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Abstracts

Arthritis
Updated: 08/26/2004

ABSTRACTS

[Experimental osteoarthritis and its course when treated with S-adenosyl-L-methionine].

Barcelo HA, Wiemeyer JC, Sagasta CL, et al.

Rev Clin Esp. 1990 Jun; 187(2):74-8.

Degenerative arthropathy was experimentally induced in the right knee of 24 rabbits. The animals were randomly divided in 3 groups of 8 rabbits each. S-Adenosyl-L-Methionine (SAMe) was administered intramuscularly to 2 groups. One group received 30 and 60 mg/kg/day i.m. The remaining group was a control and received only a diluent. After 12 weeks of therapy rabbits were sacrificed and tibial and femoral cartilage specimens of both knees were taken. The latter was stained with hematoxylin -eosine, Masson's trichromic and Safranine 0 stains and was microscopically studied. The thickness and cell density of the lesioned cartilages were significantly greater in both groups treated with SAMe than the group control (p less than 0.001). Statistical differences (p less than 0.05) were found within 60 and 30 mg/kg/day of SAMe. A greater concentration of proteoglycans in the cartilage matrix was found in animals treated were as, a severe reduction was found in controls. The severity of the lesions, based on the histologic-histochemical analysis, was significantly lower in rabbits receiving SAMe (p less than 0.0005). These differences were correlated with the administration of SAMe and the possible mechanisms of action are discussed

Proline and hydroxyproline excretion and vitamin C status in elderly human subjects.

Bates CJ.

Clin Sci Mol Med. 1977 May; 52(5):535-43.

1. Plasma and buffy-coat vitamin C, urinary proline, hydroxyproline, creatinine and total amino acid concentrations were meausred in 23 healthy elderly subjects at intervals of 3 months. 2. There was a strong positive correlation between plasma vitamin C and buffy-coat vititamin C. 3. There were not significant correlations between plasma or buffy-coat vitamin CPAMIN C. 3. There were not significant correlations between plasma or buffy-coat vitamin C and total urinary hydroxyproline, whether expressed on a creatinine basis or on a total amino acid basis. Similarly, no significant correlations could be detected involving the proline/hydroxyproline ratio in urine hydrolysates. 4. There was a significant negative correlation between plasma or buffy-coat vitamin C and total urinary proline, when expressed per unit of total urinary proline, when expressed per unit of total urinary proline, when expressed per unit of total amino acids in the hydrolysates. This correlation was not observed with unhydrolysed urine, and it appeared to reside in the diffusible fraction, part of whose proline could be liberated by prolidase digestion. In addition, in the man, there was some evidence for a positive correlation between plasma or buffy-coat vitamin C and the ratio of total urinary amino acids to creatinine. 5. These results support the view that poor vitamin C status in elderly humans may be associated with a defect in collagen proline hydroxylation, reflected by increased excretion of proline-rich, collagen-derived peptides. If this interpretation is correct, it indicates a potential defect in connective tissue repair, and could form the basis of a functional test for subclinical vitamin C deficiency

Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease.

Belluzzi A, Brignola C, Campieri M, et al.

N Engl J Med. 1996 Jun 13; 334(24):1557-60.

BACKGROUND: Patients with Crohn's disease may have periods of remission, interrupted by relapses. Because fish oil has antiinflammatory actions, it could reduce the frequency of relapses, but it is often poorly tolerated because of its unpleasant taste and gastrointestinal side effects. METHODS: We performed a one-year, double-blind, placebo-controlled study to investigate the effects of a new fish-oil preparation in the maintenance of remission in 78 patients with Crohn's disease who had a high risk of relapse. The patients received either nine fish-oil capsules containing a total of 2.7 g of n-3 fatty acids or nine placebo capsules daily. A special coating protected the capsules against gastric acidity for at least 30 minutes. RESULTS: Among the 39 patients in the fish-oil group, 11 (28 percent) had relapses, 4 dropped out because of diarrhea, and 1 withdrew for other reasons. In contrast, among the 39 patients in the placebo group, 27 (69 percent) had relapses, 1 dropped out because of diarrhea, and 1 withdrew for other reasons (difference in relapse rate, 41 percentage points; 95 percent confidence interval, 21 to 61; P < 0.001). After one year, 23 patients (59 percent) in the fish-oil group remained in remission, as compared with 10 (26 percent) in the placebo group (P = "0.003)." Logistic-regression analysis indicated that only fish oil and not sex, age, previous surgery, duration of disease, or smoking status affected the likelihood of relapse (odds ratio for the placebo group as compared with the fish-oil group, 4.2; 95 percent confidence interval, 1.6 to 10.7). CONCLUSIONS: In patients with Crohn's disease in remission, a novel enteric-coated fish-oil preparation is effective in reducing the rate of relapse

Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors.

Bertolini DR, Nedwin GE, Bringman TS, et al.

Nature. 1986 Feb 6; 319(6053):516-8.

When leukocytes are exposed to mitogens or antigens in vitro, they release bone-resorbing activity into the culture supernatants which can be detected by bioassay. Like many lymphocyte-monocyte products, this activity has been difficult to purify because of its low abundance in activated leukocyte cultures and the unwieldy bioassay required to detect biological activity. Partially purified preparations of this activity inhibit bone collagen synthesis in organ cultures of fetal rat calvariae. Recent data suggest that both activated lymphocytes and monocytes release factors which could contribute to this activity. Recently, monocyte-derived tumour necrosis factor alpha (TNF-alpha) and lymphocyte-derived tumour necrosis factor beta (TNF-beta) (previously called lymphotoxin), two multifunctional cytokines which have similar cytotoxic effects on neoplastic cell lines, have been purified to homogeneity and their complementary DNAs cloned and expressed in Escherichia coli. As both of these cytokines are likely to be present in activated leukocyte supernatants, we tested purified recombinant preparations for their effects on bone resorption and bone collagen synthesis in vitro, and report here that both cytokines at 10(-7) to 10(-9) M caused osteoclastic bone resorption and inhibited bone collagen synthesis. These data suggest that at least part of the bone-resorbing activity present in activated leukocyte culture supernatants may be due to these cytokines

Matrix metalloproteinases: a review.

Birkedal-Hansen H, Moore WG, Bodden MK, et al.

Crit Rev Oral Biol Med. 1993; 4(2):197-250.

Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases

Integrating anti-tumor necrosis factor therapy in inflammatory bowel disease: current and future perspectives.

Blam ME, Stein RB, Lichtenstein GR.

Am J Gastroenterol. 2001 Jul; 96(7):1977-97.

Crohn's disease and ulcerative colitis are two idiopathic inflammatory disorders of the GI tract. Manifestations of disease can be severe and lead to long term therapy with a variety of medications and/or surgery. Standard medical therapy consists of agents that either treat suppurative complications or modulate the inflammatory cascade in a nonspecific manner. Many specific chemokine and cytokine effectors that promote intestinal inflammation have been identified. Such work has led to experimental clinical trials with a variety of cytokine antagonists. Compounds directed against one such cytokine, tumor necrosis factor alpha (TNF), have demonstrated the greatest clinical efficacy to date. This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade. Infliximab is a chimeric monoclonal antibody against TNF that has been demonstrated to be effective for the treatment of Crohn's disease. Infliximab is Food and Drug Administration approved for the treatment of Crohn's disease. There exist several other TNF antagonists in various phases of investigation, including the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide. The clinical efficacy of these agents and the role of TNF in the pathogenesis of inflammatory bowel disease is reviewed

Healing Anxiety Naturally.

Bloomfield H.

1998;

Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2.

Brock TG, McNish RW, Peters-Golden M.

J Biol Chem. 1999 Apr 23; 274(17):11660-6.

The two cyclooxygenase isoforms, cyclooxygenase-1 and cyclooxygenase-2, both metabolize arachidonic acid to prostaglandin H2, which is subsequently processed by downstream enzymes to the various prostanoids. In the present study, we asked if the two isoforms differ in the profile of prostanoids that ultimately arise from their action on arachidonic acid. Resident peritoneal macrophages contained only cyclooxygenase-1 and synthesized (from either endogenous or exogenous arachidonic acid) a balance of four major prostanoids: prostacyclin, thromboxane A2, prostaglandin D2, and 12-hydroxyheptadecatrienoic acid. Prostaglandin E2 was a minor fifth product, although these cells efficiently converted exogenous prostaglandin H2 to prostaglandin E2. By contrast, induction of cyclooxygenase-2 with lipopol- ysaccharide resulted in the preferential production of prostacyclin and prostaglandin E2. This shift in product profile was accentuated if cyclooxygenase-1 was permanently inactivated with aspirin before cyclooxygenase-2 induction. The conversion of exogenous prostaglandin H2 to prostaglandin E2 was only modestly increased by lipopolysaccharide treatment. Thus, cyclooxygenase-2 induction leads to a shift in arachidonic acid metabolism from the production of several prostanoids with diverse effects as mediated by cyclooxygenase-1 to the preferential synthesis of two prostanoids, prostacyclin and prostaglandin E2, which evoke common effects at the cellular level

NSAID and osteoarthritis--help or hindrance?

Brooks PM, Potter SR, Buchanan WW.

J Rheumatol. 1982 Jan; 9(1):3-5.

Herbal Prescriptions for Better Health.

Brown D.

1996;

Is diet important in rheumatoid arthritis?

Buchanan HM, Preston SJ, Brooks PM, et al.

Br J Rheumatol. 1991 Apr; 30(2):125-34.

There is evidence from several well documented case reports that occasional patients with rheumatoid arthritis (RA) may develop aggravation of their arthritis as a result of allergy to some ingredient in the diet. A variety of foodstuffs have been implicated including milk and milk products, corn and cereals. Total fasting results in improvement in rheumatoid arthritis, but appears to be mediated by diminution in production of chemical mediators of inflammation, rather than by elimination of a dietary allergen. There is conflicting evidence from studies using various intestinal probes that patients with rheumatoid arthritis may have a 'leaky' intestinal mucosa allowing food allergens to be more easily absorbed. Clinical therapeutic trials of exclusion diets have employed the standard strategy of the double-blind randomized method. However, this presupposes that patients entered into such a study are capable of improvement with dietary manipulation. Since this is often not the case, a more appropriate method would be to employ the 'intensive research design' also known as 'single case experiment' and 'N of 1' study. 'Masked food intolerance' is an attractive hypothesis, but extremely difficult to prove. It is doubtful whether fish oils and/or evening primrose oil will be of significant long term benefit for patients with RA. However, they do provide for the possibility that a fatty acid-like substance may be found which may be incorporated into cell membranes, thereby preventing production of mediators of inflammation, such as prostaglandin E2 and leukotriene B4

Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis.

Bucsi L, Poor G.

Osteoarthritis Cartilage. 1998 May; 6 Suppl A:31-6.

Patients with osteoarthritis (OA) of the knee were treated with chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, CH) in a randomized, double-blind, placebo-controlled study, performed in two centres. The efficacy and tolerability of oral CS capsules 2 x 400 mg/day vs placebo was assessed in a 6-month study period. Patients with idiopathic or clinically symptomatic knee OA, with Kellgren and Lawrence radiological scores I-III, were included in this trial. Clinical controls were performed at months 0, 1, 3 and 6. Eighty patients completed the 6-month treatment period. Lequesne's Index and spontaneous joint pain (VAS) decreased constantly in the CS group; on the contrary, slight variations of the scores were reported in the placebo group. The walking time, defined as the minimum time to perform a 20-meter walk, showed a statistically significant constant reduction only in the CS group. ANOVA with repeated measures showed a statistically significant difference in favor of the CS group for these three parameters. During the study, patients belonging to the placebo group reported a higher paracetamol consumption, but this consumption was not statistically different between the two treatment groups. Efficacy judgements were significant in favor of the CS group. Both treatments were very well tolerated. All these results strongly suggest that chondroitin sulfate acts as a symptomatic slow-acting drug in knee OA

Kava: Nature's Answer to Stress, Anxiety, and Insomnia.

Cass H.

1998;

The effect on human tumor necrosis factor a and interleukin-1b production of diets enriched in n-3 fatty acids from vegetable oil or fish oil.

Caugey GE.

Am J Clin Nutr. 1996;(63):116-22.

