LE Magazine October 2002
Page 2 of 4
Phospholipase A2 is a major component
of the salt-extractable pool of matrix proteins in adult human
articular cartilage.
Adult human articular cartilage contains a component with
an apparent molecular weight of 16 kd, which is extractable
with high ionic strength buffers. This protein, which, in
addition to lysozyme, is one of the most prominent components
in salt extracts of adult cartilage, is not detectable in
cartilage from newborns. We performed N-terminal sequence
analysis to identify the protein. The amino acid sequence
obtained for the first 20 residues was identical to that
reported for phospholipase A2 (PLA2) from human placenta and
human synovial cells. The extractable PLA2 was found to be
active. The lack of PLA2 in salt extracts from newborn
cartilage observed by sodium dodecyl sulfate-polyacrylamide
gel electrophoresis analysis was confirmed by the very low
levels of PLA2 activity detectable in these preparations. PLA2
was clearly present in cartilage extracts from an 18-year-old
subject and a 19-year-old subject, suggesting that its
accumulation begins at some stage during the adolescent growth
period. The enzyme does not appear to be released from
cartilage matrix under normal physiologic conditions, and it
is possible that the accumulation of PLA2 in maturing
cartilage is a result of the decreased matrix turnover
associated with the termination of skeletal growth. Whether
PLA2 is active in the cartilage matrix, its precise
localization, and its effects on the resident chondrocytes
remain to be determined.
Arthritis Rheum 1991
Sep;34(9):1106-15
Anti-inflammatory activity of
orpanoxin administered orally and topically to rodents.
Orpanoxin, a nonsteroidal anti-inflammatory drug (NSAID)
lacking gastric ulcerogenic effects in the therapeutic dose
range in rats, was compared with six reference NSAIDs for oral
activity in the rat paw carrageenin-induced edema assay.
Tested NSAIDs were ranked on the basis of oral mg/kg ED50
values: piroxicam, 0.55; orpanoxin, 35.6; diflunisal, 59.6;
benoxaprofen, greater than 300; tolmetin sodium, greater than
300; and sulindac, greater than 300. Zomepirac sodium was
inactive. Only the three most potent compounds produced
greater than 60% inhibition of edema. Inhibition was generally
greater at 4 h than at 6 h post carrageenin for all compounds.
Oral activity of orpanoxin was also demonstrated in the
guinea-pig u.v.-induced erythema model (ED50 = 24.2 mg/kg p.o.
when given 1 h before irradiation) and in the mouse ear croton
oil induced edema test (ED50 value = 131 mg/kg p.o.). Topical
activity of orpanoxin was assessed in both the guinea-pig and
mouse models. In the guinea-pig u.v.-induced erythema model,
application (1 h after u.v.) of 1, 5, and 10% (w/v) orpanoxin
creams (containing 10% urea) significantly inhibited erythema
at 2, 3, and 4 h post-irradiation. Orpanoxin, mefenamic acid,
and indomethacin as 1% creams inhibited total erythema scores
70, 92 and 74%, respectively. Evidence for topical activity in
the mouse ear assay was also obtained for orpanoxin in diethyl
ether or 10% urea cream, but not in dimethylsulfoxide. It was
concluded that orpanoxin has anti-inflammatory activity
comparable to reference NSAIDs in the rat paw edema test, is
active orally in rat, mouse, and guinea-pig models, and shows
topical activity in the guinea-pig and the mouse.
Agents Actions 1985
Jul;16(5):369-76
Percutaneous therapy of painful
arthritis.
Pain in osteoarthrosis of the big weight bearing joints is
either derived from periarticular ligaments, tendons, fasciae,
muscles, bursae—peri-arthropathy as sign of
decompensation—or from the reactive synovitis with or
without effusion. NSAIDs systemically administered have been
so far considered as first choice medication together with
physical therapy. New pharmacokinetic data on the topical,
percutaneous application of NSAIDs (ibuprofen, diclofenac,
indomethacin, some salicylates and to a lesser degree for
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 at the site of application,
reach high effective concentrations in subcutis, fasciae,
tendons, ligaments and muscles, lesser 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 much lesser concentration—only one tenth—in
particular 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
osteoarthrosis and in all other inflammatory degenerative and
posttraumatic alterations of soft tissue structures.
