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.     

Tolerability of ibuprofen and flurbiprofen in G-6-PD deficient subjects: in vitro study.

1 A 'GSH (reduced glutathione) stability test' which consists of incubating blood samples with acetylphenylhydrazine and other test drugs and measuring GSH level before and after incubation, was carried out. 2 Application of this test to the blood of eight normal volunteers and twelve known G-6-PD deficient persons demonstrated that acetylphenylhydrazine and primaquine produced a significant decrease in GSH levels in G-6-PD deficient red cells compared to the reduction seen in normal red cells incubated with these drugs. No such change was observed with aspirin, ibuprofen and flurbiprofen. 3 The results of this in vitro study seem to indicate that ibuprofen and flurbiprofen are relatively innocuous in G-6-PD deficient individuals.     

Drug-induced immune hemolytic anemia

Background: Drug-induced immune hemolytic anemia is frequently associated with serious complications. Objective: To identify which drugs are implicated in drug-induced immune hemolytic anemia, how they stimulate the production of antibodies and how they could be identified. Methods: Individual studies were selected from Pubmed and Scholar databases without any time restrictions placed on the studies. All English language reports including those from the cross-references (～ 560) were carefully studied. The results of the most relevant clinical and serological studies in this field are summarized and discussed in this review. Results: Drugs may lead to the production of two types of antibodies. One type reacts with red blood cells (RBCs) only in the presence of the drug and/or its metabolites, and predominantly causes complement-mediated intravascular hemolysis. The second type reacts with RBCs, also in the absence of the drug, belongs to the IgG class, does not activate complement and causes Fc-mediated extravascular hemolysis. Some drugs may stimulate the production of both types of antibodies. Meanwhile, > 130 drugs have been reported to be the cause of immune hemolytic anemia (IHA) but the data are frequently incomplete or implausible. Conclusion: The number of drugs involved in inducing IHA is increasing. However, the vast majority of these drugs seem to cause IHA only in isolated cases. Based on the number of reports in the literature, new drugs that most frequently cause IHA are the new generation of cephalosporins, diclofenac, oxaliplatin and fludarabin.     

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro

The pathogenesis of Alzheimer's disease (AD) is characterized by cerebral deposits of amyloid beta-peptides (A beta) and neurofibrillary tangles which are surrounded by inflammatory cells. Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of NSAIDs such as ibuprofen, aspirin, meclofenamic acid sodium salt, diclofenac sodium salt, ketoprofen, flurbiprofen, naproxen, sulindac sulfide and indomethacin on the formation, extension, and destabilization of beta-amyloid fibrils (fA beta) at pH 7.5 at 37 degrees C in vitro. All examined NSAIDs dose-dependently inhibited formation of fA beta from fresh A beta(1-40) and A beta(1-42), as well as their extension. Moreover, these NSAIDs dose-dependently destabilized preformed fA betas. The overall activity of the molecules examined was in the following order: ibuprofen approximately sulindac sulfide >or= meclofenamic acid sodium salt>aspirin approximately ketoprofen >or= flurbiprofen approximately diclofenac sodium salt>naproxen approximately indomethacin. Although the mechanisms by which these NSAIDs inhibit fA beta formation from A beta, and destabilize preformed fA beta in vitro are still unclear, NSAIDs may be promising for the prevention and treatment of AD.     

Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro

The aggregation of alpha-synuclein (alphaS) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) [Parkinson's disease (PD)/dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA). The involvement of neuroinflammation and microglial activation has been emphasized in the pathogenesis of PD. Recent epidemiological studies have revealed that therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing PD. Here, we examined the effects of NSAIDs, such as ibuprofen, aspirin, acetaminophen, meclofenamic acid sodium salt, sulindac sulfide, ketoprofen, flurbiprofen, diclofenac sodium salt, naproxen, and indomethacin, on the formation and destabilization of alphaS fibrils (falphaS) at pH 7.5 and 37 degrees C in vitro, using fluorescence spectroscopy with thioflavin S and electron microscopy. All examined NSAIDs, except for naproxen and indomethacin, inhibited the formation of falphaS in a dose-dependent manner. Moreover, these molecules dose-dependently destabilized preformed falphaS. The overall activity was in the order: ibuprofen approximately aspirin approximately acetaminophen approximately meclofenamic acid sodium salt approximately sulindac sulfide>ketoprofen approximately flurbiprofen approximately diclofenac sodium salt>naproxen approximately indomethacin. These findings indicate that NSAIDs could be key molecules for the development of therapeutic or preventive agents for LBD and MSA.     

