Renal adverse effects of nonsteroidal anti-inflammatory drugs

NSAIDs depress prostaglandins synthesis through inhibition of COX-1 that is involved in maintaining cell integrity and COX-2 that, although presents particularly in the kidneys, is overexpressed in response to inflammation. Both the beneficial and side effects of NSAIDs are, therefore, through their inhibition of COX enzymes. Introduction of COX-2-selective inhibitors has improved the safety profile of the drugs with regard to their most common side effect which occurs at the gastrointestinal level but has not rendered them less cardio-nephrotoxic. Renal side effects of NSAIDs are rare, sometimes transient and often reversible upon drug withdrawal. The incident rate and the severity of the renal side effect, however, increase in patients with risk factors such as those with diabetes, heart failure, renal dysfunction and in the elderly. The side effects range from electrolyte retention and reduce glomerular filtration to nephritic syndrome and chronic renal failure. These effects are shared among NSAIDs with evidence of dose and exposure dependency. There is no known predictor for the nephrotoxicity. However, a relationship has been found between high plasma concentration and the renal adverse effect of NSAIDs. The usefulness of therapeutic drug monitoring in patients with risk factors needs to be explored.     

Prostaglandin H synthase-2 inhibitors interfere with prostaglandin H synthase-1 inhibition by nonsteroidal anti-inflammatory drugs

Ram seminal vesicle microsomes, a rich source of prostaglandin H synthase-1, were incubated with 100 nM of the prostaglandin H synthase-2 inhibitors N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) and 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl) thiophene (DuP-697) prior to exposure to the prostaglandin H synthase inhibitors aspirin, indomethacin, ibuprofen or naproxen. Activity of the enzyme was measured by following the conversion of arachidonic acid to prostaglandin E(2) and prostaglandin F2alpha. Although prostaglandin H synthase-1 activity was not altered by these concentrations of the prostaglandin H synthase-2 inhibitors, it was found that exposure to these agents prior to aspirin or indomethacin (irreversible prostaglandin H synthase inhibitors) significantly attenuated the inhibition obtained by the latter inhibitors. On the other hand, the same concentrations of the prostaglandin H synthase-2 inhibitors did not interfere with prostaglandin H synthase-1 inhibition that was induced by naproxen or ibuprofen (competitive prostaglandin H synthase inhibitors). Attenuation of the indomethacin inhibition of prostaglandin H synthase-1 by prostaglandin H synthase-2 inhibitors was observed only when the microsomes were pre-exposed to DuP-697 or NS-398 in the absence, but not in the presence, of arachidonic acid. The effect of DuP-697 was found to be irreversible, however, washing away the agent reversed the action of NS-398. Similar phenomena have been reported by us in bovine aortic endothelial cells and in human dermal fibroblasts. Attenuation of the inhibition by aspirin and indomethacin, without altering the enzyme's basal activity or the inhibition induced by ibuprofen or naproxen may suggest the possibility that the prostaglandin H synthase-2 specific inhibitors DuP-697 and NS-398 affect prostaglandin H synthase-1 by interaction with a site different from the enzyme's catalytic site.     

Managing the adverse effects of nonsteroidal anti-inflammatory drugs

Conventional medical treatment for rheumatoid arthritis and osteoarthritis includes the use of NSAIDs (traditional and selective inhibitors of cyclooxygenase [COX]-2), because they provide unmistakable and significant health benefits in the treatment of pain and inflammation. However, they are associated with an increased risk of serious gastrointestinal (GI) and cardiovascular (CV) adverse events. Both beneficial and adverse effects are due to the same mechanism of action, which is inhibition of COX-dependent prostanoids. Since CV and GI risk are related to drug exposure, a reduction in the administered dose is recommended. However, this strategy will not eliminate the hazard owing to a possible contribution of individual genetic background. Further studies will be necessary to develop genetic and/or biochemical markers predictive of the CV and GI risk of NSAIDs.     

The unexpected side effects of new nonsteroidal anti-inflammatory drugs

Conventional nonselective NSAIDs are classically associated with a risk of gastrointestinal disorders. These drugs have a broad range of relative selectivity towards the COX family, mainly towards two isoforms of these enzymes: COX-1 and -2. As examples, ketorolac, flurbiprofen, ketoprofen and indomethacin have increased COX-1 selectivity when compared with naproxen and ibuprofen.     