Ther Umsch 1991 Jan;48(1):42-5
Comparative tissue absorption of oral
14C-aspirin and topical triethanolamine 14C-salicylate in
human and canine knee joints.
The local, articular, and systemic absorption of oral and
topical salicylates was studied in dogs and humans using
radioisotope techniques. Topical triethanolamine
14C-salicylate was found capable of percutaneous absorption
into the knee joint and surrounding tissues. In dogs, topical
salicylate application resulted in higher salicylate
concentrations than oral aspirin in a number of tissues,
despite lower blood levels. In patients with rheumatoid
arthritis, intraarticular 14C-salicylate levels after
triethanolamine 14C-salicylate cream were 60% of those
obtained with oral aspirin. Four of six patients reported
equal improvement in local discomfort after oral and topical
salicylates. A potential role for topical salicylate cream in
the treatment of localized rheumatic disorders is
suggested.
J Clin Pharmacol 1982
Jan;22(1):42-8
Effect of topical capsaicin in the
therapy of painful osteoarthritis of the hands.
Topical capsaicin 0.075% was evaluated for the treatment of
the painful joints of rheumatoid arthritis (RA) and
osteoarthritis (OA) in a four week double blind, placebo
controlled randomized trial. Twenty-one patients were
selected, all of whom had either RA (n = 7) or OA (n = 14)
with painful involvement of the hands. Assessments of pain
(visual analog scale), functional capacity, morning stiffness,
grip strength, joint swelling and tenderness (dolorimeter)
were performed before randomization. Treatment was applied to
each painful hand joint four times daily with reassessment at
one, two and four weeks after entry. One subject did not
complete the study. Capsaicin reduced tenderness (p less than
0.02) and pain (p less than 0.02) associated with OA, but not
RA as compared with placebo. A local burning sensation was the
only adverse effect noted. These findings suggest that topical
capsaicin is a safe and potentially useful drug for the
treatment of painful OA of the hands.
J Rheumatol 1992 Apr;19(4):604-7
Topical application of doxepin
hydrochloride, capsaicin and a combination of both produces
analgesia in chronic human neuropathic pain: a randomized,
double-blind, placebo-controlled study.
AIMS: To assess the analgesic efficacy of topical
administration of 3.3% doxepin hydrochloride, 0.025% capsaicin
and a combination of 3. 3% doxepin and 0.025% capsaicin in
human chronic neuropathic pain. METHODS: A randomized,
double-blind, placebo-controlled study of 200 consenting adult
patients. Patients applied placebo, doxepin, capsaicin or
doxepin/capsaicin cream daily for four weeks. Patients
recorded on a daily basis overall pain, shooting, burning,
paraesthesia and numbness using a 0-10 visual analogue scale
during the week prior to cream application (baseline levels)
and for the four-week study period. Side-effects and desire to
continue treatment were also recorded. RESULTS: Overall pain
was significantly reduced by doxepin, capsaicin and
doxepin/capsaicin to a similar extent. The analgesia with
doxepin/capsaicin was of more rapid onset. Capsaicin
significantly reduced sensitivity and shooting pain. Burning
pain was increased by doxepin and by capsaicin and to a lesser
extent by doxepin/capsaicin. Side-effects were minor. One
patient requested to continue placebo cream, 17 doxepin cream,
13 capsaicin and nine the combination of doxepin and
capsaicin. CONCLUSIONS: Topical application of 3.3% doxepin,
0.025% capsaicin and 3.3% doxepin/0. 025% capsaicin produces
analgesia of similar magnitude. The combination produces more
rapid analgesia.
Br J Clin Pharmacol 2000
Jun;49(6):574-9
Topical capsaicin for chronic neck
pain. A pilot study.
