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At least 163 records · Page 9Linked to original sources
PubMed2005

Effect of anti-inflammatory drugs on splenocyte membrane fluidity.

In this study, fluorescence anisotropy measurements were performed using the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene to investigate the effects on membrane fluidity resulting from the interaction between nonsteroidal anti-inflammatory drugs (NSAIDs)-indomethacin, diclofenac, piroxicam, tenoxicam, indoprofen, clonixin, and etodolac-and mouse splenocyte membranes. This study was performed in splenocyte membranes because most of the fluidity studies have been performed in membrane models; thus, clear correlations of the pharmacological action of drugs with molecular effects at the cellular membrane level were lacking. Besides providing a basis for studying the molecular mechanism of pharmacological action of NSAIDs, this research provides a data analysis of steady-state anisotropy measurements, taking into account that the probe itself strongly influences the data given that this problem is usually overlooked. Results show that the anti-inflammatory drugs indomethacin, diclofenac, piroxicam, and tenoxicam increase the membrane fluidity in a concentration-dependent manner. Their order of effectiveness reflected in their respective IC50 values (concentration of each NSAID required to increase the fluidizing effect ratio by 50%) is as follows: tenoxicam>piroxicam>indomethacin>clonixin. For the other drugs, the perturbation in membrane fluidity is not evident under these circumstances.

Animals↗
PubMed2004

Cationic vesicles as chiral selector for enantioseparations of nonsteroidal antiinflammatory drugs by micellar electrokinetic chromatography.

A vesicle-forming chiral cationic surfactant (1R,2S)-(-)-N-dodecyl-N-methyl-ephedrinium bromide was evaluated as a pseudo-stationary phase in micellar electrokinetic chromatography (MEKC) for enantioseparation of eight non-steroidal anti-inflammatory drugs e.g., carprofen, flurbiprofen, fenoprofen, ibuprofen, indoprofen, ketoprofen, naproxen and suprofen by capillary electrophoresis. The effects of varying experimental conditions such as pH and concentration of surfactant in the running buffer on the enantiomer separation of the drugs are reported. A mixture of five of the above drugs was separated and each enantiomeric pair was also separated simultaneously in a single run by use of the surfactant. The strong electrostatic interactions between the analytes and the vesicles seemed to have a major role in the enantiomeric separation of the profens.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Investigating the potential of erythromycin and derivatives as chiral selector in capillary electrophoresis.

Macrocyclic antibiotics are present in an increasing number of chiral separation applications. In this study, erythromycin and some derivatives, belonging to the group of macrolide antibiotics, were investigated for their potential as chiral selector. Erythromycin A itself and five related substances namely erythromycin A N-oxide, anhydroerythromycin A, anhydroerythromycin A N-oxide, erythralosamine and erythralosamine N-oxide were included. Twenty-one chiral compounds with a wide difference in physico-chemical properties were used to test the chiral activity of the erythromycins. The chiral compounds were analysed using capillary zone electrophoresis with the erythromycins dissolved in the running buffer at different concentrations ranging from 0.1 to 10mM, with three different BGEs: sodium phosphate pHs 3.0 and 7.0 and sodium borate pH 9.2. The erythromycins showed more interactions with the acidic compounds (as observed with leucovorin, dopa, carbidopa, ketoprofen, indoprofen and warfarin) than with the neutral or weakly basic ones, especially in acidic medium. Unfortunately, no chiral separations were obtained for any of the 21 racemic mixtures. The complexation constants were calculated for the compounds showing interaction, based on the variation of electrophoretic mobility of the compounds in the presence of different concentrations of erythromycins. Finally, the size of erythromycin A was calculated using computational modelling. It was shown that the aglycone ring is only half as big as the beta-cyclodextrin cavity, giving a possible explanation for the negative response of erythromycin in this study.

Buffers↗
PubMed2002

Capillary electrochromatographic separation of non-steroidal anti-inflammatory drugs with a histidine bonded phase.

