central cholinergic modulation would be an additional mechanism for the antinociceptive action of NSAIDs, unrelated to prostaglandin biosynthesis inhibition.     

Tuberculosis and nonsteroidal anti-inflammatory drugs.

In 1980 and 1982 two case reports documented reactivation of pulmonary tuberculosis in patients who had used nonsteroidal anti-inflammatory drugs (NSAIDs). A case-control study was designed to test the hypothesis that such an association does exist. Data for 38 patients were obtained from the patients'' family physicians, and each patient was matched with a control from the same practice for age, sex, race and length of time in that practice. A statistically significant relation was found between the reactivation of tuberculosis and the use of NSAIDs. However, further research is imperative to determine whether the association is direct, indirect or secondary to an unknown factor. Physicians should keep in mind that NSAIDs are potent anti-inflammatory agents and may thus activate, spread and mask infections.     

Resolution of pseudophakic cystoid macular edema with combination therapy of topical corticosteroids and nonsteroidal anti-inflammatory drugs

A 69 years old women underwent uneventful cataract surgery of her left eye with phacoemulsification and posterior chamber intraocular lens implantation in topical anesthesia. Patient was postoperatively treated with combination of antibiotic and steroid in decreasing dosages during five weeks: one drop five times a day the first week, three times a day second to forth week and one time a day the fifth week. In each checkup, performed first postoperative day, 7 days, 5 weeks and 12 weeks after the operation, visual acuity with and without correction, tonometry, corneal transparency, biomicroscopy of posterior pole and measure of macular thickness by optical coherence tomography (OCT) were performed. At first day follow-up visit, the patient's visual acuity was 20/25 but 6 weeks after the operation, the patient's vision had worsened to 20/60 after a slow steroid tapper. At that time OCT showed foveal thickening and cystic changes specific for cystoid macular edema (CME). Combination of corticosteroid and non-steroidal anti-inflammatory drug four times daily was included in therapy. The dose was tapered off over the ensuing 8 weeks. The total treatment duration was 12 weeks. At the patient's 2-month follow-up visit, vision has improved to 20/20 and the fovea appeared flat. OCT showed complete resolution of foveal thickening and cystic changes. Combination of corticosteroid and NSAID is effective and safe therapy for treating pseudophakic CME. Patient showed significant improvement in visual acuity and retinal thickness at 2 months post treatment.     

Spectroscopic behavior of copper complexes of nonsteroidal anti-inflammatory drugs

The proposed curative properties of Cu-based nonsteroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous Cu(II) complexes of NSAIDs with enhanced anti-inflammatory activity. Crystalline complexes, Cu(II)-NSAID (ibuprofen, naproxen, tolmetin, and diclofenac), with a carboxylic function have been studied by means of infrared and Raman spectroscopy. All NSAIDs bind the metal through the carboxylate group. On the basis of the comparison between the wavenumber of the COO(-) group vibrations and Delta nu (nu(asimm)COO(-) - nu(simm)COO(-)) between Na salts and Cu(II) complexes, conclusions on the probable structure of the complexes have been drawn. The spectroscopic data support the formation of dimeric [Cu(2)L(4)(H(2)O)(2)] complexes in which the COO(-) group behaves as a bridging bidentate ligand. The low wavenumber region of the Raman spectrum provided information on Cu-O and Cu-Cu bonds in the complexes. Thermogravimetric results gave further support to the vibrational data.     

Low concentrations of nonsteroidal anti-inflammatory drugs affect cell functions

The effect of 10⁻¹⁴ − 10⁻⁴M ibuprofen and aspirin both on arachidonic acid metabolism in peritoneal murine macrophages and on the concanavalin A-induced proliferation of murine splenocytes were investigated. It was shown that 10⁻⁷ − 10⁻⁴M ibuprofen inhibits the arachidonic acid metabolism. On the other hand, 10⁻¹² −10⁻¹¹M ibuprofen causes pronounced activation of arachidonic acid metabolism. The low concentration (10⁻¹⁴ − 10⁻¹⁰M) effects also take place when non-steroidal anti-inflammatory drugs influence other functions of the immune system: that is, they activate the splenocyte mitogen-induced proliferative response. These results are in accord with our suggestion that the low concentration effects of these drugs do not depend upon cell types and may have an important physiological significance.     

