In vivo inhibition of prostaglandin synthesis in rabbit kidney by non-steroidal anti-inflammatory drugs

To define dose- and time-response properties for in vivo inhibition of renal prostaglandin (PG) synthesis, aspirin, diclofenac sodium, indomethacin and d-naproxen were injected intravenously in different doses to unanaesthetized rabbits. After 30 min. the animals were killed and the post mortem accumulation of PGE2 and PGF2alpha in the renal medulla was determined by mass fragmentography. In control animals, the accumulated levels of PGE2 and PGF2alpha in the medulla were 9.2+/-2.2 (S.D.) and 1.5+/-0.6 microgram/g, respectively. Dose-dependent inhibition was demonstrated with all the drugs. The ED95 was for aspirin 15 mg/kg, for diclofenac sodium 1.5 mg/kg, for indomethacin 1.5 mg/kg and for d-naproxen 5 mg/kg. The duration of inhibition was studied by radioimmunoassay in anaesthetized rabbits by following the urinary excretion of PGF2alpha and PGE2 after an intravenous injection of solvent or test drug in doses twice the ED95. For three hours following aspirin, diclofenac sodium, indomethacin and d-naproxen, the decreases in urinary excretion of PGF2alpha ranged from 64 to 88, 87 to 95, 64 to 90 and from 40 to 77 per cent of the control, respectively, and the decreases in PGE2 excretion were of similar magnitude. Together these results indicate that diclofenac sodium might be used as a long-lasting and potent alternative to indomethacin and aspirin in experimental studies on the renal PG system in vivo.     

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

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.     

Antioxidant activity and inhibition of human neutrophil oxidative burst mediated by arylpropionic acid non-steroidal anti-inflammatory drugs

It has been suggested that the anti-inflammatory activity of some non-steroidal anti-inflammatory drugs (NSAIDs) may be partly due to their ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS), as well as to inhibit the respiratory burst of neutrophils triggered by various activating agents. Therefore, the aim of the present work was to evaluate and compare the potential scavenging activity for an array of ROS (O2*-, H2O2, HO*, ROO* and HOCl) and RNS (*NO and ONOO-) using in vitro non-cellular screening systems as well as a cellular screening system (human neutrophil oxidative burst), mediated by the arylpropionic acid derivatives (APAs) NSAIDs ibuprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, naproxen and indoprofen. The results obtained in the present work demonstrate that under the present experimental conditions, many of the studied APA NSAIDs showed O2*- scavenging activity (fenbufen approximately equal to flurbiprofen approximately equal to indoprofen approximately equal to ketoprofen), H2O2 (ketoprofen approximately equal to indoprofen approximately equal to fenbufen>flurbiprofen>naproxen), HO* (fenoprofen approximately equal to ibuprofen>fenbufen approximately equal to flurbiprofen>ketoprofen>indoprofen approximately equal to naproxen), *NO (indoprofen>naproxen), ONOO- (indoprofen>naproxen>fenoprofen approximately equal to flurbiprofen approximately equal to ibuprofen), as well as inhibit myeloperoxidase (MPO) activity (indoprofen) and scavenge human neutrophil derived ROS (ketoprofen>indoprofen>fenbufen>flurbiprofen). The observed effects, if confirmed in vivo, may strongly contribute to the anti-inflammatory therapeutical activity observed with these NSAIDs.     

Inhibitory effects of non-steroidal anti-inflammatory drugs on human liver microsomal morphine glucuronidation: Implications for drug-drug interaction liability

The inhibitory effects of fifteen NSAIDs from six structurally distinct classes on human liver microsomal morphine glucuronidation were investigated. K_i values of selected NSAIDs were generated and employed to assess DDI liability in vivo. Potent inhibition was observed for mefenamic acid and tolfenamic acid; respective IC₅₀ values for morphine 3- and 6-glucuronidation were 9.2 and 13.5 μM, and 5.3 and 8.3 μM. Diclofenac and celecoxib showed moderate inhibition with IC₅₀ values of 78 and 52 μM, and 83 and 214 μM, respectively. Estimated IC₅₀ values for the other NSAIDs screened were >100 μM. Mefenamic acid, diclofenac, and S-naproxen competitively inhibited morphine 3- and 6-glucuronidation, with the K_i values of 11 and 12 μM, 110 and 76 μM, and 319 and 650 μM, respectively. Using the static mechanistic IVIVE approach, an approximate 40% increase in the AUC of morphine was predicted when co-administered with mefenamic acid, whereas the increase was <10% with diclofenac and S-naproxen. PBPK modeling predicted <15% increases in the morphine AUC from diclofenac and S-naproxen inhibition in virtual healthy and cirrhotic subjects. The data suggest that potential clinically significant DDIs arising from NSAID inhibition of morphine glucuronidation is unlikely, with the possible exception of some fenamates.     