Reactivity of nonsteroidal anti-inflammatory drugs with peroxidase: a classification of nonsteroidal anti-inflammatory drugs

Objectives To improve understanding of the essential effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on prostaglandin H synthase (PGHS), the reactivity of NSAIDs with peroxidases and the tyrosyl radical derived from myoglobin was examined. Methods Horseradish peroxidase and myoglobin were used as models of peroxidase and cyclooxygenase of PGHS, respectively. Key findings From the results, a new classification of NSAIDs has been proposed. Class 1 includes the majority of NSAIDs, which reacted with horseradish peroxidase compound I, thus causing a spectral change by PGHS peroxidase and also including diminished electron spin resonance signals of the tyrosyl radical of myoglobin. They reduced compound I of horseradish peroxidase and scavenged the tyrosyl radical. The branched-chain mechanism by which the porphyrin radical is transferred to the tyrosine residue of the protein might be blocked by these NSAIDs. Class 2 includes salicylic acid derivatives that reacted only with the porphyrin radical and not with horseradish peroxidase compound II (oxoferryl species). Class 3 includes aspirin, nimesulide, tolmetin, and arylpropionic acid derivatives, including ibuprofen and the coxibs of celecoxib and rofecoxib, which are not substrates for horseradish peroxidase or PGHS peroxidase. Conclusions Understanding the essential mode of action of NSAIDs is particularly important for designing an effective therapeutic strategy against inflammatory diseases.     

The synovial prostaglandin system in chronic inflammatory arthritis: differential effects of steroidal and nonsteroidal anti-inflammatory drugs

1 The present study was undertaken to characterize the spectrum of arachidonic acid metabolites present in synovial effusions of patients with rheumatoid or psoriatic arthritis, and to compare changes in their concentration following a short-term treatment with 6α-methyl-prednisolone (6-MeP: 4-8 mg/day) or indoprofen (1.2 g/day), a nonsteroidal anti-inflammatory agent with proven synovial prostaglandin inhibitory effect.

2 Measurements of prostaglandin E₂ (PGE₂), thromboxane (TX) B₂, 6-keto-PGF_1α and PGF_2α were performed by radioimmunoassay techniques in synovial effusions obtained from 23 patients, and validated by thin-layer chromatographic analysis of the extracted immunoreactivity.

3 PGE₂ and TXB₂ accounted for more than 60% of the total immunoreactivity in untreated patients. The absence of any constant ratio between the different arachidonic acid metabolites detected in synovial fluid is consistent with a heterogeneous cellular origin of these compounds.

4 Indoprofen treatment was associated with a consistent reduction of synovial prostaglandin and thromboxane concentrations, ranging from 36% in the case of 6-keto-PGF_1α to 90% in the case of PGE₂.

5 In contrast, 6-MeP caused opposite changes on different metabolites originating via the cyclo-oxygenase pathway. Thus, 6-keto-PGF_1α concentrations were reduced by 35%, PGF_2α concentrations were increased by 30%, while PGE₂ and TXB₂ were unchanged following 6-MeP.

6 Although the mechanism(s) underlying the failure of 6-MeP to reduce synovial PGE₂ and TXB₂ levels are uncertain, the results of the present study clearly indicate that therapeutic doses of steroidal and nonsteroidal anti-inflammatory drugs cause quite distinct changes in arachidonic acid metabolism, which might be relevant to their specific therapeutic actions and side-effects.

     

释放一氧化氮型非甾体抗炎药

目前传统的非甾体抗炎药(NSAIDs)仍然是应用最广泛的药物之一〔1〕。为了克服NSAIDs的胃肠道不良反应,研制了肠衣片、前药(pro-drugs)、选择性环氧合酶(COX)-2抑制剂。近10年又出现一类新药,即释放一氧化氮(NO)型非甾体抗炎药(NO-NSAIDs)。NO生理功能广泛,许多病理过程与缺乏NO有关。这一事实构成了NO替代治疗的生理学基础。当机体内不能产生足够NO来维持正常生物学功能时,外源性NO成为补充NO的有效方式。将有机硝酸结构通过化学间隔物(连接基),如脂肪链、芳香链或者杂环链连结到现存药物分子上获得释放NO的药物,以可控制的…     

Lipid peroxidation modifies the effect of phenolic anti-inflammatory drugs on prostaglandin biosynthesis