Evidence for antirheumatic effectiveness of Herba Urticae dioicae in acute arthritis: a pilot study.

Chrubasik S.

Phytomedicine. 1997;(4):105-8.

Mechanisms for protection against copper toxicity.

Dameron CT, Harrison MD.

Am J Clin Nutr. 1998 May; 67(5 Suppl):1091S-7S.

Essential transition metals such as copper, molybdenum, and zinc and nonessential metals like cadmium, mercury, and lead can be toxic at the cellular, tissue, and organ levels when present in excess. To avoid metal-induced toxicity most organisms use a redundant combination of metal-regulated import inhibition, sequestration, and enhanced export mechanisms. Combinations of these mechanisms are used to form detoxification pathways controlled through metal-binding proteins at transcriptional, translational, or enzymatic levels. In mammalian pathways copper is partially detoxified by sequestration in the metal-binding metallothioneins or export via the copper-translocating ATPases. Copper regulation of these two mechanisms is afforded by specific conformational changes induced in regulatory proteins on metal binding

Prostaglandins can modify gamma-radiation and chemical induced cytotoxicity and genetic damage in vitro and in vivo.

Das UN, Ramadevi G, Rao KP, et al.

Prostaglandins. 1989 Dec; 38(6):689-716.

The effect of prostaglandin E1, E2, and F2 alpha on gamma-radiation, benzo(a)pyrene and diphenylhydantoin-induced cytotoxicity in vivo and genotoxicity in vitro was investigated. Prostaglandin E1 prevented both cytotoxic and genotoxic actions of all the three agents, where as both PGE2 and PGF2 alpha were ineffective. In fact, it was seen that both PGE2 and PGF2 alpha are genotoxic by themselves. Gamma-linolenic acid and dihomogamma-linolenic acid, the precursor of PGE1 were also as protective as that of PGE1, where as arachidonic acid, the precursor of 2 series PGs, has genotoxic actions to human lymphocytes in vitro. These results suggest that prostaglandins and their precursors can determine the susceptibility of cells to cytotoxic and genotoxic actions of chemicals and radiation. This study is particularly interesting since, it is known that some tumor cells contain excess of PGE2 and PGF2 alpha and many carcinogens can augment the synthesis of 2 series of PGs

Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how?

Das UN.

Prostaglandins Leukot Essent Fatty Acids. 2000 Dec; 63(6):351-62.

Low rates of coronary heart disease was found in Greenland Eskimos and Japanese who are exposed to a diet rich in fish oil. Suggested mechanisms for this cardio-protective effect focused on the effects of n-3 fatty acids on eicosanoid metabolism, inflammation, beta oxidation, endothelial dysfunction, cytokine growth factors, and gene expression of adhesion molecules; But, none of these mechanisms could adequately explain the beneficial actions of n-3 fatty acids. One attractive suggestion is a direct cardiac effect of n-3 fatty acids on arrhythmogenesis. N-3 fatty acids can modify Na+ channels by directly binding to the channel proteins and thus, prevent ischemia-induced ventricular fibrillation and sudden cardiac death. Though this is an attractive explanation, there could be other actions as well. N-3 fatty acids can inhibit the synthesis and release of pro-inflammatory cytokines such as tumor necrosis factoralpha (TNFalpha) and interleukin-1 (IL-1) and IL-2 that are released during the early course of ischemic heart disease. These cytokines decrease myocardial contractility and induce myocardial damage, enhance the production of free radicals, which can also suppress myocardial function. Further, n-3 fatty acids can increase parasympathetic tone leading to an increase in heart rate variability and thus, protect the myocardium against ventricular arrhythmias. Increased parasympathetic tone and acetylcholine, the principle vagal neurotransmitter, significantly attenuate the release of TNF, IL-1beta, IL-6 and IL-18. Exercise enhances parasympathetic tone, and the production of anti-inflammatory cytokine IL-10 which may explain the beneficial action of exercise in the prevention of cardiovascular diseases and diabetes mellitus. TNFalpha has neurotoxic actions, where as n-3 fatty acids are potent neuroprotectors and brain is rich in these fatty acids. Based on this, it is suggested that the principle mechanism of cardioprotective and neuroprotective action(s) of n-3 fatty acids can be due to the suppression of TNFalpha and IL synthesis and release, modulation of hypothalamic-pituitary-adrenal anti-inflammatory responses, and an increase in acetylcholine release, the vagal neurotransmitter. Thus, there appears to be a close interaction between the central nervous system, endocrine organs, cytokines, exercise, and dietary n-3 fatty acids. This may explain why these fatty acids could be of benefit in the management of conditions such as septicemia and septic shock, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, diabetes mellitus, essential hypertension and atherosclerosis

Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative.

Daynes RA, Araneo BA, Ershler WB, et al.

J Immunol. 1993 Jun 15; 150(12):5219-30.

Normal aging in humans has been recently shown to be accompanied by reduced control over production of the multifunctional cytokine IL-6. This cytokine was reported to be quantitatively elevated in most serum samples obtained from "normal" elderly humans. In the present investigation, we report that IL-6 levels are elevated in serum samples obtained from aged mice, and its spontaneous production could also be easily detected in culture supernatants of unstimulated lymphoid cells obtained from aged, but not mature, adult donors. Spontaneous production of IL-6 was consistently observed in culture supernatants of lymphoid cells from both the spleen and mesenteric lymph nodes from aged donors, but was absent from supernatants derived from their peripheral lymph nodes. In aged mice, the reduced regulation of IL-6 production could be effectively prevented and/or reversed by supplementing aging animals with dehydroepiandrosterone sulfate, a steroid hormone whose endogenous production is known to decline with advancing age in all species tested. It was also established that serum obtained from old dehydroepiandrosterone sulfate-treated mice contained lower (normal) levels of serum amyloid P substance (an acute phase reactant), reduced levels of serum Ig (all classes and isotypes) and lower titers of tissue-specific autoantibodies than untreated aged controls. Therefore, a number of well described, age-related conditions, some of which could be contributing to the pathologic phenotype of old age, may actually represent secondary effects to this age-associated change in IL-6 production

Structural requirements for inhibition of cytokine-induced endothelial activation by unsaturated fatty acids.

De Caterina R, Bernini W, Carluccio MA, et al.

J Lipid Res. 1998 May; 39(5):1062-70.

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation, including inflammation and atherosclerosis. We have previously shown that the n-3 FA docosahexaenoate (DHA) inhibits endothelial activation in the range of nutritionally achievable plasma concentrations. The present study assessed structural determinants for this effect. Saturated, monounsaturated, and n-6 and n-3 polyunsaturated FA were incubated with cultured endothelial cells for 24-72 h alone, and then in the presence of interleukin-1, tumor necrosis factor, or bacterial lipopolysaccharide for an additional 24 h before assessing the expression of the vascular cell adhesion molecule-1 (VCAM-1) or other products of endothelial activation. No FA tested per se elicited endothelial activation. While saturated FA did not inhibit cytokine-induced expression of adhesion molecules, a progressively increasing inhibitory activity was observed, for the same chain length, with an increase in double bonds. Comparison of FA with the same length and number of unsaturation and only differing for the double bond position or for the cis/trans configuration indicated no difference in inhibitory potency, indicating no effect of the double bond position or configuration. As judged by Northern analysis, these latter FA also inhibited VCAM-1 messenger RNA steady state levels to the same extent, indicating a pre-translational site of action attributable to the single double bond. Thus the double bond is the minimum necessary and sufficient requirement for FA inhibition of endothelial activation. These properties are likely relevant to the anti-atherogenic and anti-inflammatory properties ascribed to n-3 FA, which are able to accommodate the highest number of double bonds in a fatty acid of given chain length

The inhibition of endothelial activation by unsaturated fatty acids.

De Caterina R, Spiecker M, Solaini G, et al.

Lipids. 1999; 34 Suppl:S191-S194.

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation and leukocyte-endothelial interactions, such as inflammation and atherosclerosis. We previously showed that the n-3 FA docosahexaenoate (22:6n-3, DHA) inhibits cytokine-stimulated expression of endothelial-leukocyte adhesion molecules and soluble cytokines in the range of nutritionally achievable plasma concentrations. More recently we assessed structural determinants of VCAM-1 inhibition by FA. Cultured endothelial cells were incubated first with various saturated, monounsaturated, n-6 or n-3 polyunsaturated FA alone and then together with interleukin-1 or tumor necrosis factor. Saturated FA did not inhibit cytokine-induced endothelial activation, while a progressive increase in inhibitory activity was observed, for the same chain length, with the increase in double bonds accompanying the transition from monounsaturates to n-6 and, further, to n-3 FA. Comparison of various FA indicated no role of the double-bond position or configuration; the greater number of double bonds could explain the greater inhibitory activity of n-3 vs. n-6 FA. In order to ascertain mechanisms for these effects, we demonstrated inhibition of nuclear factor-kappaB (NF-kappaB) activation by DHA in parallel with a reduction in hydrogen peroxide (a critical mediator of NF-kappaB activation) released by endothelial cells either extracellularly or intracellularly. This suggests that a property related to fatty acid peroxidability (the presence of multiple double bonds) is related to inhibitory properties of hydrogen peroxide release and, consequently, of endothelial activation

Antiplatelet effect of pentoxifylline in human whole blood.

de la Cruz JP, Romero MM, Sanchez P, et al.

Gen Pharmacol. 1993 May; 24(3):605-9.

1. Pentoxifylline inhibits platelet aggregation in whole blood more than in platelet-rich plasma. 2. An inhibition of the erythrocyte uptake of adenosine contributes to the antiaggregatory effect of pentoxifylline

Effects of gammalinolenic acid on interleukin-1 beta and tumor necrosis factor-alpha secretion by stimulated human peripheral blood monocytes: studies in vitro and in vivo.

DeLuca P, Rossetti RG, Alavian C, et al.

J Investig Med. 1999 May; 47(5):246-50.

BACKGROUND: Oils enriched in gammalinolenic acid, an unsaturated fatty acid, reduce joint pain and swelling in patients with rheumatoid arthritis. The cytokines interleukin-1 beta and tumor necrosis factor-alpha appear to contribute directly to joint tissue damage in patients with rheumatoid arthritis. Agents designed to interfere with the actions of interleukin-1 beta and tumor necrosis factor-alpha are being used to treat rheumatoid arthritis. METHODS: We examined the influence of gammalinolenic acid added to cells in vitro and administered orally in vivo on interleukin-1 beta and tumor necrosis factor-alpha secretion from activated human peripheral blood monocytes. Secretion of both cytokines was reduced by gammalinolenic acid. Administration of safflower oil as a polyunsaturated fatty acid control devoid of gammalinolenic acid did not change secretion of either cytokine. CONCLUSION: Suppression of IL-beta and TNF-alpha secretion by activated cells may be one mechanism whereby gammalinolenic acid suppresses synovitis in patients with rheumatoid arthritis

Cross-talk between IL-1 and IL-6 signaling pathways in rheumatoid arthritis synovial fibroblasts.

Deon D, Ahmed S, Tai K, et al.

J Immunol. 2001 Nov 1; 167(9):5395-403.

The balance between pro- and anti-inflammatory cytokines plays an important role in determining the severity of inflammation in rheumatoid arthritis (RA). Antagonism between opposing cytokines at the level of signal transduction plays an important role in many other systems. We have begun to explore the possible contribution of signal transduction cross-talk to cytokine balance in RA by examining the effects of IL-1, a proinflammatory cytokine, on the signaling and action of IL-6, a pleiotropic cytokine that has both pro- and anti-inflammatory actions, in RA synovial fibroblasts. Pretreatment with IL-1 suppressed Janus kinase-STAT signaling by IL-6, modified patterns of gene activation, and blocked IL-6 induction of tissue inhibitor of metalloproteases 1 expression. These results suggest that proinflammatory cytokines may contribute to pathogenesis by modulating or blocking signal transduction by pleiotropic or anti-inflammatory cytokines. The mechanism of inhibition did not require de novo gene activation and did not depend upon tyrosine phosphatase activity, but, instead, was dependent on the p38 stress kinase. These results identify a molecular basis for IL-1 and IL-6 cross-talk in RA synoviocytes and suggest that, in addition to levels of cytokine expression, modulation of signal transduction also plays a role in regulating cytokine balance in RA

Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients.

