Contribution of cAMP to the inhibitory effect of non-steroidal anti-inflammatory drugs in rat uterine smooth muscle

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Effects of phenylbutazone, tolbutamide, and clofibric acid on binding of racemic warfarin and its enantiomers to human serum albumin

The effect of phenylbutazone, tolbutamide, and clofibric acid on the binding of racemic warfarin and its enantiomers to human serum albumin was studied by equilibrium dialysis. Warfarin had one primary and two secondary binding sites on the albumin molecule. No difference in binding was detected at the primary binding site; the extent of R(+)-isomer binding at the secondary binding sites was 2.5 times greater than the corresponding S(-)-isomer binding. Phenylbutazone and warfarin appear to compete for the same primary binding site on the albumin molecule. Tolbutamide interferes with the binding of warfarin enantiomers at their secondary sites. Clofibric acid has a less pronounced effect on warfarin binding than does phenylbutazone or tolbutamide.     

Drug therapy reviews: antirheumatic agents.

The pathophysiology, symptoms and drug treatment of rheumatic disease are reviewed. Antirheumatic drugs reviewed are salicylates (including aspirin, sodium salicylate, choline salicylate, choline magnesium salicylate, salsalate), phenylpropionic acid derivatives (fenoprofen, ibuprofen, naproxen), indole derivatives (sulindac, tolmetin and indomethacin), pyrazolone derivatives (phenylbutazone, oxyphenbutazone), gold compounds, penicillamine, antimalarials mefenamic acid, corticosteroids and immunosuppressives. Simple analgesic therapy (acetaminophen, aspirin, propoxyphene) is used in the early stage of the disease. As the disease progresses, aspirin remains the drug of choice for antiinflammatory activity but the phenylpropionic acid or indole derivatives may be preferred in patients unable to tolerate salicylates. If such nonsteroidal antiinflammatory agents are not effective, parenteral therapy with gold compounds or oral penicillamine usually is indicated. Indomethacin or phenylbutazone, then antimalarials, are resorted to next. Corticosteroids or immunosuppressives are reserved for patients who are unsuccessfully controlled or who have major side effects with the other drugs. Mefenamic acid occupies a very secondary place in rheumatoid arthritis treatment.     

Protein binding of non-steroidal anti-inflammatory drugs in plasma and synovial fluid of arthritic patients

1 The protein binding of seven non-steroidal anti-inflammatory drugs (indomethacin, tolmetin, salicylic acid, ibuprofen, flurbiprofen, naproxen and GP53,633) and warfarin was investigated by equilibrium dialysis in simultaneous samples of synovial fluid and plasma from 12 arthritic patients. 2 The protein binding of all drugs studied except warfarin and flurbiprofen was significantly lower in synovial fluid than in plasma. 3 The decreased protein binding of these drugs is likely to explain the lower total drug concentrations found in synovial fluid in comparison to plasma. 4 The lower albumin concentration plays an important role in determination of reduced drug binding in synovial fluid compared to plasma and the fatty acid concentration in synovial fluid may also influence the protein binding of some of these drugs.     

Structural requirements for binding of nonsteroidal anti-inflammatory drugs to human serum albumin

The binding of representative chemical classes of nonsteroidal anti-inflammatory drugs (NSAIDs) to human serum albumin (HSA) was investigated by equilibrium dialysis. Warfarin enantiomers were used as specific markers in displacement studies. Data were analyzed by a computerized nonlinear least squares approach designed for binding of small ligands to macromolecules at equilibrium. The binding data indicated comparable affinities to the primary site by the warfarin enantiomers, phenylbutazone, and meclofenamate sodium. Naproxen, sulindac, and zomepirac showed lower affinity by one order of magnitude. The displacement data revealed stereoselectivity. The R(+) isomer was displaced to a significantly greater extent than the S(-) isomer by meclofenamate sodium, while the reverse was observed for phenylbutazone. Naproxen displaced both isomers to the same extent. No significant displacement of either isomer was seen with sulindac or zomepirac. Examination of the chemical structures of the high affinity compounds indicated the common feature of a hydrophobic area bearing a widely delocalized negative charge. Hydrophobic binding of these compounds to HSA at the warfarin site is possibly stabilized by the attraction of the delocalized negative charge to the basic lysine and arginine residues adjoining the lone tryptophan.     