The effects of phenolic anti-inflammatory drug, MK-447, on prostaglandin (PG) I2 and thromboxane (TX) A2 biosynthesis by rat dental pulp tissue were evaluated in the presence of 10 mM mannitol (MA) or 1 mM ascorbic acid with 0.3 mM Fe2+ (A + F). Although MK-447 alone at 1 and 10 microM had no significant effects, MK-447 at 100 microM stimulated both PGI2 and TXA2 biosynthesis, and suppressed the lipid peroxidation in the pulp tissue as estimated by thiobarbituric acid method. MA also reduced the lipid peroxidation, but had no effect on PG and TX production. However, in the presence of MA, the stimulatory effect of MK-447 was potentiated, and the significant effects were observed at concentrations higher than 1 microM. In contrast, A + F remarkably stimulated the lipid peroxidation, and inhibited both PG and TX biosynthesis. In the presence of A + F, MK-447 showed no stimulatory effect, and contrary, at 100 microM inhibited PG and TX production. These results suggest that the cellular levels of lipid peroxidation exert a significant influence on the effects of phenolic anti-inflammatory drugs like MK-447 on PG biosynthesis. The possible mechanism of action for such drugs has been discussed in view of the significance of lipid peroxidation in inflammatory condition.     

A new approach to encapsulating nonsteroidal anti-inflammatory drugs. III. Coating acidic as well as basic nonsteroidal anti-inflammatory drugs with cellulose derivatives having different functional groups

Abstract

Acidic and basic nonsteroidal anti-inflammatory drugs were encapsulated with cellulose derivatives having different functional groups, acidic (carboxymethyl cellulose), basic (chitosan), and neutral (hydroxypropylmethyl cellulose). the properties of the microcapsules were studied and the interaction of the drugs with chitosan was assessed.     

Decrease of urinary prostaglandin E2 and prostaglandin F2 alpha excretion by nonsteroidal anti-inflammatory drugs in rats. Relationship to anti-inflammatory activity

An analytical method for measuring in vivo inhibition of prostaglandin (PG) synthesis by nonsteroidal anti-inflammatory drugs was developed for estimation of urinary prostaglandin levels in rats. Drugs were administered orally to rats (Wistar, male, 200-250 g), and water (2.5 ml/100 g body weight) was given 1 hr after drug administration to yield a constant volume of urine. Urine was collected for 4 hr after drug administration, and urinary PGE2 and PGF2 alpha were determined by radioimmunoassay. The urine volume in the 4-hr period was 5.0 +/- 0.30 ml per rat, and prostaglandin contents in the 4-hr urine were 4.56 +/- 0.56 ng PGE2 and 1.31 +/- 0.24 ng PGF2 alpha per rat in the no-drug control group. Administration of nonsteroidal anti-inflammatory drugs decreased the urinary PGE2 and PGF2 alpha dose dependently. The activities of ten typical nonsteroidal anti-inflammatory drugs in reducing urinary PGE2 excretion were compared with their anti-inflammatory activities in rats. A close correlation (r = 0.98, P less than 0.001) between the dose required for 50% reduction of urinary PGE2 excretion and the dose required for 50% inhibition of carrageenin edema was found for each drug. These drugs were also tested for their inhibitory effects on PGE2 biosynthesis in a cultured system of mouse 3T6 fibroblast cells and on prostaglandin synthesizing system in bovine seminal vesicle microsomes. No close correlation was observed between anti-inflammatory activities and inhibition of prostaglandin biosynthesis in vitro.     

A new approach to encapsulating nonsteroidal anti-inflammatory drugs. III. Coating acidic as well as basic nonsteroidal anti-inflammatory drugs with cellulose derivatives having different functional groups

Acidic and basic nonsteroidal anti-inflammatory drugs were encapsulated with cellulose derivatives having different functional groups, acidic (carboxymethyl cellulose), basic (chitosan), and neutral (hydroxypropylmethyl cellulose). The properties of the microcapsules were studied and the interaction of the drugs with chitosan was assessed.     

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs: novel gastrointestinal-sparing drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have unacceptable morbidity and mortality due to their gastrointestinal toxicity. Attempts so far to improve the safety profile of NSAIDs have met with limited clinical acceptance. Nitric oxide (NO) functions as an endogenous mediator of gastric mucosal health and defense. Recent medicinal chemistry approaches attempt to exploit the tissue-protective function of NO against NSAID-induced gastric injury. Both nitroxybutyl-ester and nitrosothiol NSAID derivatives have been synthesized. Profiling of these NO-donating NSAIDs in both the laboratory and the clinic suggests that they might offer a unique solution to the problem of NSAID-induced gastropathy without sacrificing the well-accepted pharmacological activity of these agents in the management of pain and inflammation.