Devaraj S, Jialal I.

Free Radic Biol Med. 2000 Oct 15; 29(8):790-2.

Type 2 diabetic subjects have an increased propensity to premature atherosclerosis. Alpha tocopherol (AT), a potent antioxidant, has several anti-atherogenic effects. There is scanty data on AT supplementation on inflammation in Type 2 diabetic subjects. The aim of the study was to test the effect of RRR-AT supplementation (1200 IU/d) on plasma C-reactive protein (CRP) and interleukin-6 (IL-6) release from activated monocyte in Type 2 diabetic patients with and without macrovascular complications compared to matched controls. The volunteers comprised Type 2 diabetic subjects with macrovascular disease (DM2-MV, n = 23), Type 2 diabetic subjects without macrovascular complications (DM2, n = 24), and matched controls (C, n = 25). Plasma high sensitive CRP (Hs-CRP) and Monocyte IL-6 were assayed at baseline, following 3 months of supplementation and following a 2 month washout phase. DM2-MV subjects have elevated HsCRP and monocyte IL-6 compared to controls. AT supplementation significantly lowered levels of C-reactive protein and monocyte interleukin-6 in all three groups. In conclusion, AT therapy decreases inflammation in diabetic patients and controls and could be an adjunctive therapy in the prevention of atherosclerosis

Drugs affecting plasma fibrinogen levels.

Di Minno G, Mancini M.

Cardiovasc Drugs Ther. 1992 Feb; 6(1):25-7.

Current knowledge indicates that high plasma levels of fibrinogen help predict stroke and myocardial infarction. It is known that plasma fibrinogen is synthesized in the liver, that interleukin-6 (IL-6) affects this synthesis, and that, when exposed to appropriate stimuli, monocytes generate a variety of monokines, including IL-6. It is also known that prolonged administration of N-3 fatty acids, ticlopidine, fibrates, pentoxifylline, or alcohol lower plasma fibrinogen levels. The mechanism(s) involved in this effect are poorly understood. However, in view of the role of IL-6 and monocytes in the regulation of plasma fibrinogen levels, it is conceivable that the lowering effect of these drugs involves effects on some steps of the regulatory machinery. In addition to fibrinogen, IL-6 regulates the synthesis of other acute-phase proteins. This raises the question of whether high plasma fibrinogen levels do reflect the response of an acute-phase reactant to the severity of the atherosclerotic vascular damage taking place. Current evidence is inconclusive with respect to this possibility. On the other hand, the epidemiological data available indicate that measurements of plasma fibrinogen should be included in the cardiovascular risk-factor profile. In view of this, we believe that information emerging from population-based studies in which plasma fibrinogen is measured is important to identify appropriate directions to be followed to address unsolved issues in the area

Cytokine levels affected by gamma-linolenic acid.

Dirks J, van Aswegen CH, du Plessis DJ.

Prostaglandins Leukot Essent Fatty Acids. 1998 Oct; 59(4):273-7.

This study was undertaken to assess whether gamma-linolenic acid (GLA) in the form of evening primrose oil (EPO) could affect rat serum cytokines, interferon-gamma (IFN-gamma), monocyte chemotactic protein-1 (MCP-1) and tumour necrosis factor-alpha (TNF-alpha). The following diets were administered: control, glucan, Freund's adjuvant and glucan plus Freund's adjuvant with and without GLA. In the presence of GLA, the IFN-gamma and MCP-1 levels were significantly decreased in contrast to the control group of TNF-alpha, which was significantly stimulated. On account of interaction between diets and GLA, the remaining diet groups of TNF-alpha were either not affected or were inhibited in the presence of GLA. The observations indicate that GLA may modulate the level of serum IFN-gamma, MCP-1 and TNF-alpha, which may be a worthwhile line of treatment in certain human diseases

A double-blind trial of ademetionine vs naproxen in activated gonarthrosis.

Domljan Z, Vrhovac B, Durrigl T, et al.

Int J Clin Pharmacol Ther Toxicol. 1989 Jul; 27(7):329-33.

The efficacy and safety of ademetionine (A) vs naproxen (N) were tested in a double-blind trial carried out in 20 patients, each with activated gonarthrosis. The trial lasted 6 weeks. During the first week, A was administered at a daily dose of 3 x 400 mg and afterwards at a dose of 2 x 400 mg, whereas the daily dose of N during the first week was 3 x 250 mg and subsequently 2 x 250 mg. During the first two weeks, the patients were allowed to take paracetamol as an additional analgesic. The patients were examined at the beginning of the study and after 2, 4 and 6 weeks. The parameters tested were: pain (under different conditions), crepitation, joint swelling, circumference of joint, extent of motility and walking time over 10 meters. In addition to the usual laboratory tests, the serum keratane-sulphate concentrations (with monoclonal antibodies according to the ELISA technique of Eugene et al. [1985]) were also determined. At the end of the 6th week no statistically significant difference between the two patient groups treated was found; both groups exhibited a marked improvement on all parameters. At the end of medication, the keratane-sulphate concentrations were not significantly changed. Five patients under A and 3 under N reported gastrointestinal side effects which were possibly drug-related. This study, performed in a small number of patients, showed a good efficacy and safety of ademetionine. Only further studies on a larger scale will show the importance of ademetionine in the therapy of rheumatic diseases

Body, Mind and Sport.

Douillard J.

2001;

Therapeutic activity of oral glucosamine sulfate in osteoarthrosis: a placebo-controlled double-blind investigation.

Drovanti A, Bignamini AA, Rovati AL.

Clin Ther. 1980; 3(4):260-72.

Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis. Results of a prospective placebo controlled double blind trial.

Edmonds SE, Winyard PG, Guo R, et al.

Ann Rheum Dis. 1997 Nov; 56(11):649-55.

OBJECTIVE: Vitamin E, the most potent naturally occurring lipid soluble antioxidant has been suggested to possess both anti-inflammatory and analgesic activity in humans. This double blind and randomised study used a broad spectrum of clinical and laboratory parameters to investigate whether there was any additional anti-inflammatory or analgesic effects, or both, of orally administered alpha-tocopherol in rheumatoid arthritis patients who were already receiving anti-rheumatic drugs. METHODS: Forty two patients were enrolled and treated with alpha-tocopherol (n = 20) at a dose of 600 mg twice a day (2 x 2 capsules) or with placebo (n = 22) for 12 weeks. The following parameters were measured: (1) Three clinical indices of inflammation--the Ritchie articular index, the duration of morning stiffness, and the number of swollen joints; (2) three measures of pain--pain in the morning, pain in the evening, and pain after chosen activity; (3) haematological and biochemical measures of inflammatory activity; (4) assays for the oxidative modification of proteins and lipids. RESULTS: All laboratory measures of inflammatory activity and oxidative modification were unchanged. Furthermore, the clinical indices of inflammation were not influenced by the treatment. However, the pain parameters were significantly decreased after vitamin E treatment when compared with placebo. CONCLUSION: The results provide preliminary evidence that vitamin E may exert a small but significant analgesic activity independent of a peripheral anti-inflammatory effect, but which complements standard anti-inflammatory treatment

Effect of low-dose aspirin in combination with stable fish oil on whole blood production of eicosanoids.

Engstrom K, Wallin R, Saldeen T.

Prostaglandins Leukot Essent Fatty Acids. 2001 Jun; 64(6):291-7.

The effect of a combination of aspirin and fish oil on eicosanoids was studied. Four subjects were given 37.5 mg aspirin orally, and 6 weeks later they received a natural, stable fish oil daily for 1 week before taking the same single dose of aspirin. Blood samples for determination of whole blood production of eicosanoids were taken before and after each experimental period. Serum thromboxane A(2)was decreased by 40% (P

Dietary gamma-linolenic acid enhances mouse macrophage-derived prostaglandin E1 which inhibits vascular smooth muscle cell proliferation.

Fan YY, Ramos KS, Chapkin RS.

J Nutr. 1997 Sep; 127(9):1765-71.

We previously demonstrated that macrophages isolated from mice fed gamma-linolenic acid (GLA)-enriched diets reduce vascular smooth muscle cell (SMC) proliferation in a cyclooxygenase-dependent fashion and may therefore favorably modulate the atherogenic process. The present study was conducted to elucidate the mechanism(s) by which dietary GLA influences the ability of macrophages to modulate SMC growth programs. Resident peritoneal macrophages were isolated from C57BL/6 female mice fed diets containing variable GLA compositions at 10% (wt/wt), treated with various antibodies and co-cultured with cycling naive vascular SMC isolated from nonpurified diet-fed mice. Smooth muscle cell proliferation and intracellular cAMP levels were measured after co-culture. In parallel experiments, cycling naive vascular SMC isolated from nonpurified diet-fed mice were dosed with exogenous prostaglandin E1 (PGE1 ) for various periods and challenged with cycloheximide for 4 h (8-12 h after PGE1 addition), and intracellular cAMP levels were measured at various time points. Macrophages isolated from mice fed GLA-enriched dietary oils significantly reduced SMC proliferation in co-culture compared with controls (macrophages from mice fed a corn oil diet containing no GLA). Anti-PGE1 antiserum treatment (1:50 or 1:100) blocked the ability of GLA-enriched macrophages to down-regulate SMC proliferation, a response reversed by exogenous PGE1 treatment. Macrophages isolated from mice fed GLA-enriched dietary oils elevated SMC intracellular cAMP levels in a biphasic fashion. In addition, exogenous PGE1 (1 nmol/L to 10 micromol/L) exerted a similar biphasic cAMP response in SMC, and the second phase of cAMP elevation was antagonized by cycloheximide. In conclusion, dietary GLA enhances mouse macrophage-derived prostaglandin E1, which inhibits vascular SMC proliferation

Role of chondrocytes in the development of osteoarthritis.

Fassbender HG.

Am J Med. 1987 Nov 20; 83(5A):17-24.

The chondrocyte holds a key position in the development of osteoarthritis. As the only living element of the articular cartilage, it produces the components of the matrix, i.e., collagens and proteoglycans. In the course of its life, the chondrocyte is susceptible to nutrient and toxic dangers. This leads to a qualitative and quantitative jeopardy of the matrix production. Collagens and proteoglycans are also subject to metabolic influences. Whatever the cause(s), osteoarthritis results in deficient masking of the collagen fibers and in roughening of the cartilaginous surface. Thus, the phase of "wear and tear" is initiated, which is characteristic of osteoarthritis. This process may provoke a total loss of cartilage and opening of the subchondral medullary spaces. However, osteoarthritis probably only becomes clinically manifest when a secondary synovitis supervenes, which is caused by mediators developing from degradation products of the cartilaginous matrix. Thus, osteoarthritis can be considered to develop from a disproportion between the quality of the matrix and load to the cartilage. Aside from avoiding non-physiologic overload to the articular cartilage, therapy must influence the secondary synovitis. Furthermore, an attempt should be made to interfere effectively with the chondrocytic metabolism by means of "chondroprotective substances."

Role of cytokines in rheumatoid arthritis.

Feldmann M, Brennan FM, Maini RN.

Annu Rev Immunol. 1996; 14:397-440.

Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease

Anti-tumor necrosis factor alpha therapy of rheumatoid arthritis. Mechanism of action.

Feldmann M, Brennan F, Paleolog E, et al.

Eur Cytokine Netw. 1997 Sep; 8(3):297-300.

The role of cytokines in osteoarthritis pathophysiology.

Fernandes JC, Martel-Pelletier J, Pelletier JP.

Biorheology. 2002; 39(1-2):237-46.