In-vitro protein binding interaction between a metabolite of triflusal, 2-hydroxy-4-trifluoromethylbenzoic acid and other drugs.

2-Hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of triflusal, an antiplatelet drug. The in-vitro binding of HTB to human serum was studied in the presence of different drugs. The results indicate that no statistically significant changes are observed in the HTB binding in the presence of caffeine, theophylline, glisentide, enalapril, cimetidine or warfarin. The free fraction of HTB increases significantly in the presence of the non-steroidal anti-inflammatory drugs studied: diclofenac, ibuprofen, indomethacin, naproxen, piroxicam and salicylic acid. At high concentrations, HTB displaces these anti-inflammatory drugs and also glisentide and warfarin from their protein binding sites.     

Drugs and gastric damage.

The effects of aspirin, salicylate formulations and substitutes, smoking (nicotine), indomethacin, corticosteroids, phenylbutazone, ethanol, caffeine and reserpine on the gastric mucosa are discussed. The damaging effects of the drugs are considered in terms of the gastric mucosal barrier, gastric erosions, microbleeding and haematemesis and melaena and finally whether they cause peptic ulcer. There is suggestive evidence that unbuffered aspirin is a cause of haematemesis and melaena and of gastric ulcer but the incidence rates for hospital admission are low, being 10 to 15 per 100,000 heavy users per year. Aspirin in solution as acetylsalicylate buffered to maintain a neutral pH protects against gastric damage. Newer aspirin substitutes (mefenamic acid, fenoprofen, naproxen, tolmetin and ibuprofen) appear to cause less faecal blood loss than aspirin but their long-term effects have not been fully evaluated. Smoking is definitely associated with peptic ucler but the mechanism is unknown. Corticosteroids are probably not ulcerogenic despite clinical bias that they are. Indomethacin and phenylbutazone may be ulcerogenic but there is insufficient evidence to make firm judgements. Ethanol, caffeine and reserpine, on available evidence, are probably not ulcerogenic.     

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

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.     

Stereoselective disposition of ibuprofen enantiomers in man.

This study has examined the stereoselective disposition of the enantiomers of ibuprofen in four healthy male subjects following separate administration of racemic ibuprofen (800 mg) and of each enantiomer (400 mg). A mean of 63 +/- 6% of an administered dose of R(-) ibuprofen was stereospecifically inverted to the S(+) enantiomer. There were no measurable inversion of the S(+) to R(-) ibuprofen. The kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode. It is likely that this change reflects an interaction between the enantiomers at plasma protein binding sites. It was found that formation of ester glucuronide conjugates stereoselectively favoured the S(+) enantiomer. The data have demonstrated that the pharmacokinetics of ibuprofen and other alpha-methylarylacetic acids cannot be interpreted adequately without studying the pharmacokinetics of the individual enantiomers.     

Pyrogenic fever and blood plasma glucocorticoids after nonsteroid anti-inflammatory drugs

Rabbits were injected with the lipopolysaccharide from E. coli (LPS) and received orally nonsteroid anti-inflammatory drugs (NSAIDs): acetylsalicylic acid, indomethacin, mefenamic acid, ibuprofen, aminophenazone, metamizole sodium, and phenylbutazone. These NSAIDs exerted antipyretic action without inhibiting the increase in the level of plasma glucocorticoids induced by LPS. This finding indicates the lack of correlation between the pyrogenic action of bacterial pyrogen and pyrogenic increase in the plasma glucocorticoid level. The investigated NSAIDs when given alone to normothermic rabbits differently affected the plasma glucocorticoid level: acetylsalicylic acid, indomethacin and ibuprofen depressed the plasma level of these hormones, mefenamic acid and phenylbutazone elevated it, and aminophenazone and metamizole sodium did not alter it significantly.     

