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October 2002

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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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