Morphological changes observed in OA include cartilage erosion as well as a variable degree of synovial inflammation. Current research attributes these changes to a complex network of biochemical factors, including proteolytic enzymes, that lead to a breakdown of the cartilage macromolecules. Cytokines such as IL-1 and TNF-alpha produced by activated synoviocytes, mononuclear cells or by articular cartilage itself significantly up-regulate metalloproteinases (MMP) gene expression. Cytokines also blunt chondrocyte compensatory synthesis pathways required to restore the integrity of the degraded extrecellular matrix (ECM). Moreover, in OA synovium, a relative deficit in the production of natural antagonists of the IL-1 receptor (IL-1Ra) has been demonstrated, and could possibly be related to an excess production of nitric oxide in OA tissues. This, coupled with an upregulation in the receptor level, has been shown to be an additional enhancer of the catabolic effect of IL-1 in this disease.IL-1 and TNF-alpha significantly up-regulate MMP-3 steady-state mRNA derived from human synovium and chondrocytes. The neutralization of IL-1 and/or TNF-alpha up-regulation of MMP gene expression appears to be a logical development in the potential medical therapy of OA. Indeed, recombinant IL-1receptor antagonists (ILRa) and soluble IL-1 receptor proteins have been tested in both animal models of OA for modification of OA progression. Soluble IL-1Ra suppressed MMP-3 transcription in the rabbit synovial cell line HIG-82. Experimental evidence showing that neutralizing TNF-alpha suppressed cartilage degradation in arthritis also support such strategy. The important role of TNF-alpha in OA may emerge from the fact that human articular chondrocytes from OA cartilage expressed a significantly higher number of the p55 TNF-alpha receptor which could make OA cartilage particularly susceptible to TNF-alpha degradative stimuli. In addition, OA cartilage produces more TNF-alpha and TNF anglealpha convertase enzyme (TACE) mRNA than normal cartilage. By analogy, an inhibitor to the p55 TNF-alpha receptor may also provide a mechanism for abolishing TNF-alpha-induced degradation of cartilage ECM by MMPs. Since TACE is the regulator of TNF-alpha activity, limiting the activity of TACE might also prove efficacious in OA. IL-1 and TNF-alpha inhibition of chondrocyte compensatory biosynthesis pathways which further compromise cartilage repair must also be dealt with, perhaps by employing stimulatory agents such as transforming growth factor-beta or insulin-like growth factor-I.Certain cytokines have antiinflammatory properties. Three such cytokines - IL-4, IL-10, and IL-13 - have been identified as able to modulate various inflammatory processes. Their antiinflammatory potential, however, appears to depend greatly on the target cell. Interleukin-4 (IL-4) has been tested in vitro in OA tissue and has been shown to suppress the synthesis of both TNF-alpha and IL-1beta in the same manner as low-dose dexamethasone. Naturally occurring antiinflammatory cytokines such as IL-10 inhibit the synthesis of IL-1 and TNF-alpha and can be potential targets for therapy in OA. Augmenting inhibitor production in situ by gene therapy or supplementing it by injecting the recombinant protein is an attractive therapeutic target, although an in vivo assay in OA is not available, and its applicability has yet to be proven. Similarly, IL-13 significantly inhibits lipopolysaccharide (LPS)-induced TNF-alpha production by mononuclear cells from peripheral blood, but not in cells from inflamed synovial fluid. IL-13 has important biological activities: inhibition of the production of a wide range of proinflammatory cytokines in monocytes/macrophages, B cells, natural killer cells and endothelial cells, while increasing IL-1Ra production. In OA synovial membranes treated with LPS, IL-13 inhibited the synthesis of IL-1beta, TNF-alpha and stromelysin, while increasing IL-1Ra production.In summary, modulation of cytokines that control MMP gene up-regulation would appear to be fertile targets for drug development in the treatment of OA. Several studies illustrate the potential importance of modulating IL-1 activity as a means to reduce the progression of the structural changes in OA. In the experimental dog and rabbit models of OA, we have demonstrated that in vivo intraarticular injections of the IL-Ra gene can prevent the progression of structural changes in OA. Future directions in the research and treatment of osteoarthritis (OA) will be based on the emerging picture of pathophysiological events that modulate the initiation and progression of OA

An in vitro Model for Studying Mechanisms Underlying Synoviocyte-Mediated Cartilage Invasion in Rheumatoid Arthritis.

Frye CA, Yocum DE, Tuan R, et al.

Pathol Oncol Res. 1996; 2(3):157-66.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints involving the pathological development of an invasive and destructive pannus tissue which contributes to the loss of cartilage and bone. To further analyze the process of cartilage degradation and invasion, we have developed an in vitro model composed of cartilage matrix and synoviocytes (isolated from RA pannus tissue, as well as normal synovial membrane). The matrix is derived from pig articular cartilage and contains collagen type II and proteoglycans and is similar in composition to human cartilage. Data generated from this model reveal that synoviocytes isolated from RA pannus tissue invaded cartilage matrix in a manner which directly correlated with the severity of the disease. Analysis of mechanisms associated with the invasive process demonstrate that highly invasive RA synoviocytes maintain a round morphology during attachment and spreading on cartilage matrix, compared with their normal counterparts. Furthermore, the level of secretion of matrix metalloproteinase (MMP) activity was shown to correlate with the RA phenotype, which could be modulated with a novel MMP inhibitor. Normal synoviocytes could be "converted" to an RA phenotype by specific inflammatory cytokines, such that invasion of cartilage matrix was augmented by culturing these cells in the presence of 5 U/ml IL-1b or 18 U/ml TGFb. Invasion was inhibited by 150 U/ml TNFa, and unaffected by 100 ng/ml PDGF. In addition, synovial fluid from RA patients induced invasion of normal synoviocytes, in a concentration dependent manner, from 150% to 460%; however, synovial fluid from another inflammatory arthritidy (Crohn's) did not augment invasion to the same degree. Moreover, this "conversion effect" appears to be specific for synoviocytes, since similar effects could not be achieved with human skin fibroblasts. This in vitro model of synoviocyte-mediated cartilage invasion allows for further molecular characterization of the invasive properties of the synoviocyte which contribute to RA

Relation between interleukin-18 and PGE2 in synovial fluid of osteoarthritis: a potential therapeutic target of cartilage degradation.

Futani H, Okayama A, Matsui K, et al.

J Immunother. 2002 Mar; 25 Suppl 1:S61-S64.

Osteoarthritis (OA) is characterized by articular cartilage degradation and hypertrophic joint changes. Interleukin (IL)-18 is a potent inducer of prostaglandin (PG) E2 in vitro. We determined the relation between IL-18 and PGE2 in synovial fluid (SF) of human OA, and discussed the role of IL-18 in the pathogenesis of OA and also its therapeutic consequences. SF was collected from 30 patients with knee OA. The concentrations of IL-18 and other cytokines including IL-1beta, tumor necrosis factor (TNF)-alpha, IL-6, and IL-8 were measured by enzyme-linked immunosorbent assay (ELISA). The concentration of PGE2 was also assessed by inhibitory ELISA. The average value of IL-18 was 248 +/- 310 pg/mL. The average value of PGE2 was 93 +/- 103 pg/mL. There was a relatively strong correlation between IL-18 and PGE2 (r = 0.78, p = 0.0001). In contrast, IL-1beta was undetectable (cutoff point of 20 pg/mL), except for one case. TNF-alpha was also undetectable (cutoff point of 20 pg/mL), except for two cases. The average value of IL-6 was 1,310 +/- 2,623 pg/mL (n = 17), whereas IL-8 was 5,208 +/- 6,031 pg/mL (n = 5). Furthermore, IL-6 and IL-8 correlated with IL-18 (r = 0.69, p = 0.0024 and r = 0.87, p = 0.0527, respectively). Our results suggest that IL-18 could play a major role in vivo in inducing the production of PGE2, which in turn can cause cartilage degradation in OA pathogenesis. Thus, targeting this cytokine appears to be an important therapeutic approach in OA

[The effect of pentoxifylline and nicergoline on the systemic and cerebral hemodynamics and on the blood rheological properties in patients with an ischemic stroke and atherosclerotic lesions of the major cerebral arteries].

Gara II.

Zh Nevropatol Psikhiatr Im S S Korsakova. 1993; 93(3):28-32.

Pentoxifylline versus nicergoline therapy has been studied in 56 patients with atherosclerosis of major cerebral arteries who had ischemic apoplexy. Pentoxifylline enhances circulation primarily in the stenotic vessels, while nicergoline in the intact cerebral arteries. The former is more potent in inducing antiaggregation inhibiting spontaneous platelet and red cell aggregation and reducing blood viscosity. The results of the study suggest better response in case of pentoxifylline treatment of patients with hypo- and eukinetic circulation, while in nicergoline treatment hyperkinetic hemodynamics patients benefit more in view of the drug cardiodepressive activity

Effect of anti-platelet therapy (aspirin + pentoxiphylline) on plasma lipids in patients of ischaemic stroke.

Gaur SP, Garg RK, Kar AM, et al.

Indian J Physiol Pharmacol. 1993 Apr; 37(2):158-60.

Twenty-one patients of ischaemic stroke were put on prolonged administration of antiplatelet drugs (aspirin 320 mg once daily with pentoxiphylline 400 mg thrice daily). The serum lipids along with other biochemical parameters were estimated before starting the treatment and after completion of 2 months of therapy. No significant changes were observed in any of the biochemical parameters including lipid profile except in serum high density lipoprotein (HDL) which increased significantly (< 0.05) after 2 months therapy. It is concluded that 2 months antiplatelet therapy has no adverse metabolic effect in patients of ischaemic stroke and the raised serum HDL may contribute to cerebral protective effect

Double-blind multicentre study of the activity of S-adenosylmethionine in hip and knee osteoarthritis.

Glorioso S, Todesco S, Mazzi A, et al.

Int J Clin Pharmacol Res. 1985; 5(1):39-49.

A randomized double-blind multicentre clinical trial was carried out to verify the effectiveness and tolerance of S-adenosylmethionine (SAMe) versus ibuprofen in 150 patients with hip and/or knee osteoarthritis. Both drugs were given orally 400 mg thrice daily for 30 days. SAMe exhibited a slightly more marked activity than the reference drug in the management of the various painful manifestations of the joint disease. Minor side-effects developed in five patients of SAMe group, and in 16 patients of ibuprofen group. No drop-outs occurred. No changes were observed in the routine laboratory tests

Oxpentifylline in Parkinson's disease.

Godwin-Austen RB, Twomey JA, Hanks G, et al.

J Neurol Neurosurg Psychiatry. 1980 Apr; 43(4):360-4.

The effects of oxpentifylline were assessed in a double-blind trial in 11 patients with Parkinson's disease already under treatment. No significant improvement was noted. Eight patients developed involuntary movements or a worsening of movements if already present. The significance of this unexpected finding is discussed

Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages.

Gosset P, Wallaert B, Tonnel AB, et al.

Eur Respir J. 1999 Jul; 14(1):98-105.

Reactive oxygen intermediates exert signalling functions and modulate gene transcription, particularly for pro-inflammatory cytokines. Since exogenous as well as endogenous thiols could be potent inhibitors of the production of cytokines, the effects of N-acetylcysteine (NAC), glutathione (GSH) and modulated GSH synthesis on the production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8 by human alveolar macrophages (AMs) was evaluated, as well as the potential role of intracellular GSH depletion on the effect of exogenous thiols. AMs were stimulated with lipopolysaccharide (LPS) and cytokine production was measured by evaluating messenger ribonucleic acid (mRNA) expression and protein secretion. Depletion of intracellular GSH by treatment with buthionine sulphoximine (BSO) reached 45.2% after 3 h and was nearly complete at 24 h. Whereas a 24-h preincubation of AMs with BSO significantly increased LPS-induced secretion of TNF-alpha and IL-8, a 3-h preincubation only enhanced LPS-stimulated production of IL-8 (p

SAMe restores the changes in the proliferation and in the synthesis of fibronectin and proteoglycans induced by tumour necrosis factor alpha on cultured rabbit synovial cells.

Gutierrez S, Palacios I, Sanchez-Pernaute O, et al.

Br J Rheumatol. 1997 Jan; 36(1):27-31.

S-Adenosyl-L-methionine (SAMe) is a naturally occurring compound involved in transmethylation and trans-sulphuration reactions. The administration of SAMe to patients with osteoarthritis (OA) seems to have a protective effect, although the mechanisms of its action are largely unknown. We have studied the effect of SAMe as a protective agent against the modifications induced by tumour necrosis factor alpha (TNF alpha) on synovial cell proliferation and extracellular matrix protein synthesis, two important hallmarks of progressive articular diseases. The stimulation of cells with 100 U/ml TNF alpha for 24 h decreased the proliferative rate (58 +/- 14% with TNF alpha vs basal 100%, P < 0.05), fibronectin (FN) mRNA expression (36 +/- 14% vs basal, P 0.05). By contrast, TNF alpha raised total protein and proteoglycan synthesis (127 +/- 12% vs basal and 239 +/- 40% vs basal, respectively, P < 0.05). The addition of increasing concentrations of SAMe (10(-10)-10(-6) M) to synoviocytes incubated with TNF alpha reversed the effects induced by the cytokine, while SAMe alone did not modify significantly the metabolic processes studied. These results indicate that, in cultured synovial cells, SAMe restores basal conditions after cell damage elicited by TNF alpha stimulation

Effects of age on serum dehydroepiandrosterone sulfate, IGF-I, and IL-6 levels in women.

