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LE Magazine October 2002


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Interleukin-1 beta induces cytosolic phospholipase A2 and prostaglandin H synthase in rheumatoid synovial fibroblasts. Evidence for their roles in the production of prostaglandin E2.

OBJECTIVE. In order to investigate potential regulatory mechanisms for the increased production of prostaglandin E2 (PGE2) in interleukin-1 beta (IL-1 beta)-stimulated rheumatoid synovial fibroblasts (RSF), this study examined the induction of phospholipase A2 (PLA2) and prostaglandin H synthase (PGHS) enzymes and the correlation of these events with PGE2 production in IL-1 beta-stimulated RSF. METHODS. Protein and messenger RNA (mRNA) levels of cytosolic PLA2 (cPLA2) and PGHS-2 enzymes in IL-1 beta-stimulated RSF were measured by Western and Northern blotting, respectively, using specific antisera and complementary DNA probes. Enzymatic activity of cPLA2 was determined in cell-free reaction mixtures utilizing mixed micelles of 14C-phosphatidylcholine and Triton X-100 as the substrate. PGE2 levels were quantitated using a commercial enzyme immunoassay kit. RESULTS. Incubation of RSF with IL-1 beta increased the mRNA and protein levels for the high molecular weight cPLA2 as well as for the mitogen/growth factor-responsive PGHS (PGHS-2). The IL-1 receptor antagonist completely abolished the induction of these two enzymes and the stimulation of PGE2 production by IL-1 beta in RSF. In contrast, levels of the other known forms of these enzymes, i.e., the 14-kd secretory group II PLA2 (sPLA2) and the constitutive form of PGHS (PGHS-1), were unaffected by IL-1 beta treatment. CONCLUSION. These are the first data to demonstrate the coordinate induction by IL-1 of cPLA2 and PGHS-2 in RSF. The time-course for the induction of these enzymes suggests that their increase contributes to the increased production of PGE2 in IL-1-treated RSF, and may help explain the capacity of RSF to produce large amounts of PGE2.

Arthritis Rheum 1994 May;37(5):653-61

Interleukin-1-mediated phospholipid breakdown and arachidonic acid release in human synovial cells.

OBJECTIVE. Interleukin-1 (IL-1), an important mediator contributing to joint destruction in rheumatoid arthritis, is known to stimulate the release of arachidonic acid (AA) and prostaglandin E2 (PGE2) from adherent synoviocytes. To study the intracellular pathways involved in these functions, we stimulated cultures of human synovial cells with recombinant IL-1 beta. METHODS. AA liberation was measured after labeling synovial cells with 3H-AA, and PGE2 levels were determined by high performance liquid chromatography or radioimmunoassay. Identification of 3H-AA-labeled phospholipids was performed by thin layer chromatography. Cell-associated phospholipase A2 (PLA2) enzymatic activity was determined by an assay with cell-free systems and exogenous substrates. RESULTS. Stimulation of synovial cells with recombinant IL-1 beta induced a decrease in phosphatidylcholine (PC), phosphatidylinositol (PI), and phosphatidylethanolamine (PE), and a marked increase in cell-associated PLA2 activity as compared with controls. In the presence of either quinacrine, an inhibitor of PLA2 pathway activation, or neomycin, which binds to PI mono- and biphosphate thus blocking their degradation by phospholipases, AA and PGE2 secretion were reduced in a dose-dependent manner. Kinetic studies revealed that quinacrine had little blocking activity on the IL-1-mediated AA release after one hour of stimulation but completely abolished it after five or eight hours. In contrast, neomycin exerted a partial but significant inhibitory effect from the first hour of stimulation onward. Addition of quinacrine was also demonstrated to abolish the IL-1-induced hydrolysis of PC and PE but not PI, indicating that PC and PE are the preferred substrates for PLA2 enzymatic activity in human synovial cells. CONCLUSION. Our findings strongly suggest that AA and PGE2 production by IL-1-triggered synoviocytes are largely dependent upon PLA2-mediated hydrolysis of PC and PE and to a lesser extent upon the earlier degradation of PI.