Inhibition of prostanoid synthesis by human gastric mucosa

Non-steroidal anti-inflammatory drugs (NSAIDs) damage the gastric mucosa, and an important part of this effect is probably due to inhibition of prostaglandin synthesis. We have therefore studied various drugs for their ability to reduce prostaglandin and thromboxane formation by human isolated gastric mucosa. The overall relative potencies for inhibiting the endogenous production of PGE, 6-keto-PGF1 alpha and thromboxane B2 by mucosal pieces was generally: indomethacin = naproxen greater than ibuprofen greater than piroxicam; diflunisal, the prodrug sulindac, and the analgesic paracetamol usually had small or variable effects. This rank order was mainly similar to the inhibition of gastric microsomal PGE2 formation from exogenous arachidonic acid, the relative potencies being: indomethacin greater than naproxen greater than ibuprofen = piroxicam = diflunisal; again sulindac and paracetamol had little or no effect. The relative propensity of NSAIDs to cause gastric mucosal damage is controversial, but aspirin and indomethacin may be worst, and ibuprofen seems to be among the safest. Potency as an inhibitor of prostaglandin synthesis correlates better with the reported propensity for damage than does potency x dose. For reasons that are given in the discussion, this may indicate that gastric mucosal damage by NSAIDs with short or moderate half-lives is due largely to locally absorbed drug. Whereas inhibition of prostaglandin synthesis is probably the major cause of the damage, the simultaneous reduction of thromboxane formation might be advantageous for gastric mucosal integrity. Various implications arise from our hypotheses concerning the design of anti-inflammatory drugs.     

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit vascular smooth muscle cell proliferation via differential effects on the cell cycle

Abnormal vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of both atherosclerosis and restenosis. Recent studies suggest that high-dose salicylates, in addition to inhibiting cyclooxygenase activity, exert an antiproliferative effect on VSMC growth both in-vitro and in-vivo. However, whether all non-steroidal anti-inflammatory drugs (NSAIDs) exert similar antiproliferative effects on VSMCs, and do so via a common mechanism of action, remains to be shown. In this study, we demonstrate that the NSAIDs aspirin, sodium salicylate, diclofenac, ibuprofen, indometacin and sulindac induce a dose-dependent inhibition of proliferation in rat A10 VSMCs in the absence of significant cytotoxicity. Flow cytometric analyses showed that exposure of A10 cells to diclofenac, indometacin, ibuprofen and sulindac, in the presence of the mitotic inhibitor, nocodazole, led to a significant G0/G1 arrest. In contrast, the salicylates failed to induce a significant G1 arrest since flow cytometry profiles were not significantly different from control cells. Cyclin A levels were elevated, and hyperphosphorylated p107 was present at significant levels, in salicylate-treated A10 cells, consistent with a post-G1/S block, whereas cyclin A levels were low, and hypophosphorylated p107 was the dominant form, in cells treated with other NSAIDs consistent with a G1 arrest. The ubiquitously expressed cyclin-dependent kinase (CDK) inhibitors, p21 and p27, were increased in all NSAID-treated cells. Our results suggest that diclofenac, indometacin, ibuprofen and sulindac inhibit VSMC proliferation by arresting the cell cycle in the G1 phase, whereas the growth inhibitory effect of salicylates probably affects the late S and/or G2/M phases. Irrespective of mechanism, our results suggest that NSAIDs might be of benefit in the treatment of certain vasculoproliferative disorders.     

Effect of meseclazone and other non-steroidal anti-inflammatory drugs on isolated tracheal chain tone.

Meseclazone, 5-CSA and several representative NSAIDs caused concentration-dependent relaxation of the tracheal ring preparation and are listed in order of descending potency: isoproterenol greater than naproxen greater than ibuprofen greater than diflunisal greater than tolmetin approximately equal to fenoprofen approximately equal to indomethacin greater than phenylbutazone greater than meseclazone greater than 5-CSA greater than aspirin. This relaxation may be related to inhibition of prostaglandin synthetase, but relative potencies of NSAIDs in this test do not necessarily correspond to their potency in inhibiting PG synthethase in other tissue. Thus other factors may play a role.     