An open tubular wall-coated capillary column containing histidine functional groups was prepared and employed for the capillary electrochromatographic separation of non-steroidal anti-inflammatory drugs. The anion exchange along with the hydrogen bonding and hydrophobic properties of the surface coating allowed the separation of analytes with very similar ionic mobility. Selectivity and resolution were studied by changing the pH over the range from 3.5 to 5.0 and the concentration of the buffer from 10 to 25 mM, as well as variation of the organic modifier, such as methanol, ethanol and 1-propanol over the range 7.5 to 20%. The optimum experimental conditions for the separation of a drug mixture, which consisted of indoprofen, ketoprofen, suprofen, naproxen, flurbiprofen, fenoprofen and ibuprofen were using a mixture of acetate buffer (20 mM, pH 5.0)-ethanol (1:5, v/v) as background electrolyte and an applied voltage of -20 kV with UV detection at 220 nm. The separation of these drugs could be achieved with an average plate number of 1.0 x 10(5) m(-1).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Cationic beta-cyclodextrin derivative for chiral separations.

A novel hepta-substituted beta-cyclodextrin bearing the methoxyethylamine group linked to the upper cyclodextrin rim was successfully used as a chiral selector for enantiomeric separation of non-steroidal anti-inflammatory drugs (NSAIDs) and phenoxypropionic acid herbicides (PPAHs). Separation parameters such as pH and concentration were found to have major influences on enantiomeric resolution of the NSAIDs and PPAHs. Results indicate that heptakis(6-methoxyethylamine-6-deoxy)-beta-cyclodextrin [beta-CD-OMe (VII)] performs exceptionally well for the enantiomeric resolution of NSAIDs: indoprofen and fenoprofen (Rs = 11 and 14, respectively). In addition, baseline enantiomeric separation of a mixture of six pairs of PPAHs was achieved in under 30 min. Compared to other cationic beta-cyclodextrins reported in the literature, the beta-CD-OMe (VII) showed improved selectivity for both classes of the aforementioned anionic racemates.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1983

Indomethacin and sulindac inhibition of ACTH stimulated cortisol release from adrenal glands in vitro.

In slices of adrenal glands of guinea pig added ACTH (from femtograms to picograms levels) stimulates cortisol synthesis and release. This effect is antagonized in a non-linear competitive way by indomethacin (KE = 1.3 .10(-7)) and by sulindac (KI = 6.9 .10(-10)); indoprofen is a very weak antagonist. A number of other non-steroid antiinflammatory drug are ineffective as antagonists of ACTH.

Adrenal Glands↗
PubMed1997

Determination of dexamethasone in tears by capillary electrophoresis.

A selective capillary zone electrophoresis (CZE) microassay was developed for the simultaneous determination of dexamethasone phosphate and its major metabolite, dexamethasone, in tears. The calibration was carried out in the biological matrix with indoprofen as an internal standard which allowed the separation of dexamethasone phosphate and dexamethasone from the tear constituents. The limits of detection and quantification of the assay were 0.5 and 2.0 microg ml(-1), respectively. This quantification method is essential for the in vivo determination of dexamethasone concentration-time profiles in tears after application of the antiinflammatory drug.

Administration, Topical↗
PubMed1996

MOAT4, a novel multispecific organic-anion transporter for glucuronides and mercapturates in mouse L1210 cells and human erythrocytes.

Glucuronides and mercapturates were examined as possible high-affinity substrates for a low-affinity ATP-dependent transport system for 2,4-dinitrophenyl S-glutathione (DNP-SG) in mouse L1210 cells. Initial inhibitor studies with inside-out vesicles revealed that the low-affinity transport of [3H]DNP-SG (Km 450 microM) exhibits a high sensitivity to N-acetyl 2,4-dinitrophenyl cysteine (NAc-DNP-Cys) (Ki 5.0 microM) and alpha-naphthyl beta-D-glucuronide (naphthyl glucuronide) (Ki 8.5 microM). Direct transport measurements showed the presence of ATP-dependent uptake activities for NAc-DNP-[35S]Cys and naphthyl [14C] glucuronide, and Km values for half-maximal transport were comparable to the Ki values of these compounds for inhibition of [3H]DNP-SG transport. Transport of [3H]DNP-SG, NAc-DNP-[35S]Cys and naphthyl [14C]glucuronide each showed the same sensitivity to various anions and anion conjugates. Inhibition was competitive and was most potent for bilirubin ditaurate, indoprofen, 4-biphenylacetic acid, 4-acridine 4 beta-D-glucuronide, N-acetyl leukotriene E4, 17 beta-oestradiol 3 beta-D-glucuronide and taurolithocholate 3-sulphate. Inside-out vesicles from human erythrocytes contain a comparable ATP-dependent transport system. These results show that NAc-DNP-Cys and naphthyl glucuronide are high-affinity substrates for a single system identified previously as a low-affinity transporter of DNP-SG. Substrate and inhibitor studies identify this system as a novel multispecific organic-anion transport system (MOAT4) that accommodates glucuronides and mercapturates and is distinct from other MOAT transporters. Human erythrocytes contain an additional ATP-dependent system for NAc-DNP-Cys (Km 33 microM) that does not transport monoglucuronides.