Haden ST, Glowacki J, Hurwitz S, et al.

Calcif Tissue Int. 2000 Jun; 66(6):414-8.

Data from animal and in vitro studies suggest that the growth-promoting effects of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) may be mediated by stimulation of insulin-like growth factor-I (IGF-I) and/or inhibition of interleukin 6 (IL-6), a cytokine mediator of bone resorption. This study tests the hypotheses that there are effects of age on serum DHEAS, IGF-I, and IL-6 levels, and that levels of IGF-I and IL-6 are related to DHEAS levels. The study included 102 women: 27 premenopausal and 75 postmenopausal, including 35 postmenopausal women with osteoporosis, as defined by bone mineral density scores by dual X-ray energy absorptiometry. DHEAS levels decreased significantly with age (r = -0.52, P < 0.0001) and IGF-I levels decreased significantly with age (r = "-0.49," P < 0.0001). IL-6 levels increased significantly with age (r = "0.36," P = "0.008)." IGF-I was positively correlated to DHEAS levels (r = "0.43," P < 0. 0001, n = "102)" and IL-6 levels were negatively correlated to DHEAS levels (r = "-0.32," P = "0.021," n = "54)." Levels of DHEAS and IGF-I were correlated with T scores of the spine and some hip sites. In a multiple variable model to predict DHEAS, age was an important predictor (P < 0.001), but osteoporosis status, IGF-I, and IL-6 were not. The median DHEAS level was lower in the postmenopausal osteoporotic women (67 microg/dl, n = "35)" than in the nonosteoporotic postmenopausal women (106.3 microg/dl, n = "40," P = "0." 03), but this was not significant after correction for age. Age accounted for 32% of the variance in DHEAS levels. In summary, DHEAS levels decreased with age and had a positive association with IGF-I levels and a negative association with IL-6 levels. DHEA deficiency may contribute to age-related bone loss through anabolic (IGF-I) and anti-osteolytic (IL-6) mechanisms

Antioxidants in vegan diet and rheumatic disorders.

Hanninen O, Kaartinen K, Rauma A, et al.

Toxicology. 2000 Nov 30; 155(1-3):45-53.

Plants are rich natural sources of antioxidants in addition to other nutrients. Interventions and cross sectional studies on subjects consuming uncooked vegan diet called living food (LF) have been carried out. We have clarified the efficacy of LF in rheumatoid diseases as an example of a health problem where inflammation is one of the main concerns. LF is an uncooked vegan diet and consists of berries, fruits, vegetables and roots, nuts, germinated seeds and sprouts, i.e. rich sources of carotenoids, vitamins C and E. The subjects eating LF showed highly increased levels of beta and alfa carotenes, lycopen and lutein in their sera. Also the increases of vitamin C and vitamin E (adjusted to cholesterol) were statistically significant. As the berry intake was 3-fold compared to controls the intake of polyphenolic compounds like quercetin, myricetin and kaempherol was much higher than in the omnivorous controls. The LF diet is rich in fibre, substrate of lignan production, and the urinary excretion of polyphenols like enterodiol and enterolactone as well as secoisolaricirecinol were much increased in subjects eating LF. The shift of fibromyalgic subjects to LF resulted in a decrease of their joint stiffness and pain as well as an improvement of their self-experienced health. The rheumatoid arthritis patients eating the LF diet also reported similar positive responses and the objective measures supported this finding. The improvement of rheumatoid arthritis was significantly correlated with the day-to-day fluctuation of subjective symptoms. In conclusion the rheumatoid patients subjectively benefited from the vegan diet rich in antioxidants, lactobacilli and fibre, and this was also seen in objective measures

[Selenium concentration in erythrocytes of patients with rheumatoid arthritis. Clinical and laboratory chemistry infection markers during administration of selenium].

Heinle K, Adam A, Gradl M, et al.

Med Klin (Munich). 1997 Sep 15; 92 Suppl 3:29-31.

PATIENTS AND METHODS: Seventy patients with definitive rheumatoid arthritis were matched to built 2 groups, which were double-blind and randomized allocated to supplementation with sodium-selenit 200 micrograms/d or placebo for 3 months, each. Both groups were given fish oil fatty acids (30 mg/kg body weight), DMARDS were continued throughout the study, while variations in steroids or NSAD were admitted. RESULTS: Selenium concentrations in erythrocytes of patients with rheumatoid arthritis were 85.1 +/- 26 micrograms/l, and significantly lower than found in an average German population (123 +/- 23 micrograms/l). During the observation period of 3 months normal selenium concentrations were not restored, despite supplementation higher than RDA. At the end of the experimental period the selenium supplemented group showed less tender or swollen joints, and morning stiffness. Selen-supplemented patients needed less cortisone and NSAD than controls. In accordance with clinical improvement we found a decrease of laboratory indicators of inflammation (C-reactive protein, alpha 2-globuline, prostaglandin E2). CONCLUSION: No side effects of supplementation with selenium were noted, which can be considered as adjuvant therapy in patients with rheumatoid arthritis

The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts.

Hill PA, Murphy G, Docherty AJ, et al.

J Cell Sci. 1994 Nov; 107 ( Pt 11):3055-64.

We have compared the effects of a general matrix metalloproteinase (MMP) inhibitor (CT435) with those of a concentration-dependent specific gelatinase inhibitor (CT543; Ki < 20 nM) on bone resorption in vitro. The test systems consisted of measuring: (i) the release of 45Ca2+ from prelabelled mouse calvarial explants; (ii) the release of 45Ca2+ from prelabelled osteoid-free calvarial explants co-cultured with purified chicken osteoclasts; and (iii) lacunar resorption by isolated rat osteoclasts cultured on ivory slices. Both CT435 and CT543 dose-dependently inhibited the release of 45Ca2+ from neonatal calvarial bones stimulated by either parathyroid hormone or 1,25-dihydroxyvitamin D3. Moreover, CT543 produced a 40% inhibition at a concentration (10(-8) M) selective for the inhibition of human gelatinases A and B. CT435 (10(-5) M) and CT543 (10(-5) M) partially inhibited the release of 45Ca2+ from osteoid-free calvarial explants by chicken osteoclasts with a maximum of approximately 25% for unstimulated cultures, and approximately 36% for cultures stimulated by interleukin-1 alpha (IL-1 alpha; 10(-10) M). Neither inhibitor prevented lacunar resorption on ivory by unstimulated rat osteoclasts, but the compounds produced a partial reduction in both the number and total surface area of lacunae in IL-1 alpha-stimulated cultures, with maximal action at 10(-5) M. Neither of the inhibitors affected protein or DNA synthesis, nor the IL-1 alpha-stimulated secretion of the lysosomal enzyme beta-glucuronidase. Immunocytochemistry demonstrated that isolated rabbit osteoclasts constitutively expressed gelatinase A and synthesized gelatinase B, collagenase and stromelysin, as well as the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) following IL-1 alpha stimulation. These experiments have shown that in addition to collagenase, gelatinases A and B are likely to play a significant role in bone resorption. They further suggest that MMPs produced by osteoclasts are released into the sub-osteoclastic resorption zone where they participate in bone collagen degradation

Medicinal Mushrooms.

Hobbs C.

1996;

Sulfate could mediate the therapeutic effect of glucosamine sulfate.

Hoffer LJ, Kaplan LN, Hamadeh MJ, et al.

Metabolism. 2001 Jul; 50(7):767-70.

Glucosamine sulfate is a controversial osteoarthritis remedy that is presumed to stimulate articular cartilage glycosaminoglycan synthesis by increasing glucosamine concentrations in the joint space. However, this is not plausible because even large oral doses of the product have no effect on serum glucosamine concentrations. We propose instead that sulfate could mediate the clinical benefit attributed to this treatment. Sulfate is required for glycosaminoglycan synthesis, and unlike glucosamine, its serum level can be modified by dietary and other factors. In this study, we tested whether oral glucosamine sulfate increases serum sulfate concentrations and whether the sulfate concentration in the synovial fluid reflects that in the serum. The serum sulfate concentration of 7 normal subjects was 331 +/- 21 micromol/L before ingestion of 1.0 g glucosamine sulfate and 375 +/- 17 micromol/L 3 hours after (P

Intestinal permeability, leaky gut, and intestinal disorders.

Hollander D.

Curr Gastroenterol Rep. 1999 Oct; 1(5):410-6.

A major task of the intestine is to form a defensive barrier to prevent absorption of damaging substances from the external environment. This protective function of the intestinal mucosa is called permeability. Clinicians can use inert, nonmetabolized sugars such as mannitol, rhamnose, or lactulose to measure the permeability barrier or the degree of leakiness of the intestinal mucosa. Ample evidence indicates that permeability is increased in most patients with Crohn's disease and in 10% to 20% of their clinically healthy relatives. The abnormal leakiness of the mucosa in Crohn's patients and their relatives can be greatly amplified by aspirin preadministration. Permeability measurements in Crohn's patients reflect the activity, extent, and distribution of the disease and may allow us to predict the likelihood of recurrence after surgery or medically induced remission. Permeability is also increased in celiac disease and by trauma, burns, and nonsteroidal anti-inflammatory drugs. The major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space. As we broaden our understanding of the mechanisms and agents that control the degree of leakiness of the tight junctions, we will be increasingly able to use permeability measurements to study the etiology and pathogenesis of various disorders and to design or monitor therapies for their management

Antioxidant vitamin therapy alters burn trauma-mediated cardiac NF-kappaB activation and cardiomyocyte cytokine secretion.

Horton JW, White DJ, Maass DL, et al.

J Trauma. 2001 Mar; 50(3):397-406.

BACKGROUND: This study examined the effects of antioxidant vitamins A, C, and E on nuclear transcription factor-kappa B (NF-kappaB) nuclear translocation, on secretion of inflammatory cytokines by cardiac myocytes, and on cardiac function after major burn trauma. METHODS: Adult rats were divided into four experimental groups: group I, shams; group II, shams given oral antioxidant vitamins (vitamin C, 38 mg/kg; vitamin E, 27 U/kg; vitamin A, 41 U/kg 24 hours before and immediately after burn); group III, burns (third-degree scald burn over 40% total body surface area) given lactated Ringer's solution (4 mL/kg/% burn); and group IV, burns given lactated Ringer's solution plus vitamins as described above. Hearts were collected 4, 8, 12, and 24 hours after burn to assay for NF-kappaB nuclear translocation, and hearts collected 24 hours after burn were examined for cardiac contractile function or tumor necrosis factor-alpha secretion by cardiomyocytes. RESULTS: Compared with shams, left ventricular pressure was lower in burns given lactated Ringer's solution (group III) (88 +/- 3 vs. 64 +/- 5 mm Hg, p < 0.01) as was +dP/dt max (2,190 +/- 30 vs. 1,321 +/- 122 mm Hg/s) and -dP/dt max (1,775 +/- 71 vs. 999 +/- 96 mm Hg, p < 0.01). Burn injury in the absence of vitamin therapy (group III) produced cardiac NF-kappaB nuclear migration 4 hours after burn and cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by 24 hours after burn. Antioxidant therapy in burns (group IV) improved cardiac function, producing left ventricular pressure and +/-dP/dt (82 +/- 2 mm Hg, 1,880 +/- 44 mm Hg, and 1,570 +/- 46 mm Hg/s) comparable to those measured in shams. Antioxidant vitamins in burns inhibited NF-kappaB nuclear migration at all times after burn and reduced burn-mediated cytokine secretion by cardiomyocytes. CONCLUSION: These data suggest that antioxidant vitamin therapy in burn trauma provides cardioprotection, at least in part, by inhibiting translocation of the transcription factor NF-kappaB and interrupting cardiac inflammatory cytokine secretion

A multicentre double-blind comparison of oxaprozin aspirin therapy on rheumatoid arthritis.

