LE Magazine October 2002
Page 1 of 4
Anti-inflammatory
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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