The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes

AIMS: To estimate the relative contribution of liver, kidney and jejunum to MPA elimination via glucuronidation from in vitro kinetic data. METHODS: The kinetics of MPA glucuronidation by human liver, kidney and jejunum microsomes were characterized. Mycophenolic acid glucuronide (MPAG) concentrations in microsomal incubations were determined using a specific h.p.l.c. procedure. Non-specific microsomal binding of MPA was excluded using an equilibrium dialysis approach. RESULTS: Microsomes from all three tissues catalysed the conversion of MPA to MPAG. Mean microsomal intrinsic clearances for MPAG formation by liver, kidney and jejunum microsomes were 46.6, 73.5 and 24.5 microl (min mg)(-1), respectively. When extrapolated to the whole organ, however, hepatic intrinsic clearance was 21- and 38-fold higher than the respective intrinsic clearances for kidney and small intestine. CONCLUSIONS: The data suggest that the liver is the organ primarily responsible for the systemic clearance of MPA, with little contribution from the kidney, and that the small intestine would be expected to contribute to first-pass extraction to a minor extent only.     

Exacerbation of acetic acid ulcer induced by non-steroidal anti-inflammatory drugs in rats

The influences of non-steroidal anti-inflammatory drugs (NSAID) on acetic acid ulcer were examined in rats. NSAID used in this study were aspirin (ASP, 200 mg/kg), indomethacin (IND, 2 mg/kg) and phenylbutazone (PHE, 100 mg/kg). These NSAID were administered consecutively for 5 days once a day at the early stage of the ulcer. Eleven days after the ulceration, suppression of the healing was observed in rats treated with all of the NSAID. In the rats treated with either ASP or IND, a delay of healing was observed not only 11 days after ulceration, but also 16 days after ulceration. The ulcer index in rats treated with either ASP or IND 16 days after ulceration was greater than that at 11 days after ulceration. Further studies were performed regarding the progressive change of mucosal hexosamine content, gastric secretion and gastric emptying during the healing process of the ulcer. It was found that the increase of hexosamine plays an important role in the healing of the ulcer and that a durable fall in hexosamine content was related to the remarkable exacerbation of ulcer induced by either ASP or IND. Hypersecretion, back diffusion of hydrogen ion or a delay of gastric emptying cannot be regarded as a cause of the exacerbation of the ulcer.     

Modifications in prolactin binding capacity in the rat liver induced by non-steroidal anti-inflammatory drugs

Modifications in prolactin specific binding in the rat liver induced by different non-steroidal anti-inflammatory drugs (indomethacin, piroxicam, ketoprofen, phenylbutazone, mefenamic acid and acetylsalicylic acid) have been studied. All caused a dose-dependent inhibition of prolactin binding capacity whereas no change was found in dissociation constant values. The inhibitory effect is reversible and highly specific, since insulin binding to the same membrane preparation is not affected. The degree of inhibitory activity on prolactin binding is related to the anti-inflammatory activity of each drug, which supports the hypothesis of an involvement of prostaglandin synthesis.     

Cardiovascular hazard and non-steroidal anti-inflammatory drugs

Selective inhibitors of cyclooxygenase (COX)-2 depress prostacyclin (PGI(2)) without a concomitant inhibition of platelet COX-1-derived thromboxane (Tx)A(2). Experiments in gene-deleted mice have shown that ablation of the PGI(2) receptor (the IP) predisposes to an exaggerated response to agonists which elevate blood pressure, accelerate atherogenesis and induce thrombosis. Such a class-based effect would be expected to be modulated by the underlying risk of cardiovascular disease in patients, elements of drug exposure, such as dose, duration of action and duration of dosing, and inter-individual variability of drug response. Five placebo-controlled trials of three structurally distinct selective inhibitors of COX-2 have revealed an increased hazard of myocardial infarction and stroke consistent with a mechanism-based class-specific cardiovascular hazard. Sustained inhibition of platelet TxA(2) by aspirin affords cardiovascular benefit, despite concomitant inhibition of PGI(2). Although there is no information from randomized placebo-controlled trials, traditional non-steroidal anti-inflammatory drugs, such as naproxen, dicofenac and ibuprofen, might differ in their effects of cardiovascular biology.     

Prostaglandin synthetase systems in rat and rabbit renal medulla and inhibition by non-steroidal anti-inflammatory drugs.