Hubsher JA, Ballard IM, Walker BR, et al.

J Int Med Res. 1979; 7(1):69-76.

Preliminary clinical studies showed that oxaprozin (4,5 Diphenyl-2-oxazolepropionic acid) has anti-inflammatory and analgesic properties with a plasma half-life of about 40 hours. Consequently, a multicentre, double-blind parallel trial was conducted for 12 weeks at thirteen investigator sites, utilizing 212 patients with classic rheumatoid arthritis and comparing oxaprozin 600 mg/day, oxaprozin 1200 mg/day and aspirin 3900 mg/day. Both the oxaprozin and aspirin-treated patients had statistically significant improvement from baseline periods, in most key categories evaluated. Oxaprozin administered twice a day (b.i.d.) was as effective as aspirin administered four times a day (q.i.d.) and caused significantly less tinnitus (p less than 0.001). Fewer patients receiving high dose oxaprozin (2%) dropped out of the study because of unsatisfactory response than did those receiving aspirin (10%). There were no clinically significant laboratory abnormalities in the gastro-intestinal, renal, hepatic or haematological parameters monitored. This study suggests that oxaprozin is effective and well tolerated in the treatment of rheumatoid arthritis

Food allergy--or enterometabolic disorder?

Hunter JO.

Lancet. 1991 Aug 24; 338(8765):495-6.

The Miracle of MSM: The Natural Solution for Pain.

Jacob SW.

1999;

Dietary n-3 fatty acids and therapy for rheumatoid arthritis.

James MJ, Cleland LG.

Semin Arthritis Rheum. 1997 Oct; 27(2):85-97.

OBJECTIVE: To examine the potential for dietary n-3 fats to be component of therapy for rheumatoid arthritis (RA). METHODS: Studies of encapsulated fish oil use in RA were reviewed and critiqued, and possible biochemical mechanisms for fish oil effects were examined. The potential for use of n-3 fats was evaluated within a dietary framework rather than a quasi-pharmaceutical framework. RESULTS: There is consistent evidence from double-blind, placebo-controlled clinical trials that dietary n-3 fats, supplied as fish oil, can have beneficial effects in RA. The beneficial effects appear modest, but their size and extent may have been moderated by common trial design factors such as high n-6 polyunsaturated fat diets and concurrent antiinflammatory drug use. Mechanisms for the clinical effects of n-3 fats in RA may involve their ability to suppress production of inflammatory mediators, including n-6 eicosanoids and proinflammatory cytokines. Suppression of n-6 eicosanoid and cytokine production will be possible using foodstuffs that are rich in n-3 fats and poor in n-6 fats. CONCLUSIONS: There are many overlapping biochemical effects of n-3 fatty acids and antiinflammatory pharmaceuticals that could explain the clinical actions of n-3 fats in RA. They suggest that there is the potential for complementarity between drug therapy and dietary choices that increase intake of n-3 fats and decrease intake of n-6 fats. In particular, there is the potential for drug-sparing effects. Future studies with n-3 fats in RA need to address the fat composition of the background diet and the issue of concurrent drug use

Dietary polyunsaturated fatty acids and inflammatory mediator production.

James MJ, Gibson RA, Cleland LG.

Am J Clin Nutr. 2000 Jan; 71(1 Suppl):343S-8S.

Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = "90%" inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products

Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis.

Jikimoto T, Nishikubo Y, Koshiba M, et al.

Mol Immunol. 2002 Feb; 38(10):765-72.

There is no doubt that oxidative stress occurs in patients with rheumatoid arthritis (RA) and play an important role in both inflammation and destruction of RA joints. Thioredoxin (TRX) is a ubiquitous redox-active protein and is known to be induced in several cells against oxidative stress and to be secreted extracellularly. To clarify whether plasma thioredoxin levels could be a marker for oxidative stress in patients with RA, we measured plasma TRX levels in patients with RA using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) and investigated its relationship to TRX concentrations in the inflammatory joints.We have found that the plasma TRX levels of RA patients were significantly higher than those of normal subjects (86.8 +/-54.1 ng/ml versus 38.6 +/-18.5 ng/ml, P

Effect of curcumin and capsaicin on arachidonic acid metabolism and lysosomal enzyme secretion by rat peritoneal macrophages.

Joe B, Lokesh BR.

Lipids. 1997 Nov; 32(11):1173-80.

The inflammatory mediators secreted by macrophages play an important role in autoimmune diseases. Spice components, such as curcumin from turmeric and capsaicin from red pepper, are shown to exhibit antiinflammatory properties. The influence of these spice components on arachidonic acid metabolism and secretion of lysosomal enzymes by macrophages was investigated. Rat peritoneal macrophages preincubated with 10 microM curcumin or capsaicin for 1 h inhibited the incorporation of arachidonic acid into membrane lipids by 82 and 76%: prostaglandin E2 by 45 and 48%; leukotriene B4 by 61 and 46%, and leukotriene C4 by 34 and 48%, respectively, but did not affect the release of arachidonic acid from macrophages stimulated by phorbol myristate acetate. However, the secretion of 6-keto PG F1 alpha was enhanced by 40 and 29% from macrophages preincubated with 10 microM curcumin or capsaicin, respectively, as compared to those produced by control cells. Curcumin and capsaicin also inhibited the secretion of collagenase, elastase, and hyaluronidase to the maximum extent of 57, 61, 66%, and 46, 69, 67%, respectively. These results demonstrated that curcumin and capsaicin can control the release of inflammatory mediators such as eicosanoids and hydrolytic enzymes secreted by macrophages and thereby may exhibit antiinflammatory properties

Nuclear factor kappaB (NF-kappaB) pathway as a therapeutic target in rheumatoid arthritis.

Jue DM, Jeon KI, Jeong JY.

J Korean Med Sci. 1999 Jun; 14(3):231-8.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint swelling and progressive destruction of cartilage and bone. Current RA treatments are largely empirical in origin and their precise mechanism of action is uncertain. Increasing evidence shows that chronic inflammatory diseases such as RA are caused by prolonged production of proinflammatory cytokines including tumor necrosis factor (TNF) and interleukin 1 (IL-1). The nuclear factor kappaB (NF-kappaB) plays an essential role in transcriptional activation of TNF and IL-1. NF-kappaB is induced by many stimuli including TNF and IL-1, forming a positive regulatory cycle that may amplify and maintain RA disease process. NF-kappaB and enzymes involved in its activation can be a target for anti-inflammatory treatment. Aspirin and sodium salicylate inhibit activation of NF-KB by blocking IkappaB kinase, a key enzyme in NF-kappaB activation. Glucocorticoids suppress expression of inflammatory genes by binding glucocorticoid receptor with NF-kappaB, and increasing expression of inhibitory protein of NF-kappaB, IkappaBalpha. Sulfasalazine and gold compounds also inhibit NF-kappaB activation. Continuing advances in our understanding of action mechanism of antirheumatic agents will benefit the future development of RA regimens with greater efficacy and less toxicity

Full Catastrophe Living.

Kabat-Zinn J.

1990;

Wherever You Go There You Are.

Kabat-Zinn J.

1994;

[Pharmacologic studies on the antidegenerative effect of ademetionine in experimental arthritis in animals].

Kalbhen DA, Jansen G.

Arzneimittelforschung. 1990 Sep; 40(9):1017-21.

A standardized pharmacological model of biochemically induced osteoarthritis in the knee joint of laboratory animals was used for the study of a possible antidegenerative effect of ademetionine (S-adenosyl-methionine, active substance of Gumbaral) in-vivo. Four days after the initial induction of osteoarthritis by 2 intraarticular injections of 0.6 mg sodium iodoacetate into the left knee joint of adult hens, the therapy started with once-weekly intraarticular doses of 0.5 mg, 1.0 mg and 2.0 mg ademetionine over a period of 14 weeks. Quantitative monitoring of the intensity and progression of osteoarthritis was performed every 2 weeks by joint space measurements, topographic-radiological evaluations, and by a macroscopic post-mortem assessment of the joint cartilage and bone. These objective analytical parameters clearly demonstrated that weekly intraarticular doses of 1.0 mg ademetionine significantly reduced the intensity of degenerative processes compared to the placebo (saline) treated joints. The antidegenerative effect of doses of 0.5 mg or 2.0 mg ademetionine were less pronounced and of no statistical significance. Our findings indicate an interesting therapeutic potency of ademetionine in experimental osteoarthritis and confirm the positive clinical observations as well as in-vitro results with this new drug by other researchers

C-reactive protein (CRP) in the cardiovascular system.

Kanda T.

Rinsho Byori. 2001 Apr; 49(4):395-401.

CRP (C-reactive protein) is an acute-phase reactant, the levels of which increase dramatically in response to severe bacterial infection, physical trauma, and other inflammatory conditions. CRP is found in human atherosclerotic lesions. Atherosclerosis is clearly multifactorial in origin, and chronic inflammation is an important component in its pathogenesis. Focus on inflammation is critical in research on atherosclerosis. Elevated levels of CRP have been associated with increased risk of future coronary artery disease (CAD) events. I have summarized the recent literature on CRP studies in CAD. Both coronary heart disease and dilated cardiomyopathy(DCM) result in congestive heart failure due to myocardial damage. The inflammatory state produced by myocarditis of viral or other origin may induce advanced myocardial damage, resulting in heart failure with a poor prognosis. Routine CRP measurement proved to be valuable for identifying high-risk patients with DCM and lymphocytic myocarditis. I suggest that measurement of circulating CRP would be useful for the diagnosis of and for selecting therapeutic strategies for cardiovascular disorders

Topical treatment for arthritis. Clinical study.

Keller BC.

7777; Clinical study 2002 (unpublished)

A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice.

Kelley VE, Ferretti A, Izui S, et al.

J Immunol. 1985 Mar; 134(3):1914-9.

Dietary supplementation of fish oil as the exclusive source of lipid suppresses autoimmune lupus in MRL-lpr mice. This marine oil diet decreases the lymphoid hyperplasia regulated by the lpr gene, prevents an increase in macrophage surface Ia expression, reduces the formation of circulating retroviral gp70 immune complexes, delays the onset of renal disease, and prolongs survival. We show that a fatty acid component uniquely present in fish oil but not in vegetable oil decreases the quantity of dienoic prostaglandin E, thromboxane B, and prostacyclin normally synthesized by multiple tissues, including kidney, lung, and macrophages, and promotes the synthesis of small amounts of trienoic prostaglandin in autoimmune mice. We suggest that this change in endogenous cyclooxygenase metabolite synthesis directly suppresses immunologic and/or inflammatory mediators of murine lupus

Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6.

Khalfoun B, Thibault F, Watier H, et al.

Adv Exp Med Biol. 1997; 400B:589-97.

The interaction between lymphocytes, cytokines, and endothelial cells (EC) is a key step in the inflammatory process. Interleukin-6 (IL-6) a pleiotropic cytokine in its effects, seems to be an early indicator of acute systemic inflammation. In this study, we have examined the effects of polyunsaturated fatty acids (PUFAs) on the production of IL-6 by human unstimulated EC or EC stimulated with TNF-alpha (100 U/ml); IL-4 (100 U/ml); LPS (1 ug/ml); or allogeneic peripheral blood lymphocytes (PBL). Twenty-four hour culture supernatants of immunoreactive IL-6 were measured by Sandwich ELISA. We have shown that the production of IL-6 was potentiated when EC were stimulated with TNF-alpha; IL-4; LPS; or monocyte-depleted PBL in comparison to unstimulated EC. The addition of n-3 PUFAs in culture medium (100 ug/ml DHA or EPA) significantly reduces the production of IL-6 by unstimulated EC; or stimulated with TNF-alpha; IL-4 pg/ml); LPS or depleted PBL respectively for DHA and EPA, whereas the n-6 PUFAs (Arachidonic acid), even used at the highest concentration, was ineffective. This inhibitory effect is PUFA dose dependent but is more potent with EPA than DHA. Regardless of the mode of action, since IL-6 is known to be involved in hematopoiesis, in the regulation of the immune response and in the inflammatory reaction, these results suggest that n-3 PUFAs may play a role in suppressing inflammation. Further studies are needed to elucidate the mechanism involved and the choice between the two fatty acids for clinical and therapeutic purposes

Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor alpha and interleukin-6 [correction of interlukin-6] in astrocytes.