Oxidants, inflammation, and anti-inflammatory drugs

Species such as superoxide radical (O2-), hydrogen peroxide (H2O2), hydroxyl radical (.OH), and hypochlorous acid (HOCl) can be formed in vivo, e.g., by activated phagocytic cells. Generation of .OH from H2O2 in vivo usually involves iron-dependent reactions. Good evidence exists for increased generation of oxidants in vivo in patients with active rheumatoid disease, but the contribution of these oxidants to the disease process is still uncertain. The likelihood that anti-inflammatory drugs used in the treatment of arthritis could act by scavenging oxidants or preventing their formation is discussed.     

R- and S-isomers of nonsteroidal anti-inflammatory drugs differentially regulate cytokine production

2-arylpropionic acids, a well known class of non-steroidal anti-inflammatory drugs (NSAIDs), exist as a racemic mixture of their enantiomeric forms, with S-isomers primarily responsible for inhibition of prostaglandin (PG) production and of inflammatory events. In this study we show that S-isomers are also responsible for the paradoxical up-regulation of tumor necrosis factor (TNF) induced by ketoprofen, flurbiprofen and ibuprofen in murine peritoneal macrophages stimulated by bacterial endotoxin (LPS). This effect is in close correlation with cyclooxygenase inhibitory capacity of S-isomers and, from Northern blot analysis, seems to be mediated by the up-regulation of TNF mRNA. In addition, up-regulation of TNF production by S-isomers is associated with inhibition of interleukin-10 (IL-10) production. Conversely, we have observed that S-enantiomers reduce IL-6 production at a concentration 100 times higher than that able to inhibit cyclooxygenase activity. The unwanted pro-inflammatory effects of S-isomers through TNF and IL-10 production could therefore hinder their analgesic effect, that is, at least in part, related to IL-6 inhibition. In addition, TNF amplification by S-isomers could be correlated to the clinical evidence of their gastric toxicity. On the other hand, R-isomers did not affect TNF and IL-10 production even at cyclooxygenase-blocking concentration, while they reduced IL-6 production to the same levels as S-isomers. It is concluded that the regulation of cytokine production by S-isomers of 2-arylpropionic acids could partially mask their therapeutic effects and could be correlated to the clinical evidence of their higher gastric toxicity. On the other hand, IL-6 inhibition without the unwanted effects on TNF and IL-10 production shown by R-isomers could be correlated to the analgesic effect reported for R-2-arylpropionic acids.     

Suppression of heat- and polyglutamine-induced cytotoxicity by nonsteroidal anti-inflammatory drugs.

We have shown that sodium salicylate activates the heat shock promoter and induces the expression of heat shock proteins (hsps), with a concomitant increase in the thermotolerance of cells. To determine whether these effects are generally displayed by nonsteroidal anti-inflammatory drugs (NSAIDs), we examined the effects of a cyclooxygenase inhibitor, indomethacin, and a lipoxygenase inhibitor, nordihydroguaiaretic acid. Both inhibitors up-regulated the hsp promoter at 37 degrees C through the activation of heat shock factors, and increased cellular levels of hsps in mammalian cells, although the degree of the expression of hsps and thermotolerance of cells differed depending on the drugs. Furthermore, NSAIDs such as sodium salicylate and indomethacin suppressed the protein aggregation and apoptosis caused by an expanded polyglutamine tract in a cellular model of polyglutamine disease. These findings suggest that NSAIDs generally induce the expression of hsps in mammalian cells and may be used for the protection of cells against deleterious stressors and neurodegenerative diseases.     

PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs.

PPARB was identified as a target of APC through the analysis of global gene expression profiles in human colorectal cancer (CRC) cells. PPARdelta expression was elevated in CRCs and repressed by APC in CRC cells. This repression was mediated by beta-catenin/Tcf-4-responsive elements in the PPARdelta promotor. The ability of PPARs to bind eicosanoids suggested that PPARdelta might be a target of chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs). Reporters containing PPARdelta-responsive elements were repressed by the NSAID sulindac. Furthermore, sulindac was able to disrupt the ability of PPARdelta to bind its recognition sequences. These findings suggest that NSAIDs inhibit tumorigenesis through inhibition of PPARdelta, the gene for which is normally regulated by APC.     