Effect of rutin on warfarin anticoagulation and pharmacokinetics of warfarin enantiomers in rats

Objectives The effects of the flavonoid rutin on the anticoagulant activity of oral warfarin and the protein binding and pharmacokinetics of its enantiomers were investigated in rats. Methods A single dose of racemic warfarin, 1.5 mg/kg, was administered orally to rats either alone or on day 5 of an 8‐day oral regimen of rutin, 1 g/kg daily. Results Rutin reduced the anticoagulant effect of racemic warfarin, evident as a 31% reduction in the area under the prothrombin complex activty–time curve (P < 0.05). Key findings Rutin had no apparent effect on pre‐treatment baseline blood coagulation. It enhanced the in‐vitro serum protein binding of S‐ and R‐warfarin (reflected by 40% and 26% reductions in unbound fraction, respectively), and thus restricted distribution by 33 and 21%, respectively. Treatment with rutin significantly decreased the elimination half‐life of S‐warfarin by 37% as a result of the 69% increase in unbound clearance of the S‐enantiomer. This effect was attributed to a significant 77% increase in the unbound formation clearance of the overall oxidative and reductive metabolites, and an increase in the unbound renal clearance of the more potent S‐enantiomer of warfarin. Conclusions Concurrent rutin administration is likely to reduce the anticoagulant effect of racemic warfarin, reflecting a significant decrease in the elimination half‐life of the more potent S‐enantiomer.     

Inhibition by nonsteroidal anti-inflammatory drugs of superoxide production and granule enzyme release by polymorphonuclear leukocytes stimulated with immune complexes or formyl-methionyl-leucyl-phenylalanine

The effects of nonsteroidal anti-inflammatory agents on superoxide production and granule enzyme release by human polymorphonuclear leukocytes stimulated with either formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe] or immune complexes were investigated. Cytochrome c reduction and the release of lysozyme, beta-glucuronidase, myeloperoxidase and gelatinase were measured. Auranofin, phenylbutazone, sulfasalazine and the phospholipase A2 inhibitor, 4-bromophenacyl bromide, strongly inhibited these responses in fMet-Leu-Phe stimulated cells, at concentrations below 50 microM. Indomethacin, piroxicam, mefenamic acid, primaquine and quinacrine at 50-250 microM were inhibitory. Up to 1 mM ibuprofen and chloroquine inhibited superoxide production but had little effect on degranulation. With cells stimulated by IgG aggregates (immune complexes), up to 1 mM ibuprofen, mefenamic acid and piroxicam did not inhibit either response. Indomethacin, phenylbutazone, sulfasalazine and primaquine inhibited, but considerably higher concentrations were required than with fMet-Leu-Phe. Quinacrine inhibited superoxide production equally well with both stimuli but inhibited enzyme release only with fMet-Leu-Phe. Only auranofin, 4-bromophenacyl bromide, and the weakly effective chloroquine exerted approximately the same effect with both stimuli. D-Penicillamine did not affect enzyme release with either stimulus and interfered in the superoxide assay. Gelatinase release induced by fMet-Leu-Phe was affected to the same extent, or slightly more, than release of the other granule enzymes. With immune complexes, there was only modest inhibition of gelatinase release by any of the drugs at 250-1000 microM. Our results reinforce previous observations that many anti-inflammatory drugs affect neutrophil functions, but their effects vary with stimulus. The relative insensitivity of immune complex-induced responses to most of the drugs must be taken into account when considering their mode of action.     

Nonsteroidal anti-inflammatory agents in the treatment of primary dysmenorrhea

The physiology of primary dysmenorrhea and its treatment with nonsteroidal anti-inflammatory agents are reviewed. Primary dysmenorrhea involves incapacitating pelvic pain associated with nausea, vomiting, and diarrhea. Currently, it is thought to be caused by an overproduction of prostaglandins that are released as the endometrium degenerates. Since the nonsteroidal anti-inflammatory agents are one class of antiprostaglandin agents, they are frequently prescribed for the relief of dysmenorrhea. Naproxen and naproxen sodium have both been shown to be superior to placebo in subjective and objective assessments of dysmenorrheic patients when administered at the onset of symptoms. Indomethacin studies demonstrate its efficacy over placebo, but the frequency of side effects at the doses used (25-50 mg t.i.d.) diminish its usefulness. Few placebo-controlled studies have been published on ibuprofen, but the studies that have been performed show that ibuprofen is more beneficial than placebo for treating dysmenorrhea with a low incidence of side effects. The fenamates appear to be effective in dysmenorrhea, although they were not studied extensively with placebo and previous experience with mefenamic acid has led to warnings about side effects. Phenylbutazone and oxyphenbutazone have been found to be effective; however, their use has been less frequent since the introduction of the newer less toxic nonsteroidal agents. Comparative studies of the nonsteroidal anti-inflammatory agents have not indicated that one agent is more effective than the others. Until further well-controlled comparative research is performed, any of the agents reviewed would be an appropriate choice in the treatment of primary dysmenorrhea.     