The properties of prostaglandin synthetase systems (PSSs) in the renal medulla of the rat and rabbit, and inhibition by ketoprofen, indomethacin, ibuprofen, phenylbutazone and aspirin were investigated in relation to their anti-inflammatory, analgesic, antipyretic and ulcerogenic activities. Rat and rabbit PSSs produced prostaglandin (PG)E and PGF from arachidonic and dihomo-gamma-linolenic acids and had an optimal pH of 8.5 and 7.5 for PGE formation, respectively. Only a slight loss of activity occurred with lyophilization. In the rat PSS, all drugs tested were inhibitory in the order of ketoprofen, ibuprofen, indomethacin and aspirin, respectively. In the rabbit PSS, the same potency relationship was also found. Drug sensitivity of the rat PSS was remarkably lower than that of the rabbit PSS. Significant correlations were noted between the inhibitory potencies of the drugs against both PSSs and other in vivo pharmacological activities within the same species.     

Cyclosporin metabolism in human liver microsomes and its inhibition by other drugs

The metabolism of cyclosporin was studied in human liver microsomes. There was no metabolism in the presence of cytochrome C or carbon monoxide or in the absence of cofactors, suggesting metabolism by cytochrome P-450 enzymes. The metabolism was inhibited by ketoconazole and erythromycin, by the steroids methylprednisolone and oestradiol, and by the calcium antagonists diltiazem, nifedipine, prenylamine and verapamil. These in vitro findings correlate well with previously published clinical reports suggesting that these drugs may inhibit the metabolism of cyclosporin in vivo. Our observations suggest that metabolic interactions between cyclosporin and other drugs in vivo may be predicted in vitro under proper experimental conditions.     

结肠直肠癌和非甾类消炎药(英文)

Non-steroidal anti-inflammatory drugs ( NSAIDs) can prevent or reduce the occurrence of colorectal cancers . Anti-carcinogenic properties of NSAIDs have been demonstrated in epidemiological studies of humans and experimental animals. In addition, clinical studies of familial adenomatous polyposis and sporadic adenomas have demonstrated that NSAIDs induce regression of colorectal adenomas and prevent formation of these tumors. NSAIDs thus induce early disruption of the adenoma-carcinoma sequence and may mainly suppress subsequent cancer formation at adenoma stage. The mechanism of the anti-carcinogenic effect of these drugs is not known, but results of most studies support that cyclooxygenase-2 (an inducible isoform of prostaglandin synthetase, COX-2) is a major target of NSAIDs in this effect. Recent immunohistochemical studies have revealed that COX-2 is expressed not in tumor cells but in interstitial cells of colonic adenomas. Accordingly, NSAIDs may exhibit anti-carcinogenic property through the inh     

Cyclooxygenase-2 inhibition and side-effects of non-steroidal anti-inflammatory drugs in the gastrointestinal tract

Inhibition of prostaglandin biosynthesis via inhibition of the fatty acid cyclooxygenase (COX) is the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs). This results in an inhibition of the inflammatory and pain-producing activities of prostaglandins at a site of tissue injury but also in inhibition of prostaglandin production in the gastrointestinal tract (GI) and platelets, i.e. sites where endogenous prostaglandins are possibly involved in control of physiological functions. The discovery of two COX isoenzymes, COX-1 and COX-2, and the detection of their separate function and regulation, has initiated the search for new and putatively more selective inhibitors of prostaglandin biosynthesis. Specifically, selective inhibitors of COX-2 were developed in order to improve the anti-inflammatory and analgetic specificity and potency of the compounds and to reduce side-effects in the GI tract. Available experimental and clinical data of selective COX-2 inhibitors, including flosulide, celecoxib or rofecoxib, suggest improved gastric tolerance as compared to conventional, non-selective NSAIDs. However, experimental evidence suggests that both, the analgetic and anti-inflammatory action of COX-inhibitors, might also require inhibition of COX-1. COX-2-selective compounds at anti-inflammatory doses might have other side-effects, and for example reduce vascular prostacyclin production. Evidence is accumulating that COX-2 might not only be considered as a putatively detrimental enzyme but rather a highly regulated enzyme that also contributes to tissue protection and is even constitutively expressed in healthy human stomach mucosa. This paper reviews some of these newer aspects of COX-2-selective inhibitors in clinical use and discusses their possible benefits and risks.     

Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes

OBJECTIVES: The first aim of this investigation was to study the variability of mycophenolic acid (MPA) glucuronidation rate in human liver. The second aim was to study the inhibition type of niflumic acid (NA) for MPA glucuronidation in human liver. The third aim was to study the variability of the IC(50) value of NA for MPA glucuronidation in human liver. METHODS: The rate of MPA glucuronidation was measured by employing an assay based on uridine 5'-diphosphate-[U-(14)C]-glucuronic acid (UDPGA), and MPA glucuronide was isolated by means of thin-layer chromatography. The necessary concentration for UDPGA and MPA was 1 mM. The rate of MPA glucuronidation was measured in 50 human liver samples. The inhibition type of NA for MPA glucuronidation was studied in 5 human liver samples. The NA IC(50) value was measured in 27 human liver samples using six concentrations of NA ranging from 1.05 microM to 34 microM. RESULTS: MPA glucuronidation rate was positively skewed, was not gender regulated and did not correlate with the liver donor's age. The rate of MPA glucuronidation varied 4.8-fold within the 5th and 95th percentiles, with a mean+/-SD and a median of 2.8+/-1.0 nmol/min/mg and 2.5 nmol/min/mg, respectively. The inhibition type of NA for MPA glucuronidation was mixed non-competitive. The Ki value of NA (mean+/-SD) was 15+/-10 microM and, in non-inhibited samples, the K(m) value for MPA was 0.41+/-0.06 mM. The distribution of NA IC(50) value varied 3.3-fold within the 5th and 95th percentiles with a mean+/-SD and a median of 5.6+/-2.1 microM and 5.2 microM, respectively. The distribution of NA IC(50) value did not deviate significantly from normality. CONCLUSION: The range of hepatic rate of MPA glucuronidation is narrow relative to those of ethinyloestradiol, testosterone and zidovudine glucuronidation obtained from literature. The Ki value of NA is one order of magnitude lower than the K(m) for MPA in non-inhibited samples. This indicates that the inhibitor affinity for glucuronosyl transferase is greater than that of the substrate. The range of variation of NA IC(50) values is narrow.     

非甾体抗炎药致胃肠道黏膜损伤的研究进展

随着非甾体抗炎药(NSAIDs)在临床的广泛应用,其对胃肠道黏膜的损害已受到越来越多的关注。笔者就NSAIDs胃肠道黏膜损害的发病机制、临床表现和防治等做一综述。     

Upper gastrointestinal disorders induced by non-steroidal anti-inflammatory drugs

Aims: We examined the characteristics of upper gastrointestinal disorders induced by non-steroidal anti-inflammatory drugs (NSAIDs). Methodology: The questionnaire investigation was performed over a five year period. Results: A study was performed on 354 patients (161 men and 193 women with mean ages of 66.0 and 70.7 years, respectively) who developed NSAIDs associated upper GI disorders: 21 patients had AGML, 212 had gastric ulcer, 63 had duodenal ulcer, 17 had gastroduodenal ulcers and 41 other cases. About 75 % of patients received NSAIDs for orthopedic conditions. Sixty percent of gastric disorders induced by NSAIDs affected the antrum or angulus of the stomach. The incidence of disorders of the gastric antrum was significantly higher in women than in men whilst the incidence of disorders on the gastric angulus was significantly higher in men than in women (p < 0.05). The proportion of patients with abdominal pain was significantly lower in patients over 65 years old than in those under 65 years old, and the proportion of patients with hematemesis or melena was significantly higher in patients over 80 years old than in those under 80 years old (p < 0.05). The time taken to achieve the healing stage was significantly longer in patients with greater than 3 months NSAIDs ingestion compared to patients that had received NSAIDs for less than 3 months (p < 0.05). Conclusions: Patients 65 years old and over with continuous NSAIDs use had asymptomatic ulcers, and patients 80 years old and over had hemorrhagic ulcers. Received and accepted 20 September 2006     

Organ tolerance of non-steroidal anti-inflammatory drugs: effect on liver cells

Experimental studies in mice and in rats showed the good tolerance of a new non-steroidal anti-inflammatory drug, flunoxaprofen, by normal and CCl4 damaged liver. The activity of an enzyme-inducing drug, such as phenobarbital, showed a greater increase after pretreatment with indomethacin than with flunoxaprofen or benoxaprofen. High doses of benoxaprofen and indomethacin significantly decreased bromosulphonphthalein excretion in rats with normal or CCl4 damaged liver; the effect was not observed with flunoxaprofen administered at the same dose as benoxaprofen. Moreover, benoxaprofen and indomethacin but not flunoxaprofen induced a significant increase of some serum liver enzymes in CCl4 poisoned rats.     

非甾体类抗炎药物的质量研究进展

本文整合国内外相关文献资料,简要介绍了非甾体类药物的作用机理,并回顾了该类药物的研发历程,综合介绍了该类药物的质量研究的进展。     

非甾体抗炎药与麻醉药的相互作用

非甾体抗炎镇痛药(Non-steroidal anti-inflammatory drugs,NSAIDs)主要用于围手术期超前镇痛。本文对NSAIDs与常用的麻醉药如阿片类药、吸入麻醉药、静脉麻醉药和苯二氮艹卓类药物的相互作用加以综述。