Patients, their doctors, nonsteroidal anti-inflammatory drugs and the perception of risk

This article is about risk. Risk is probably the most misunderstood component in determining therapeutic intervention; however, it is probably the most relevant issue to consider in the context of expected benefit. The rarity of quantitative risk–benefit assessment and the lack of comparative risk–benefit when alternative therapies exist for a given condition leads to inadequate decisions. Without some quantitation of the risks associated with specific therapies, doctors and patients cannot make optimal risk–benefit calculations. Patients may abandon effective therapies for which benefits may still outweigh risks, or opt for therapies with less well-publicized potential adverse events of even greater frequency or severity. When only small incremental benefits accrue to patients from the use of a given therapy, on the other hand, even very rare serious events may play a role in decision-making by patients, by their health care providers and by regulatory authorities.     

Interaction of nonsteroidal anti-inflammatory drugs with membranes: In vitro assessment and relevance for their biological actions

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world due to their anti-inflammatory, analgesic and antipyretic properties. Nevertheless, the consumption of these drugs is still associated with the occurrence of a wide spectrum of adverse effects. Regarding the major role of membranes in cellular events, the hypothesis that the biological actions of NSAIDs may be related to their effect at the membrane level has triggered the in vitro assessment of NSAIDs-membrane interactions. The use of membrane mimetic models, cell cultures, a wide range of experimental techniques and molecular dynamics simulations has been providing significant information about drugs partition and location within membranes and also about their effect on diverse membrane properties. These studies have indeed been providing evidences that the effect of NSAIDs at membrane level may be an additional mechanism of action and toxicity of NSAIDs. In fact, the pharmacokinetic properties of NSAIDs are closely related to the ability of these drugs to interact and overcome biological membranes. Moreover, the therapeutic actions of NSAIDs may also result from the indirect inhibition of cyclooxygenase due to the disturbing effect of NSAIDs on membrane properties. Furthermore, increasing evidences suggest that the disordering effects of these drugs on membranes may be in the basis of the NSAIDs-induced toxicity in diverse organ systems. Overall, the study of NSAIDs-membrane interactions has proved to be not only important for the better understanding of their pharmacological actions, but also for the rational development of new approaches to overcome NSAIDs adverse effects.     

Scavenging of reactive oxygen species by some nonsteroidal anti-inflammatory drugs and fenofibrate

Ketoprofen and tolmetin are widely used nonsteroidal anti-inflammatory drugs, whereas fenofibrate belongs to a family of hypolipidemic drugs used in the prevention of cardiovascular diseases. The aim of this study was to assess effect of these drugs on reactions generating reactive oxygen species (ROS). The following generators of ROS were used: 18-crown-6/KO(2) dissolved in DMSO as a source of superoxide radical (O(.-)(2), the Fenton-like reaction (Cu/H(2)O(2)) for hydroxyl radical (HO(.)), 2,2'-azobis (2-amidino-propane) dichloride (AAPH) as peroxyl radical (ROO(.)) generator, and a mixture of alkaline aqueous H(2)O(2) and acetonitrile for singlet oxygen ((1)O(2)). Measurements were done using chemiluminescence, fluorescence, and spin-trapping with 2,2,6,6-tetramethylpiperidine combined with electron spin resonance spectroscopy (ESR), and a deoxyribose assay based on the spectrophotometry. The results obtained demonstrated that all tested drugs were active against O(.-)(2). There was a clear ranking of drug inhibition effects on chemiluminescence from the O(.-)(2) system: ketoprofen > tolmetin > fenofibrate. The examined compounds inhibited the HO(.)-dependent deoxyribose degradation and scavenged the ROO(.) concentration dependently with an order of potencies similar to that of the superoxide radical system. Hence, these results indicate that the studied drugs show broad ROS scavenging property and, as a consequence, might decrease tissue damage due to the ROS and thus to contribute to anti-inflammatory therapy.     

Cyclooxygenase as a target for the antiamyloidogenic activities of nonsteroidal anti-inflammatory drugs in Alzheimer's disease

A large number of epidemiological studies have addressed the possible protective effect of anti-inflammatory drug use with regard to Alzheimer's disease (AD). The most convincing of these studies--the Baltimore Longitudinal Study of Aging--utilized data collected prospectively, thereby minimizing recall bias issues. However, despite this evidence, therapeutic studies investigating nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-1 (COX-1) and COX-2 inhibitors and steroids, do not support this hypothesis. This discrepancy may be due to the fact that the bulk of epidemiological evidence has examined the likely incidence of AD prior to the onset of clinical symptoms of disease. On the basis of this information, the article will attempt to formulate a possible scenario, in which optimal NSAIDs might be tested in the most favorable clinical therapeutic conditions in order to determine whether NSAIDs can provide beneficial treatment for the clinical progression of AD dementia.