Acetylcysteine↗
PubMed1998

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii.

The fungus Verticillium lecanii has previously been shown to be capable of inverting the chirality of ibuprofen and 2-phenylpropionic acid from the (R)-enantiomer to the corresponding (S)-antipode, a phenomenon also observed in mammalian systems including man. An investigation is reported here into the substrate specificity of the enzyme system present in V. lecanii using the following 2-arylpropionic acids: ibuprofen, ketoprofen, indoprofen, suprofen, flurbiprofen and fenoprofen, together with the structurally related compounds 2-phenylbutyric acid, 2-phenoxypropionic acid, mandelic acid, atrolactic acid, etodolac and alpha-methoxyphenylpropionic acid. The results demonstrated that V. lecanii is capable of inverting the chirality of all the 2-arylpropionic acids investigated. All were inverted in the (R) to (S) direction with the exception of ketoprofen, where inversion was observed in the reverse direction. Using the structurally related compounds as substrates, the size of the alkyl substitutent at the alpha-carbon at the methyl group, and the presence of the methyl group at the chiral centre, were found to be critical. These results suggest that V. lecanii could be used as a basis for the production of pure enantiomers of the 2-arylpropionic acids in commercial biotransformations.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

ATP-dependent efflux of 2,4-dinitrophenyl-S-glutathione. Properties of two distinct transport systems in inside-out vesicles from L1210 cells and a variant subline with altered efflux of methotrexate and cholate.

The transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG) into inside-out vesicles from L1210 cells was employed to identify and characterize ATP-dependent efflux routes for DNP-SG. Measurements of ATP-dependent uptake at varying concentrations of [3H]DNP-SG revealed the presence of two distinct transport systems. Transport at low substrate concentrations occurred predominantly via a high affinity system (Km = 0.63 microM), whereas a low affinity system (Km = 450 microM) predominated at high concentrations of substrate. The high affinity system was characterized by a potent inhibition by the glutathione conjugates of bromosulfophthalein (Ki = 0.09 microM) and ethacrynic acid (Ki = 0.44 microM), leukotriene C4 (Ki = 0.20 microM), and the taurate diconjugate of bilirubin (Ki = 0.10 microM). The low affinity transport system for DNP-SG exhibited a high affinity for bilirubin ditaurate (Ki = 1.8 microM), indoprofen (Ki = 3.0 microM), and biphenylacetic acid (Ki = 5.9 microM). Different results were obtained with an L1210/C7 variant which has a defect in the efflux of methotrexate and cholate. Vesicles from the latter cells contain the same low affinity transport activity as parental cells, but the high affinity route is absent and has been replaced by a system with an intermediate affinity for DNP-SG (Km = 4.5 microM). These results indicate that L1210 cells contain two unidirectional efflux pumps for DNP-SG with substantial differences in inhibitor sensitivity. The high affinity system shows a binding preference for glutathione conjugates but can also accommodate large anionic conjugates, whereas the low affinity system has a binding preference for large organic anions. Results with the variant cells support the hypothesis that the high affinity transport system for DNP-SG also mediates the unidirectional efflux of methotrexate and cholate in intact L1210 cells.

Adenosine Triphosphate↗
PubMed1987

Nonsteroidal antiinflammatory drugs induce UV-dependent histamine and leukotriene release from peripheral human leukocytes.

The effect of UV-A radiation on the in vitro release of vasoactive mediators from human peripheral leukocytes incubated with different nonsteroidal antiinflammatory drugs (NSAIDs) was studied in the newly developed photo basophil histamine release test (PBHRT). Washed peripheral leukocytes were incubated with 10(-6) to 10(-3) M of various NSAIDs and exposed to 1-100 J/cm2 UV-A. Maximum histamine release was 4% with acetylsalicylic acid, 10% with benoxaprofen, 20% with thiophene, 28% with diclofenac, 39% with tiaprofenic acid, 40% with carprofen, 55% with ketoprofen and not demonstrable with indoprofen. Maximal reactions occurred at UV-A doses of 25 or 50 J/cm2. Leukotriene B4 (LTB4) generation in the supernatants of cells treated with UV-A or NSAID alone was below or close to the detection limit (145 pg/ml). On the contrary, UV-A irradiation of cells incubated with NSAID led to marked LTB4 generation (up to 1,000 pg/ml). The results indicate that many NSAIDs can induce photosensitization in vitro, the PBHRT being a promising new method for identification of possibly phototoxic compounds. Release of vasoactive mediators like histamine or leukotrienes may be involved in the in vivo development of phototoxic or photoallergic side reactions.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1977