Kipper-Galperin M, Galilly R, Danenberg HD, et al.

Int J Dev Neurosci. 1999 Dec; 17(8):765-75.

Dehydroepiandrosterone (DHEA) is a native neurosteroid with immunomodulating activity. DHEA effectively protects animals from several viral, bacterial and parasitic infections and it was suggested that its age-associated decline is related with immunosenescence. In the present study we examined the ability of DHEA to inhibit the production of inflammatory mediators by mycoplasma-stimulated glial cells and to change the course of acute central nervous system (CNS) inflammatory disease in vivo. Addition of DHEA (10 microg/ml) markedly inhibited tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production (98 and 95%, respectively), whereas nitric oxide (NO) and prostaglandin E2 (PGE2) production was not affected. However, daily administration of 0.5 mg DHEA to mice or 5 mg to rats did not change the clinical outcome of experimental autoimmune encephalomyelitis (EAE)

Vegetarian diet for patients with rheumatoid arthritis--status: two years after introduction of the diet.

Kjeldsen-Kragh J, Haugen M, Borchgrevink CF, et al.

Clin Rheumatol. 1994 Sep; 13(3):475-82.

We have previously reported that a significant improvement can be obtained in rheumatoid arthritis patients by fasting followed by an individually adjusted vegetarian diet for one year. The patients who changed their diet could be divided into diet responders and diet nonresponders. After the clinical trial the patients were free to change diet or medication and after approximately one year they were asked to attend a new clinical examination. We compared the change from baseline (i.e. at the time of study entry) to the time of the follow-up examination for diet responders, diet nonresponders and controls who ate an omnivorous diet. The following variables favoured diet responders: pain score, duration of morning stiffness, Stanford Health Assessment Questionnaire index, number of tender joints, Ritchie's articular index, number of swollen joints, ESR and platelet count [corrected]. The difference between the three groups were significant for all the clinical variables, except for grip strength. There was no significant difference between the groups with regard to laboratory or anthropometric variables. At the time of the follow-up examination all diet responders but only half of the diet nonresponders still followed a diet. Our findings indicate that a group of patients with rheumatoid arthritis benefit from dietary manipulations and that the improvement can be sustained through a two-year period

Vegetarian diet for patients with rheumatoid arthritis: can the clinical effects be explained by the psychological characteristics of the patients?

Kjeldsen-Kragh J, Haugen M, Forre O, et al.

Br J Rheumatol. 1994 Jun; 33(6):569-75.

In a controlled, single blind clinical trial we have demonstrated recently a beneficial effect of fasting and vegetarian diet in RA. In the present study we compared 53 patients who participated in this clinical trial with 71 other RA patients with regard to some psychological parameters. The patients who participated in the clinical trial differed significantly from other RA patients. Firstly, they had a higher internal score and a lower chance score on the Multi-dimensional Health Locus of Control Scale (MHLCS). Secondly, their belief in the effect of ordinary medical treatment, evaluated by a 10-cm visual analogue scale, was lower, and their belief in the effect of 'alternative', unconventional forms of treatment was higher. Of the patients who were randomized to a vegetarian diet, there was no significant difference between diet responders and diet non-responders with regard to the MHLCS scores. But, diet responders had a significantly lower belief in the effect of ordinary medical treatment compared with diet non-responders. The psychological distress imposed on the patients by changing from an omnivorous diet to a vegetarian diet was monitored during the clinical trial by means of the General Health Questionnaire. Throughout the clinical trial, this variable favoured the vegetarians compared with the omnivorous and the diet responders vs the diet non-responders. We conclude, firstly, that patients with certain psychological characteristics were selected to the clinical trial; secondly, that the MHLCS scores could not explain the clinical improvement, but it may have been influenced by the patients' beliefs in ordinary and 'alternative' forms of treatment; and thirdly, that dietary treatment decreased psychological distress

Decrease in anti-Proteus mirabilis but not anti-Escherichia coli antibody levels in rheumatoid arthritis patients treated with fasting and a one year vegetarian diet.

Kjeldsen-Kragh J, Rashid T, Dybwad A, et al.

Ann Rheum Dis. 1995 Mar; 54(3):221-4.

OBJECTIVE--To measure Proteus mirabilis and Escherichia coli antibody levels in patients with rheumatoid arthritis (RA) during treatment by vegetarian diet. METHODS--Sera were collected from 53 RA patients who took part in a controlled clinical trial of fasting and a one year vegetarian diet. P mirabilis and E coli antibody levels were measured by an indirect immunofluorescence technique and an enzyme immunoassay, respectively. RESULTS--The patients on the vegetarian diet had a significant reduction in the mean anti-proteus titres at all time points during the study, compared with baseline values (all p < 0.05). No significant change in titre was observed in patients who followed an omnivorous diet. The decrease in anti-proteus titre was greater in the patients who responded well to the vegetarian diet compared with diet non-responders and omnivores. The total IgG concentration and levels of antibody against E coli, however, were almost unchanged in all patient groups during the trial. The decrease from baseline in proteus antibody levels correlated significantly (p < 0.001) with the decrease in a modified Stoke disease activity index. CONCLUSION--The decrease in P mirabilis antibody levels in the diet responders and the correlation between the decrease in proteus antibody level and decrease in disease activity supports the suggestion of an aetiopathogenetic role for P mirabilis in RA

Changes in laboratory variables in rheumatoid arthritis patients during a trial of fasting and one-year vegetarian diet.

Kjeldsen-Kragh J, Mellbye OJ, Haugen M, et al.

Scand J Rheumatol. 1995; 24(2):85-93.

We have previously reported that significant improvement may be obtained in rheumatoid arthritis patients by fasting followed by a vegetarian diet for one year. The present study was carried out to examine to what extent biochemical and immunological variables changed during the clinical trial of fasting and vegetarian diet. For the patients who were randomised to the vegetarian diet there was a significant decrease in platelet count, leukocyte count, calprotectin, total IgG, IgM rheumatoid factor (RF), C3-activation products, and the complement components C3 and C4 after one month of treatment. None of the measured parameters changed significantly during this period in the group of omnivores. The course of 14 of 15 measured variables favored the vegetarians compared with the omnivores, but the difference was only significant for leukocyte count, IgM RF, and the complement components C3 and C4. Most of the laboratory variables declined considerably in the vegetarians who improved according to clinical variables, indicating a substantial reduction in inflammatory activity. The leukocyte count, however, decreased in the vegetarians irrespective of the clinical results. Thus, the decline in leukocyte count may be attributed to vegetarian diet per se and not to the reduction in disease activity. The results of the present study are in accordance with the findings from the clinical trial, namely that dietary treatment can reduce the disease activity in some patients with rheumatoid arthritis

Rheumatoid arthritis treated with vegetarian diets.

Kjeldsen-Kragh J.

Am J Clin Nutr. 1999 Sep; 70(3 Suppl):594S-600S.

The notion that dietary factors may influence rheumatoid arthritis (RA) has been a part of the folklore of the disease, but scientific support for this has been sparse. In a controlled, single-blind trial we tested the effect of fasting for 7-10 d, then consuming an individually adjusted, gluten-free, vegan diet for 3.5 mo, and then consuming an individually adjusted lactovegetarian diet for 9 mo on patients with RA. For all clinical variables and most laboratory variables measured, the 27 patients in the fasting and vegetarian diet groups improved significantly compared with the 26 patients in the control group who followed their usual omnivorous diet throughout the study period. One year after the patients completed the trial, they were reexamined. Compared with baseline, the improvements measured were significantly greater in the vegetarians who previously benefited from the diet (diet responders) than in diet nonresponders and omnivores. The beneficial effect could not be explained by patients' psychologic characteristics, antibody activity against food antigens, or changes in concentrations of prostaglandin and leukotriene precursors. However, the fecal flora differed significantly between samples collected at time points at which there was substantial clinical improvement and time points at which there were no or only minor improvements. In summary, the results show that some patients with RA can benefit from a fasting period followed by a vegetarian diet. Thus, dietary treatment may be a valuable adjunct to the ordinary therapeutic armamentarium for RA

Between Heaven and Earth: A Guide to Chinese Medicine.

Korngold E.

1991;

The effects of insulin, glucose and diabetes on prostaglandin production by rat kidney glomeruli and cultured glomerular mesangial cells.

Kreisberg JI, Patel PY.

Prostaglandins Leukot Med. 1983 Aug; 11(4):431-42.

Glomeruli isolated from streptozotocin-diabetic rats produced significantly greater amounts of immunoreactive prostaglandin (PG)E2, PGF2 alpha, and prostacyclin (PGI2) measured as the stable metabolite 6-keto-PGF1 alpha than control glomeruli. These data led to studies to determine whether the vasoactive glomerular mesangial cell exhibited alterations in arachidonic acid metabolism in diabetes. Therefore, we isolated and cultured under identical conditions, mesangial cells from normal and streptozotocin-diabetic rats. Normal mesangial cells produced predominantly PGE2 (57-72%) with PGE2 greater than PGF2 alpha greater than PGI2 after stimulation of acylhydrolase with melittin. Mesangial cells from diabetic rats produced predominantly PGI2 (55-73%) with PGI2 greater than PGE2 greater than PGF2 alpha. A similar prostaglandin profile was obtained when arginine vasopressin (AVP) was used to stimulate acylhydrolase activity. In addition, diabetic mesangial cells synthesized greater amounts of prostaglandins than normal mesangial cells cultured for the same number of passages. When cultured under high-glucose conditions (in tissue culture medium with a final glucose concentration of 550 mg/dl) to mimic the diabetic state in vitro, normal mesangial cells produced proportionately greater amounts of PGE2, PGF2 alpha and PGI2; no alteration to predominantly PGI2 production was observed. Insulin addition to the high-glucose condition tended to attenuate prostaglandin production. Diabetic mesangial cells likewise produced more prostaglandins when cultured under high-glucose conditions; however, the increases were not proportional among the 3 prostaglandins examined. PGE2 production increased to a greater degree than PGI2. With insulin present in the high-glucose condition, there was a disproportional attenuation of all prostaglandins produced, with PGI2 decreasing more than PGE2. Thus, the streptozotocin-induced diabetic state resulted in an alteration in mesangial cell arachidonic acid metabolism

Clinical studies of n-3 fatty acids supplementation in patients with rheumatoid arthritis.

Kremer JM.

Rheum Dis Clin. 1992;(17):391-402.

Effects of manipulation of dietary fatty acids on clinical manifestations of rheumatoid arthritis.

Kremer JM, Bigauoette J, Michalek AV, et al.

Lancet. 1985 Jan 26; 1(8422):184-7.

The effects of manipulation of dietary fatty acids in patients with rheumatoid arthritis were investigated in a 12-week, prospective, double-blind, controlled study. 17 patients took an experimental diet high in polyunsaturated fat and low in saturated fat, with a daily supplement (1.8 g) of eicosapentaenoic acid. 20 patients took a control diet with a lower polyunsaturated to saturated fat ratio and a placebo supplement. Compliance was monitored by plasma lipid gas-chromatographic analysis, Ivy bleeding time, and diet diaries. Results favoured the experimental group at 12 weeks for morning stiffness and number of tender joints. On follow-up evaluation 1-2 months after stopping the diet, the experimental group had deteriorated significantly in patient and physician global evaluation of disease activity, pain assessment, and number of tender joints. The control group had improved in morning stiffness and number of tender joints on follow-up

Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs. Clinical and immune correlates.

Kremer JM, Lawrence DA, Petrillo GF, et al.

Arthritis Rheum. 1995 Aug; 38(8):1107-14.