Clinical pharmacokinetics of drugs used in juvenile arthritis

Juvenile arthritis is defined as the occurrence of objective evidence of arthritis for a minimum of 6 weeks, in a child 16 years of age or younger. With a reported incidence of 9 to 19.6 per 100,000 children, juvenile arthritis is considered to be a rare disease. There is no known cure; however, up to 75% of patients will undergo remission by late adolescence. Drugs used in the treatment of juvenile arthritis are divided into 2 major classes: (a) the nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates, naproxen, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, indomethacin, sulindac, tolmetin and diclofenac, and (b) disease modifying agents which encompass drugs such as antimalarial agents, gold, methotrexate, penicillamine and sulfasalazine. In almost all the reports dealing with the pharmacokinetics of NSAIDs, the level of disease activity has not been noted. The level of activity is important since, during a flare, the plasma albumin may fall to the point that it causes a substantial and clinically significant increase in the unbound serum concentration of highly bound drugs. The relationship between the concentration of these drugs in the systemic circulation and their efficacy is not clear. However, for many of them, therapeutic drug monitoring is recommended as a means of reducing the possibility of toxic reactions. Further pharmacokinetic and -dynamic evaluations are needed for many of these drugs in juvenile arthritis.     

红细胞葡萄糖-6-磷酸脱氢酶缺乏症45例临床分析

目的 分析红细胞葡萄糖-6-磷酸脱氢酶（红细胞G-6-PD酶）缺乏症的临床特点、治疗过程及临床预后情况,提高临床的诊治水平。方法 选取45例红细胞G-6-PD酶缺乏的女患儿,观察患儿治疗前后相关指标变化。结果 患儿治疗后贫血及黄疸症状明显减轻,口唇及皮肤颜色好转,治疗3 d后和治疗5 d后其血清总胆红素及血红蛋白明显优于治疗前（P〈0.05）。结论 红细胞G-6-PD酶缺乏症多与食用蚕豆及其制品有关,临床上发病多以急性血管内溶血为主要的临床表现,换血治疗是一种行之有效的治疗方法。     

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.     

Pharmacological management of juvenile rheumatoid arthritis.

The goals of pharmacotherapy in juvenile rheumatoid arthritis (JRA) are to suppress chronic synovitis which causes potential cartilage destruction and deformities, to control the systemic effects of inflammation (including growth retardation and nutritional deficits), relieve pain and limit psychological impact of disease. Currently available methods include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, salicylates, naproxen, tolmetin, ibuprofen and indomethacin; disease modifying antirheumatic drugs (DMARDs) such as oral and injectable gold salts, hydroxychloroquine, penicillamine, oral and injectable methotrexate, and sulfasalazine; oral (daily or on alternate days), intravenous pulse or intra-articular corticosteroids; immunosuppresants, including cyclophosphamide, chlorambucil, cyclosporin, and azathioprine; and gammaglobulin and other experimental therapies. Over the past 10 years, rheumatologists have adopted more aggressive pharmacological treatment of JRA. As time progresses and the safety of certain drugs such as methotrexate and sulfasalazine becomes clearer, wider and earlier use of these agents can be expected. Still the approach to treatment is a 'step by step' one, starting with the classical NSAIDs and ending with the DMARDs as needed.     

Review article: the effect of Helicobacter pylori infection on nonsteroidal anti-inflammatory drug-induced upper gastrointestinal tract injury

Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are the two major causes of peptic ulcers. This article reviews the interaction of H. pylori and NSAIDs on the development of gastric mucosal histological changes, endoscopically confirmed ulcers, and ulcer complications, and assesses whether underlying H. pylori infection potentiates (or mitigates) the development of NSAID-induced ulcer disease. The weight of evidence does not suggest that H. pylori infection potentiates the risk of ulcer formation or ulcer complications in NSAID users. If such an effect occurs, it is likely to be relatively small. Some data even suggest that H. pylori may be protective against NSAID-induced gastric ulcers. Limited data raise the possibility that H. pylori infection, however, may potentiate the effect of low-dose aspirin with respect to ulcer bleeding. Both NSAIDs and H. pylori are independent risk factors for ulcer disease. Therefore, in an individual patient with an ulcer, one cannot be certain which factor is responsible for the ulcer, and both risks should be removed if possible.     

Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers

Background  Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most prescribed drugs worldwide and have now probably overtaken Helicobacter pylori as the most common cause of gastrointestinal injury in Western countries. Further understanding of the pathogenesis of NSAID-induced ulcers is important to enable the development of novel and effective preventive strategies.
Aims  To provide an update on recent advances in our understanding of the cellular and molecular mechanisms involved in the development of NSAID-induced ulcers.
Methods  A Medline search was performed to identify relevant literature using search terms including 'nonsteroidal anti-inflammatory drugs, aspirin, gastric ulcer, duodenal ulcer, pathogenesis, pharmacogenetics'.
Results  The mechanisms of NSAID-induced ulcers can be divided into topical and systemic effects and the latter may be prostaglandin-dependent (through COX inhibition) or prostaglandin-independent. Genetic factors may play an important role in determining individual predisposition.
Conclusions  The pathogenesis of NSAID-induced peptic ulcers is complex and multifactorial. Recent advances in cellular and molecular biology have highlighted the importance of various prostaglandin-independent mechanisms. Pharmacogenetic studies may provide further insights into the pathogenetic mechanisms of NSAID-induced ulcers and help identify patients at increased risk.     

Immunomodulatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) at the clinically available doses

Non-steroidal anti-inflammatory drugs (NSAIDs) with cyclooxygenase (COX) inhibitory activity are commonly used in various inflammatory diseases. In this study, to examine the immunomodulatory effects of well known NSAIDs at clinically available doses, macrophage- and T cell-mediated immune responses such as tumor necrosis factor (TNF)-alpha release and nitric oxide (NO) production, cell-cell adhesion, phagocytic uptake and lymphocyte proliferation were investigated. NSAIDs tested significantly enhanced TNF-alpha release from lipopolysaccharide (LPS)-activated RAW264.7 cells at certain concentrations (fenoprofen, indomethacin, piroxicam, aceclofenac, diclofenac and sulindac) or in a dose-dependent manner (aspirin and phenylbutazone). Of NSAIDs, phenylbutazone and aspirin most potently attenuated NO production, although sulindac was the only compound with cytoprotective activity against LPS-induced cytotoxicity. Most NSAIDs used displayed weak or no modulatory effects on phagocytic uptake and CD29- or CD43-mediated cell-cell adhesion. Interestingly, however, phenylbutazone itself triggered cell-cell clustering under normal culture conditions and enhanced the phagocytic activity. Aspirin and phenylbutazone also dose-dependently attenuated CD4+ T cell proliferation stimulated by concanavalin A (Con A) and CD8+ CTLL-2 cell proliferation induced by interleukin (IL)-2. Sulindac only blocked CTLL-2 cell proliferation. These results suggest that NSAIDs may differentially exert immunomodulatory effects on activated macrophages and lymphocytes, and some of the effects may enforce NSAID's therapeutic effect against inflammatory symptoms.     

Building a better aspirin: gaseous solutions to a century-old problem

The gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) have been recognized since shortly after the introduction of aspirin to the marketplace over a century ago. However, the underlying pathogenesis of NSAID-induced gastropathy remains incompletely understood. Advances in understanding some of the factors that contribute to the mucosal injury have provided clues for the development of safer NSAIDs. The inhibitory effects of nitric oxide (NO) on NSAID-induced leukocyte adherence were exploited in the development of NO-releasing NSAIDs. As well as eliciting less gastrointestinal damage than conventional NSAIDs, these drugs do not elevate blood pressure and show anti-inflammatory effects, additional to those of the parent drugs. Modification of other drugs in a similar manner (i.e., NO-releasing derivatives) has similarly resulted in more effective drugs. More recently, hydrogen sulphide-releasing derivatives of NSAIDs and of other drugs, have been developed, based on the observed ability of H(2)S to reduce inflammation and pain in experimental models. H(2)S-releasing NSAIDs produce negligible gastric damage and exhibit enhanced anti-inflammatory potency as compared to the parent drugs. The NO-NSAIDs and H(2)S-releasing NSAIDs represent examples of new anti-inflammatory drugs with greatly reduced toxicity and improved therapeutic activity, both created through the concept of exploiting the beneficial effects of endogenous gaseous mediators.