Application of nonparametric procedure for bioassay data to the evaluation of analgesics in man.

Parametric tests for bioassay data are commonly applied to scores of pain intensity and relief for the assessment of potency ratios of analgesic drugs. It has been demonstrated, however, that scores derived from semiquantitative scales often deviate from normal distribution. In addition, when scores decrease as a consequence of analgesic treatment, the variances may be nonhomogenous. Both parametric and nonparametric procedures have been employed in this study for the evaluation of results of a double-blind multicenter trial of the analgesic effect of indoprofen and ASA (both drugs at three dose levels) and placebo in episiotomy pain. There was a good agreement between potency ratios obtained with the two assays. Peak PID appeared a less efficient means of estimating potency ratio than other measurements such as SPID and TOTPAR. The nonparametric test for quantitative bioassay appears to be a valid statistical procedure for evaluating results of clinical trials, and it does not imply any assumptions as to the type of distribution of the data.

Adolescent↗
PubMed1993

Protein binding and stereoselectivity of nonsteroidal anti-inflammatory drugs.

Stereoselective binding of nonsteroidal anti-inflammatory drugs (NSAIDs) can be studied using various techniques. Thus the results obtained by different investigators may be poorly consistent and even contradictory. NSAIDs are bound stereoselectively to serum albumin to different degrees depending on the drug investigated (ibuprofen, indoprofen, carprofen, etodolac, ketoprofen and flurbiprofen). For other drugs, both enantiomers are bound to a similar extent (pirprofen, fenoprofen). This stereoselectivity could vary with experimental conditions, in particular with protein concentration (ketoprofen, etodolac), leading to individual differences. Finally, the stereoselectivity of protein binding and of pharmacokinetics can be compared: differences in binding between enantiomers can explain their differences in pharmacokinetics, once metabolic properties such as inversion have been taken into account.

Animals↗
PubMed1989

Evaluation of the efficacy and safety of NSAIDs. A new methodological approach.

When rheumatic patients were questioned concerning the most desired attributes for a nonsteroidal anti-inflammatory drug (NSAID), the majority of replies related to tolerability. For example; low frequency of gastrointestinal side-effects, safety in the elderly, a low frequency of renal side-effects and a superior anti-inflammatory effect than other drugs available, were all regarded as important NSAID properties. This focus on safety issues by patients is probably due to problems experienced in recent years with non-steroidals on the market. In particular, the withdrawal of benoxaprofen was of major concern for both doctors and patients, and this together with other events over the last few years has not really contributed to an improvement of the relationship between rheumatic patients and doctors. The NSAIDs which have experienced problems and resulted in withdrawal from the market are as follows: benoxaprofen (Coxigon), indoprofen (Flosin), indomethacin (Osmosin, Osmogit), isoxicam (Pacyl) and oxyphenbutazone (Tanderil). Additionally, there were restrictions on the usage of phenylbutazone. This has resulted in the major authorities requiring more data concerning safety issues. The following paper will discuss an overview of the methodology which is now used in the development of a NSAID, using data and procedures obtained from the evaluation of tenoxicam.

Adult↗
PubMedDate not supplied

Recognition of cyclooxygenase-2 (COX-2) active site by NSAIDs: a computer modelling study.