Enantiomeric interaction of flurbiprofen in the rat

Flurbiprofen [FL, (+/-)-2-(2-fluoro-4-biphenylyl)propionic acid] is a 2-arylpropionic acid nonsteroidal anti-inflammatory drug which is commercially available as a racemate. The anti-inflammatory activity of FL, however, appears to be mainly due to the S enantiomer. Recently, it has been postulated that, in both humans and rats, the two enantiomers of FL may interact when racemic doses are given. This study examines the above postulate in the rat by administration of single iv doses of racemic FL (10 mg/kg), and R- and S-FL (5 mg/kg of each). Plasma concentrations (0-12 h) of the enantiomers were measured using a stereospecific HPLC assay. A significant interaction was noticed between the enantiomers: mean AUC +/- SD of R-FL was reduced from 115.3 +/- 21.3 to 49.0 +/- 10.4 mg/L.h as a result of S-FL coadministration. A trend towards reduced S-FL plasma concentration was also evident when the enantiomer was given as the racemate [mean AUC +/- SD; 176.8 +/- 37.7 racemate versus 241.4 +/- 86.2 mg/L.h alone]. The reduction in S-FL, however, was not significant due perhaps to the observed interanimal variation. While the enantiomeric interaction caused a significant enlargement of the volume of distribution of R-FL, it failed to alter the terminal half-life of the enantiomer. It is suggested that the interaction is a result of displacement from plasma protein binding sites of one enantiomer by the other.     

The effects of pH,calcium and chloride ions on the binding of tolmetin to human serum albumin: circular dichroic,dialysis and fluorometric measurements

The binding of the non-steroidal anti-inflammatory drug, tolmetin (1-methyl-5-p-toluoylpyrrole-2-acetic acid) to human serum albumin (HSA) has been shown by circular dichroism, fluorescence and equilibrium dialysis to be dependent on the N-B conformational change of the albumin. The influence of calcium and chloride ions on the interaction was also investigated using the same techniques. Experiments suggested that calcium ions increased the binding constant of tolmetin to HSA whereas chloride ions decreased it. The displacement study showed that tolmetin caused a significant increase in the affinity of diazepam to HSA whereas it decreased the binding of warfarin to HSA. Tolmetin seems to cause an allosteric change in the diazepam binding site in spite of it sharing a primary site with warfarin.     

Effect of anti-inflammatory drugs on lysosomes and lysosomal enzymes from rat liver

Steroidal and nonsteroidal anti-inflammatory drugs were tested for their capacity to stabilize, in vitro, lysosomes and inhibit lysosomal enzymes. Lysosome membrane stability was measured by determining the effects of drugs on the release of aryl sulfatase and β-glucuronidase from lysosomes which were suspended in a hypo-osmotic sucrose buffer. Lysosomes obtained from a heavy mitochondrial (3500 g) rat liver fraction were found to be highly sensitive to membrane stabilization by naproxen, alclofenac, chloroquine, mefenamic acid, phenylbutazone, hydrocortisone, dexamethasone and methylprednisolone. Ibuprofen and flufenamic acid demonstrated moderate stabilizing activity, while indo-methacin, aspirin and clonixin showed only weak activity. Imuran, as well as other anti-inflammatory drugs, was inactive. In addition to their membrane-stabilizing activity, chloroquine was found to be a potent inhibitor of aryl sulfatase and phenylbutazone an inhibitor of β-glucuronidase activity. Hydrocortisone, dexamethasone and paramethasone inhibited aryl sulfatase activity, while no steroid tested was effective as an inhibitor of β-glucuronidase. The data in this report support the hypothesis that anti-inflammatory drugs inhibit the release of enzymes from lysosomes. In addition, several of these drugs may act as inhibitors of lysosomal enzyme activity.     

A quantitative circular dichroic investigation of the binding of the enantiomers of ibuprofen and naproxen to human serum albumin

The binding constants for racemic, R and S naproxen and ibuprofen to human serum albumin have been determined by a circular dichroic technique. The ibuprofens and naproxens show no measurable extrinsic optical activity on interaction with the protein, and so the extrinsic Cotton effect shown following the diazepam–albumin interaction is used as a probe. The presence of the drugs reduce the amount of diazepam bound as shown by the reduced size of the induced ellipticity. The calculated primary binding constants show that the S form of both drugs bind to the albumin more tightly than the R form and that the racemic forms bind less tightly than either enantiomer.     