Substance P is thought to be the principle neurotransmitter
of nociceptive impulses in type C sensory neurons. Prolonged
repeated applications of capsaicin cream depletes the sensory
C-fibers of substance P. In an open-labeled prospective pilot
study, 23 patients with chronic neck pain (greater than three
mo) completed the study. Patients applied topical capsaicin
(0.025%) cream four times a day to painful areas in the neck
and shoulder girdle for a five-wk treatment period. One
patient dropped out because of intolerable burning.
Statistically significant improvement was obtained in two
primary outcome variables, the visual analog pain scale (P =
0.00013) and the pain relief scale (P = 0.002). Paired t tests
failed to show a significant improvement in the McGill Pain
Questionnaire. This study demonstrated that topically applied
capsaicin cream may decrease subjective neck pain. A
double-blind, placebo-controlled trial is needed to confirm
this treatment effect.
Am J Phys Med Rehabil 1995
Jan-Feb;74(1):39-44
Treatment of painful diabetic
neuropathy with topical capsaicin. A multicenter,
double-blind, vehicle-controlled study. The Capsaicin Study
Group.
A multicenter study was conducted to establish the efficacy
of topical 0.075% capsaicin cream in relieving the pain
associated with diabetic neuropathy. Capsaicin or vehicle
cream was applied to painful areas four times per day for
eight weeks in patients randomly assigned to one of two
groups. Pain intensity and relief were recorded at two-week
intervals using physician’s global evaluation and visual
analog scales. Analysis at final visit for 252 patients showed
statistical significance favoring capsaicin compared with
vehicle for the following: 69.5% vs 53.4% pain improvement by
the physician’s global evaluation scale, 38.1% vs 27.4%
decrease in pain intensity, and 58.4% vs 45.3% improvement in
pain relief. With the exception of transient burning,
sneezing, and coughing, capsaicin was well tolerated. Study
results suggest that topical capsaicin cream is safe and
effective in treating painful diabetic neuropathy.
Arch Intern Med 1991
Nov;151(11):2225-9
A double-blind evaluation of topical
capsaicin in pruritic psoriasis.
BACKGROUND: Substance P, an undecapeptide neurotransmitter,
has been implicated in the pathophysiology of psoriasis and
pruritus. OBJECTIVE: Safety and efficacy of topical capsaicin,
a potent substance P depletor, were evaluated in patients with
pruritic psoriasis. METHODS: Patients applied capsaicin 0.025%
cream (n = 98) or vehicle (n = 99) four times a day for six
weeks in this double-blind study. Efficacy was based on a
physician’s global evaluation and a combined psoriasis
severity score including scaling, thickness, erythema and
pruritus. RESULTS: Capsaicin-treated patients demonstrated
significantly greater improvement in global evaluation (p =
0.024 after four weeks and p = 0.030 after six weeks) and in
pruritus relief (p = 0.002 and p = 0.060, respectively), as
well as a significantly greater reduction in combined
psoriasis severity scores (p = 0.030 and p = 0.036,
respectively). The most frequently reported side effect in
both treatment groups was a transient burning sensation at
application sites. CONCLUSION: Topically applied capsaicin
effectively treats pruritic psoriasis, a finding that supports
a role for substance P in this disorder.
J Am Acad Dermatol 1993
Sep;29(3):438-42
Gamma tocopherol
Gamma tocopherol, the major form of
vitamin E in the U.S. diet, deserves more attention.
Gamma tocopherol is the major form of vitamin E in many
plant seeds and in the U.S. diet, but has drawn little
attention compared with alpha tocopherol, the predominant form
of vitamin E in tissues and the primary form in supplements.
However, recent studies indicate that gamma tocopherol may be
important to human health and that it possesses unique
features that distinguish it from alpha tocopherol. gamma
tocopherol appears to be a more effective trap for lipophilic
electrophiles than is alpha tocopherol. Gamma tocopherol is
well absorbed and accumulates to a significant degree in some
human tissues; it is metabolized, however, largely to
2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman
(gamma-CEHC), which is mainly excreted in the urine.