The energetics and models of COX-2 complexed with nonsteroidal anti-inflammatory drugs (NSAIDs) having different degrees of selectivity for two isoforms of COX (COX-2 and COX-1) have been studied using computer modelling approach. The models are obtained for complexes of NS398 (NS), a selective COX-2 inhibitor; indoprofen (Ind), a non-selective inhibitor; di-tert-butylbenzofurans (DHDMBFs) with substituents at the 5th position: CONH(CH2)2OMe (BF1), CONH-c-Pr (BF2), 3-methylene-gamma-butyrolactonyl (BF3) and oxicams namely, meloxicam (Mel), piroxicam (Pir) and tenoxicam (Ten). These were optimized using molecular mechanics (MM) and molecular dynamics (MD) techniques. The binding energies and structures were compared with pharmacological parameters and available results with COX-1. In case of NS a larger difference in the binding energies between COX-2 and COX-1 was noticed as compared to that of Ind. It also had stronger interaction with His90 and Tyr355 which is considered important for COX-2 selectivity. There was a difference in the compactness at the channel entrance between COX-2 selective and non-selective ligands. Models with DHDMBFs and oxicams showed a similar correlation. The results were used to design a peptide inhibitor, Tyr-Arg-Cys-Ala-delta Phe-Cys (Pept) which could fit better in the COX-2 cavity. As per our MD simulation results this peptide inhibitor showed both higher activity and COX-2 selectivity.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Evidence for the existence of a specific binding site for indomethacin on bovine vesicular gland microsomes.

Using bovine vesicular gland microsomes and [14C]indomethacin we demonstrated the presence of a specific binding site for nonsteroidal anti-inflammatory drugs. Specific binding of [14C]indomethacin to microsomes was rapid, with most of the ligand bound by 2 min at 4 degrees C. In routine binding assays the incubation temperature was maintained at 4 degrees C, because the maximal specific binding was obtained. Specific [14C]indomethacin binding appeared to increase linearly with increasing protein concentration over the range of 0.1-1.0 mg of microsomal protein. Specific binding was saturable and Scatchard analysis of binding data showed a single class of binding sites with a dissociation constant (Kd) of 3.8 microM and a maximal number of binding sites (Bmax) of about 1272 pmol/mg of protein. When these binding data were plotted according to the Hill equation, a straight line was obtained with a Hill coefficient of 1.0. Structural specificity of the nonsteroidal anti-inflammatory drug site was studied with diclofenac, arylpropionic acids (ketoprofen and indoprofen), and aspirin. Diclofenac and arylpropionic derivatives were able to compete with [14C]indomethacin for binding to microsomes, while aspirin was a weak inhibitor.

Animals↗
PubMed1986

Duodenogastric reflux and gastric damage from non-steroidal antiinflammatory drugs.

The authors describe cases urgently admitted for iatrogenic gastric lesions due to non-steroid antiinflammatory treatment during the past year. Nine patients were affected by peptic ulcer (bleeding in five cases), while in the remaining 11 an erosive acute gastritis could be observed. Among them, ten patients had been taking acetylsalicylic acid, one indomethacin and the others ketoprofen, indoprofen or similar drugs. In 11 patients, five presenting gastric ulcer and six affected by haemorrhagic gastric damage, an evident duodenogastric reflux was demonstrated. Fifteen patients were treated pharmacologically and complete healing of the lesions was obtained, while in five patients surgical treatment was necessary. The authors conclude by pointing out the high incidence (over 50%) and the pathogenetic role of duodenogastric reflux in gastric lesions appearing in patients treated with non-steroidal antiinflammatory drugs.

Adult↗
PubMed1985

In vivo phototoxicity of non-steroidal anti-inflammatory drugs evaluated by the mouse tail technique.

Skin photosensitivity is a side-effect reported for several non-steroidal anti-inflammatory drugs (NSAID). In vitro studies have revealed phototoxic properties in a majority of these compounds with a preponderance for derivatives of propionic acid. Fourteen NSAIDs, the majority commercial preparations in clinical use, have been assayed by the mouse tail technique for in vivo phototoxicity evaluation. Intraperitoneal single doses in the range 12.5-200 mg/kg were given in combination with UVA irradiation for 5 h (total dose 54 J/cm2). The phototoxic reaction was measured 24 h later as the wet weight increase of tail tissue over non-irradiated, drug-treated controls. Four out of 9 propionic acid derivatives were phototoxic: tiaprofenic acid, carprofen, benoxaprofen and naproxen. Among NSAID compounds of other chemical structure only diclofenac and diflunisal were weakly photoactive. The propionic acid derivatives fenoprofen, flurbiprofen, ibuprofen, indoprofen and ketoprofen were negative, as were azapropazone, piroxicam and sulindac among the unrelated compounds. Phototoxicity is one important aspect of NSAID photosensitization. It is advisable to perform predictive studies including in vivo models, such as the mouse tail technique, before new NSAIDs are introduced on the market.

Animals↗