Contribution of cytochrome P450 and UDT-glucuronosyltransferase to the metabolism of drugs containing carboxylic acid groups: risk assessment of acylglucuronides using human hepatocytes

Abstract

1.?In order to evaluate the inhibition activity of 1-aminobenzotriazole (ABT) and (?)-borneol (borneol) against cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), the substrates of these metabolic enzymes were incubated with ABT and borneol in human hepatocytes. We found that 3?mM ABT and 300?μM borneol were the most suitable experimental levels to specifically inhibit CYP and UGT.

2.?Montelukast, mefenamic acid, flufenamic acid, diclofenac, tienilic acid, gemfibrozil, ibufenac and repaglinide were markedly metabolized in human hepatocytes, and the metabolism of gemfibrozil, mefenamic acid and flufenamic acid was inhibited by borneol. With regard to repaglinide, montelukast, diclofenac and tienilic acid, metabolism was inhibited by ABT. Ibufenac was partly inhibited by both inhibitors. Zomepirac, tolmetin, ibuprofen, indomethacin and levofloxacin were moderately metabolized by human hepatocytes, and the metabolism of zomepirac, ibuprofen and indomethacin was equally inhibited by both ABT and borneol. The metabolism of tolmetin was strongly inhibited by ABT, and was also inhibited weakly by borneol. Residual drugs, telmisartan, valsartan, furosemide, naproxen and probenecid were scarcely metabolized.

3.?Although we attempted to predict the toxicological risks of drugs containing carboxylic groups from the combination chemical stability and CL_int via UGT, the results indicated that this combination was not sufficient and that clinical daily dose is important.     

Stereoselective plasma protein binding of ibuprofen enantiomers

Summary We have developed a novel and reproducible method for determining the plasma protein binding of the two ibuprofen enantiomers in the presence of each other. The method involves the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of the enantiomers to diastereomeric amides, high-performance liquid chromatography, and radiochemical analysis.We have determined the plasma protein binding of R(–)- and S(+)-ibuprofen in 6 healthy male volunteers after the oral administration of 800 mg racemic ibuprofen.The mean time-averaged percentage unbound of the R(–)-enantiomer, 0.419 was significantly less than that of the S(+)-enantiomer, 0.643, consistent with stereoselective plasma protein binding.The percentage unbound of each ibuprofen enantiomer was concentration-dependent over the therapeutic concentration range and was influenced by the presence of its optical antipode.     

Induction of hemolytic anemia by nonsteroidal antiinflammatory drugs

The incidence of immune hemolytic anemia (IHA) is increasing. The proliferation of pharmaceuticals is a contributing factor to this increase. IHA is an uncommon, though significant, adverse effect of a wide variety of drugs. Several recent case reports have implicated the nonsteroidal antiinflammatory drugs (NSAIDs). Because of the extensive use of this class of drugs, a review of case reports, clinical studies, and in vitro research was conducted on NSAID-induced IHA. Mefenamic acid, ibuprofen, sulindac, naproxen, tolmetin, feprazone, and aspirin are reported to cause IHA, with mefenamic acid most frequently implicated. Mefenamic acid appears to cause hemolytic anemia by an autoimmune mechanism similar to methyldopa and aspirin by an immune complex mechanism. However, there is insufficient information concerning ibuprofen, sulindac, naproxen, tolmetin, and feprazone to assign specific mechanisms of immune hemolysis. In individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, aspirin at usual therapeutic doses is not a predisposing factor to hemolysis unless other risk factors are present. Although individuals with G-6-PD deficiency are at increased risk of developing hemolytic anemia when exposed to oxidizing stresses, the use of NSAIDs does not appear to increase this risk significantly. Because NSAID-induced IHA occurs infrequently and the sensitivity of currently used tests to detect drug-dependent antibodies is limited, routine serologic testing in patients receiving NSAIDs is not justified. If hemolytic anemia occurs in a NSAID-treated patient and the history is consistent with a drug-induced etiology, the NSAID should be discontinued. With discontinuation of the offending agent, the prognosis is good. There is a rapid hematologic recovery, with a slow resolution of abnormal serologic findings.