gamma-CEHC, but not the corresponding metabolite derived from
alpha tocopherol, has natriuretic activity that may be of
physiologic importance. Both gamma tocopherol and gamma-CEHC,
but not alpha tocopherol, inhibit cyclooxygenase activity and,
thus, possess anti-inflammatory properties. Some human and
animal studies indicate that plasma concentrations of gamma
tocopherol are inversely associated with the incidence of
cardiovascular disease and prostate cancer. These
distinguishing features of gamma tocopherol and its metabolite
suggest that gamma tocopherol may contribute significantly to
human health in ways not recognized previously. This
possibility should be further evaluated, especially
considering that high doses of alpha tocopherol deplete plasma
and tissue gamma tocopherol, in contrast with supplementation
with gamma tocopherol, which increases both. We review current
information on the bioavailability, metabolism, chemistry and
nonantioxidant activities of gamma tocopherol and
epidemiologic data concerning the relation between gamma
tocopherol and cardiovascular disease and cancer.
Am J Clin Nutr 2001
Dec;74(6):714-22
Association between alpha tocopherol,
gamma tocopherol, selenium and subsequent prostate cancer.
BACKGROUND: Selenium and alpha tocopherol, the major form
of vitamin E in supplements, appear to have a protective
effect against prostate cancer. However, little attention has
been paid to the possible role of gamma tocopherol, a major
component of vitamin E in the U.S. diet and the second most
common tocopherol in human serum. A nested case-control study
was conducted to examine the associations of alpha tocopherol,
gamma tocopherol and selenium with incident prostate cancer.
METHODS: In 1989, a total of 10,456 male residents of
Washington County, MD, donated blood for a specimen bank. A
total of 117 of 145 men who developed prostate cancer and 233
matched control subjects had toenail and plasma samples
available for assays of selenium, alpha tocopherol and gamma
tocopherol. The association between the micronutrient
concentrations and the development of prostate cancer was
assessed by conditional logistic regression analysis. All
statistical tests were two-sided. RESULTS: The risk of
prostate cancer declined, but not linearly, with increasing
concentrations of alpha tocopherol (odds ratio (highest versus
lowest fifth) = 0.65; 95% confidence interval = 0.32--1.32;
P(trend) =.28). For gamma tocopherol, men in the highest fifth
of the distribution had a fivefold reduction in the risk of
developing prostate cancer than men in the lowest fifth
(P:(trend) =.002). The association between selenium and
prostate cancer risk was in the protective direction with
individuals in the top four fifths of the distribution having
a reduced risk of prostate cancer compared with individuals in
the bottom fifth (P(trend) =.27). Statistically significant
protective associations for high levels of selenium and alpha
tocopherol were observed only when gamma tocopherol
concentrations were high. CONCLUSIONS: The use of combined
alpha and gamma tocopherol supplements should be considered in
upcoming prostate cancer prevention trials, given the observed
interaction between alpha tocopherol, gamma tocopherol and
selenium.
J Natl Cancer Inst 2000 Dec
20;92(24):2018-23
Carotenoids, retinol and vitamin E and
risk of proliferative benign breast disease and breast
cancer.
We investigated the relationship between serum levels of
retinol, beta-carotene, alpha-carotene, lycopene, alpha
tocopherol, and gamma tocopherol as well as intakes of
retinol, carotene, and vitamin E and the risks of breast
cancer and proliferative benign breast disease (BBD) in a
case-control study of postmenopausal women in the Boston, MA
(United States) area. Serum nutrient data were available for
377 women with newly diagnosed stage I or II breast cancer and
173 women with proliferative BBD. Controls were 403 women who
were evaluated at the same institutions but did not require a
breast biopsy or whose biopsy revealed nonproliferative BBD.
We observed no significant associations between serum levels
of these micronutrients and risk of proliferative BBD or
breast cancer. The risk of breast cancer was decreased among
women in the highest quintile of intake of vitamin E from food
sources only (odds ratio [OR] for the highest quintile = 0.4,
95 percent confidence interval [CI] = 0.2-0.9; P, trend across
quintiles = 0.02) but less so for total vitamin E intake
including supplements (OR = 0.7, CI = 0.4-1.3; P, trend =
0.07).
Cancer Causes Control 1992
Nov;3(6):503-12
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