Arthritis Rheum 1993 Feb;36(2):158-67

The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: a randomized, double blind, placebo controlled study.

The aim of this study was to assess if the pain of osteoarthritis is reduced by topical capsaicin and to determine whether addition of glyceryl trinitrate has an effect on analgesic efficacy and tolerability of capsaicin. A randomized, double blind, placebo controlled study was carried out on 200 adult patients attending a Pain Clinic with osteoarthritis pain. Patients applied one of four creams topically over the affected joint over a six-week period. Creams contained either placebo (vehicle), 0.025% capsaicin, 1.33% glyceryl trinitrate or 0.025% capsaicin + 1.33% glyceryl trinitrate. Analgesic efficacy, tolerability of cream and analgesic consumption were assessed. One hundred and sixty-seven of 200 patients completed the study. Baseline visual analogue scores (0-10 scale) for pain were 6.40. There was a significant reduction in pain scores in the glyceryl trinitrate group (mean decrease 0.59, p< 0.05, 95% confidence limits 0.04-1.14), 0.025% capsaicin group (mean decrease 0.5, p< 0.05, 95% confidence limits 0.05-1.05) and the glyceryl trinitrate capsaicin group (mean decrease 1.1, p<0.05, 95% confidence limits 0.22-1.98). Baseline discomfort of application scores were similar for all but the capsaicin groups (they were significantly higher (by 2.1 units, p< 0.001)). The odds ratio in favor of continuing treatment was 2.1 (95% confidence limits 1.0-4.4) for glyceryl trinitrate and 2.4 (95% confidence limits 1.2-5.1) for capsaicin and 5.0 (95% confidence limits 3.8-6.4) for capsaicin GTN combination. The study showed that topical capsaicin and glyceryl trinitrate have an analgesic effect in painful osteoarthritis. When used together this effect is increased with the combination being more tolerable than capsaicin alone. Analgesic consumption is decreased by capsaicin, glyceryl trinitrate and to a greater extent by both combined.

Eur J Pain 2000;4(4):355-60

Use of topical non-steroidal anti-inflammatory drugs in aggravated and decompensated arthroses.

Pain in osteoarthritis of the big weight bearing joints is either derived from periarticular ligaments, tendons, fascias, muscles, bursae—periarthropathy as sign of decompensation or from the reactive synovitis with or without effusion. NSAIDs (ibuprofen, diclofenac, indometacin, some salicylates, etofenamate and piroxicam) have demonstrated relevant advantages of the percutaneous route over the systemic one in soft tissue rheumatism. NSAIDs, mentioned above, locally administered as cream, gel or spray, quickly penetrate through the corneal layer of the skin and the site of application, reach highly effective concentrations in subcutis, fascias, tendons, ligaments and muscles, less in joint-capsule and -fluid indicating direct penetration. The blood levels of topical NSAIDs are extremely low with no systemic side effects, especially no gastric toxicity; however, local skin irritation is observed (1% to 2%). In contrast to this, systemic (oral) NSAIDs lead primarily via high blood levels to a lower concentration—only one tenth—in periarticular soft tissues with a high incidence of side effects. In conclusion the percutaneous application of certain NSAIDs has become a well established therapeutic regimen in painful osteoarthritis and in all other inflammatory degenerative and posttraumatic alterations of soft tissue structure.

Wien Med Wochenschr 1999;149(19-20):546-7

Getting control of osteoarthritis pain. An update on treatment options.

Osteoarthritis consists of a heterogeneous group of disorders that result in articular cartilage degeneration and is diagnosed on the basis of clinical findings. Pathogenesis involves an imbalance between the synthetic and degradative processes that occur in joints. Current interest in the role of cytokines and metalloproteinases may lead to improved treatment of osteoarthritis. For now, management consists of combinations of pharmacologic and nonpharmacologic therapies. A general pharmacologic approach is to begin with acetaminophen and add a low-dose NSAID, nonacetylated salicylate, selective COX-2 inhibitor, or topical capsaicin cream if needed. If pain persists, full-dose NSAID therapy, with the addition of a protective agent in patients at risk for gastrointestinal bleeding, or full-dose COX-2 inhibitor therapy may be tried. Joint injections, irrigation or arthroscopy may be beneficial in some cases. In patients who continue to have pain and limited function despite these measures, surgical intervention should be considered.

Postgrad Med 1999 Oct 1;106(4):127-34

Treatment of arthritis with topical capsaicin: a double-blind trial.

The neuropeptide substance P has been implicated in the pathogenesis of inflammation and pain in arthritis. In this double-blind randomized study, 70 patients with osteoarthritis (OA) and 31 with rheumatoid arthritis (RA) received capsaicin (a substance P depletor) or placebo for four weeks. The patients were instructed to apply 0.025% capsaicin cream or its vehicle (placebo) to painful knees four times daily. Pain relief was assessed using visual analog scales for pain and relief, a categorical pain scale, and physicians’ global evaluations. Most of the patients continued to receive concomitant arthritis medications. Significantly more relief of pain was reported by the capsaicin-treated patients than the placebo patients throughout the study; after four weeks of capsaicin treatment, RA and OA patients demonstrated mean reductions in pain of 57% and 33%, respectively. These reductions in pain were statistically significant compared with those reported with placebo (P = 0.003 and P = 0.033, respectively). According to the global evaluations, 80% of the capsaicin-treated patients experienced a reduction in pain after two weeks of treatment. Transient burning was felt at the sites of drug application by 23 of the 52 capsaicin-treated patients; two patients withdrew from treatment because of this side effect. It is concluded that capsaicin cream is a safe and effective treatment for arthritis.

Clin Ther 1991 May-Jun;13(3):383-95

Anti-inflammatory effect of diclofenac-sodium ointment (cream) in topical application.

This study was performed to develop a topical ointment of diclofenac-Na which has a potent anti-inflammatory activity by oral administration. At first, research was carried out on the ointment base which influences the external anti-inflammatory effect of the drug. Ointments of diclofenac-Na were prepared with three kinds of bases: lipophilic, emulsion (cream) and gel bases; and their anti-inflammatory effects were compared. The cream was found to have the most potent effect. Therefore, in the next experiment, an optimum concentration of diclofenac-Na in cream was determined comparing the anti-inflammatory effect among the cream preparations containing 0.5, 0.75, 1.0 and 1.5% of the drug. Obvious effects were observed with the cream containing 1.0% and 1.5% of the drug concentration, and there was no significant difference in the anti-inflammatory activities of these two concentrations. Based on these results, the cream preparation containing 1.0% of diclofenac-Na (DF cream) was adopted as the external ointment of the drug. The anti-inflammatory effect of this cream was compared with that of existing anti-inflammatory ointments, i.e., indomethacin gel (IM gel), bufexamac cream (BM cream) and mobilat ointment (ML ointment). DF cream produced obvious inhibition on increased vascular permeability and on acute edema and remarkable suppression of ultraviolet erythema. These activities of DF cream were similar to those of IM gel and more potent than those of BM cream and ML ointment. The inhibitory effect of DF cream on the proliferation of granulation tissue was almost equal to that of ML ointment and more distinguishable than that of IM gel and BM cream. In adjuvant arthritis, DF cream reduced the swelling remarkably in the treated paw and slightly in the untreated paw. The anti-adjuvant activity of DF cream was equal to that of IM gel and more potent than that of BM cream and ML ointment. In pain to pressure stimulation, an analgesic effect was observed in the early stage of DF cream application, and its activity was slightly stronger than that of the other ointments. These results show that DF cream has an obvious anti-inflammatory effect as an external preparation, and the activity is comparable or superior to that of similar existing anti-inflammatory ointments. This cream may be considered as useful in the clinical field as a topical anti-inflammatory preparation.

Jpn J Pharmacol 1983 Feb;33(1):121-32

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