OBJECTIVE. To determine the following: 1) whether dietary supplementation with fish oil will allow the discontinuation of nonsteroidal antiinflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA); 2) the clinical efficacy of high-dose dietary omega 3 fatty acid fish oil supplementation in RA patients; and 3) the effect of fish oil supplements on the production of multiple cytokines in this population. METHODS. Sixty-six RA patients entered a double-blind, placebo-controlled, prospective study of fish oil supplementation while taking diclofenac (75 mg twice a day). Patients took either 130 mg/kg/day of omega 3 fatty acids or 9 capsules/day of corn oil. Placebo diclofenac was substituted at week 18 or 22, and fish oil supplements were continued for 8 weeks (to week 26 or 30). Serum levels of interleukin-1 beta (IL-1 beta), IL-2, IL-6, and IL-8 and tumor necrosis factor alpha were measured by enzyme-linked immunosorbent assay at baseline and during the study. RESULTS. In the group taking fish oil, there were significant decreases from baseline in the mean (+/- SEM) number of tender joints (5.3 +/- 0.835; P < 0.0001), duration of morning stiffness (-67.7 +/- 23.3 minutes; P = "0.008)," physician's and patient's evaluation of global arthritis activity (-0.33 +/- 0.13; P = "0.017" and -0.38 +/- 0.17; P = "0.036," respectively), and physician's evaluation of pain (-0.38 +/- 0.12; P = "0.004)." In patients taking corn oil, no clinical parameters improved from baseline. The decrease in the number of tender joints remained significant 8 weeks after discontinuing diclofenac in patients taking fish oil (-7.8 +/- 2.6; P = "0.011)" and the decrease in the number of tender joints at this time was significant compared with that in patients receiving corn oil (P = "0.043)." IL-1 beta decreased significantly from baseline through weeks 18 and 22 in patients consuming fish oil (-7.7 +/- 3.1; P = "0.026)." CONCLUSION. Patients taking dietary supplements of fish oil exhibit improvements in clinical parameters of disease activity from baseline, including the number of tender joints, and these improvements are associated with significant decreases in levels of IL-1 beta from baseline. Some patients who take fish oil are able to discontinue NSAIDs without experiencing a disease flare

Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs. Clinical and immune correlates.

Kremer JM, Lawrence DA, Petrillo GF, et al.

Arthritis Rheum. 1995 Aug; 38(8):1107-14.

OBJECTIVE. To determine the following: 1) whether dietary supplementation with fish oil will allow the discontinuation of nonsteroidal antiinflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA); 2) the clinical efficacy of high-dose dietary omega 3 fatty acid fish oil supplementation in RA patients; and 3) the effect of fish oil supplements on the production of multiple cytokines in this population. METHODS. Sixty-six RA patients entered a double-blind, placebo-controlled, prospective study of fish oil supplementation while taking diclofenac (75 mg twice a day). Patients took either 130 mg/kg/day of omega 3 fatty acids or 9 capsules/day of corn oil. Placebo diclofenac was substituted at week 18 or 22, and fish oil supplements were continued for 8 weeks (to week 26 or 30). Serum levels of interleukin-1 beta (IL-1 beta), IL-2, IL-6, and IL-8 and tumor necrosis factor alpha were measured by enzyme-linked immunosorbent assay at baseline and during the study. RESULTS. In the group taking fish oil, there were significant decreases from baseline in the mean (+/- SEM) number of tender joints (5.3 +/- 0.835; P < 0.0001), duration of morning stiffness (-67.7 +/- 23.3 minutes; P = "0.008)," physician's and patient's evaluation of global arthritis activity (-0.33 +/- 0.13; P = "0.017" and -0.38 +/- 0.17; P = "0.036," respectively), and physician's evaluation of pain (-0.38 +/- 0.12; P = "0.004)." In patients taking corn oil, no clinical parameters improved from baseline. The decrease in the number of tender joints remained significant 8 weeks after discontinuing diclofenac in patients taking fish oil (-7.8 +/- 2.6; P = "0.011)" and the decrease in the number of tender joints at this time was significant compared with that in patients receiving corn oil (P = "0.043)." IL-1 beta decreased significantly from baseline through weeks 18 and 22 in patients consuming fish oil (-7.7 +/- 3.1; P = "0.026)." CONCLUSION. Patients taking dietary supplements of fish oil exhibit improvements in clinical parameters of disease activity from baseline, including the number of tender joints, and these improvements are associated with significant decreases in levels of IL-1 beta from baseline. Some patients who take fish oil are able to discontinue NSAIDs without experiencing a disease flare

Nutrient intake of patients with rheumatoid arthritis is deficient in pyridoxine, zinc, copper, and magnesium.

Kremer JM, Bigaouette J.

J Rheumatol. 1996 Jun; 23(6):990-4.

OBJECTIVE: To determine nutrient intake of patients with active rheumatoid arthritis and compare it with the typical American diet (TAD) and the recommended dietary allowance (RDA). METHODS: 41 patients with active RA recorded a detailed dietary history. Information collected was analyzed for nutrient intake of energy, fats, protein, carbohydrate, vitamins and minerals, which were then statistically compared with the TAD and the RDA. RESULTS: Both men and women ingested significantly less energy from carbohydrates [women 47.4% (6.4) vs 55% RDA. p = 0.0001: men = 48.9% (7.4). p = 0.025] and more energy from fat [women = 36.8% (4.5) vs 30% RDA. p = 0.001 and men = 35.2% (5.9) p = 0.02]. Women ingested significantly more saturated and mono-unsaturated fat than the RDA (p = 0.02 and p = 0.04 respectively) while men ingested significantly less polyunsaturated fat (PUFA) (p = 0.0001). Both groups took in less fiber (p = 0.0001). Deficient dietary intake of pyridoxine was observed vs the RDA for both sexes (men and women p = 0.0001). Deficient folate intake was seen vs the TAD for men (p = 0.02) with a deficient trend in women (p = 0.06). Zinc and magnesium intake was deficient vs the RDA in both sexes (p values < or = "0.001)" and copper was deficient vs the TAD in both sexes (p = "0.004" women and p = "0.02" men). CONCLUSION: Patients with RA ingest too much total fat and too little PUFA and fiber. Their diets are deficient in pyridoxine, zinc and magnesium vs the RDA and copper and folate vs the TAD. These observations, also documented in previous studies, suggest that routine dietary supplementation with multivitamins and trace elements is appropriate in this population

n-3 fatty acid supplements in rheumatoid arthritis.

Kremer JM.

Am J Clin Nutr. 2000 Jan; 71(1 Suppl):349S-51S.

Ingestion of dietary supplements of n-3 fatty acids has been consistently shown to reduce both the number of tender joints on physical examination and the amount of morning stiffness in patients with rheumatoid arthritis. In these cases, supplements were consumed daily in addition to background medications and the clinical benefits of the n-3 fatty acids were not apparent until they were consumed for > or =12 wk. It appears that a minimum daily dose of 3 g eicosapentaenoic and docosahexaenoic acids is necessary to derive the expected benefits. These doses of n-3 fatty acids are associated with significant reductions in the release of leukotriene B(4) from stimulated neutrophils and of interleukin 1 from monocytes. Both of these mediators of inflammation are thought to contribute to the inflammatory events that occur in the rheumatoid arthritis disease process. Several investigators have reported that rheumatoid arthritis patients consuming n-3 dietary supplements were able to lower or discontinue their background doses of nonsteroidal antiinflammatory drugs or disease-modifying antirheumatic drugs. Because the methods used to determine whether patients taking n-3 supplements can discontinue taking these agents are variable, confirmatory and definitive studies are needed to settle this issue. n-3 Fatty acids have virtually no reported serious toxicity in the dose range used in rheumatoid arthritis and are generally very well tolerated

Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis.

Langlois M, Duprez D, Delanghe J, et al.

Circulation. 2001 Apr 10; 103(14):1863-8.

BACKGROUND: Peripheral arterial disease (PAD) is a severe atherosclerotic condition frequently accompanied by inflammation and oxidative stress. We hypothesized that vitamin C antioxidant levels might be low in PAD and are related to inflammation and disease severity. METHODS AND RESULTS: We investigated vitamin C (L-ascorbic acid) levels in 85 PAD patients, 106 hypertensives without PAD, and 113 healthy subjects. Serum L-ascorbic acid concentrations were low among PAD patients (median, 27.8 micromol/L) despite comparable smoking status and dietary intake with the other groups (P

Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis--a double-blind placebo controlled study.

Lau CS, Morley KD, Belch JJ.

Br J Rheumatol. 1993 Nov; 32(11):982-9.

Maxepa contains eicosapentaenoic acid (EPA) (171 mg/capsule) and docosahexaenoic acid (DHA) (114 mg/capsule). EPA acts as an alternative substrate to arachidonate, leading to the formation of the less proinflammatory prostaglandins ('3' series) and leukotrienes ('5' series). If Maxepa has anti-inflammatory properties it could be expected to reduce the requirement for NSAIDs in patients with RA. This has not been investigated nor has Maxepa therapy been studied over a full 1-yr period. Sixty-four patients with stable RA requiring NSAID therapy only were studied. Patients received either 10 Maxepa or air-filled placebo capsules per day for 12 months. All then received placebo capsules for a further 3 months. Patients were reviewed at 3-monthly intervals. NSAID requirement at entry visit for each patient was assigned as 100%. Patients were instructed to slowly reduce their NSAID dosage providing there was no worsening of their symptoms. Clinical and laboratory parameters of RA activity were also measured. There was a significant reduction in NSAID usage in patients on Maxepa when compared with placebo from month 3 [mean (95% C.I. for mean) requirement--71.1 (55.9-86.2)% and 89.7 (73.7-105.7)%, respectively]. This effect reached its maximum at month 12 [40.6 (24.5-56.6)% and 84.1 (62.7-105.5)%, respectively] and persisted to month 15 [44.7 (27.6-61.8)% and 85.8 (60.5-111.1)%, respectively] (P < 0.001, ANOVA). These patients were able to reduce their NSAID requirement without experiencing any deterioration in the clinical and laboratory parameters of RA activity

Lignisul MSM (Methylsulfonylmethane): A Double Blind Study of Its Use in Degenerative Arthritis 1998.

Lawrence RM.

1998

Treatment of rheumatoid arthritis with gammalinolenic acid.

Leventhal LJ, Boyce EG, Zurier RB.

Ann Intern Med. 1993 Nov 1; 119(9):867-73.

OBJECTIVE: To assess the clinical efficacy and side effects of gammalinolenic acid, a plant-seed-derived essential fatty acid that suppresses inflammation and joint tissue injury in animal models. DESIGN: A randomized, double-blind, placebo-controlled, 24-week trial. SETTING: Rheumatology clinic of a university hospital. PATIENTS: Thirty-seven patients with rheumatoid arthritis and active synovitis. INTERVENTION: Treatment with 1.4 g/d gammalinolenic acid in borage seed oil or cotton seed oil (placebo). MEASUREMENTS: Physicians' and patients' global assessment of disease activity; joint tenderness, joint swelling, morning stiffness, grip strength, and ability to do daily activities. RESULTS: Treatment with gammalinolenic acid resulted in clinically important reduction in the signs and symptoms of disease activity in patients with rheumatoid arthritis (P < 0.05). In contrast, patients given a placebo showed no change or showed worsening of disease. Gammalinolenic acid reduced the number of tender joints by 36%, the tender joint score by 45%, swollen joint count by 28%, and the swollen joint score by 41%, whereas the placebo group did not show significant improvement in any measure. Overall clinical responses (significant change in four measures) were also better in the treatment group (P < 0.05). No patients withdrew from gammalinolenic acid treatment because of adverse reactions. CONCLUSION: Gammalinolenic acid in doses used in this study is a well-tolerated and effective treatment for active rheumatoid arthritis. Gammalinolenic acid is available worldwide as a component of evening primrose and borage seed oils. It is usually taken in far lower doses than used in this trial. It is not approved in the United States for the treatment of any condition and should not be viewed as therapy for any disease. Further controlled studies of its use in rheumatoid arthritis are warranted

Treatment of rheumatoid arthritis with blackcurrant seed oil.

Leventhal LJ, Boyce EG, Zurier RB.

Br J Rheumatol. 1994 Sep; 33(9):847-52.

The objective of this study was to assess the clinical efficacy and side effects of blackcurrant seed oil (BCSO), in a randomized, double-blind, placebo controlled, 24-week trial in patients with RA and active synovitis. BCSO is rich in gammalinolenic acid (GLA) and alphalinolenic acid (ALA). Both GLA and eicosapentaenoic acid which derives from ALA suppress inflammation and joint tissue injury in animal models. Treatment with BCSO resulted in reduction in signs and symptoms of disease activity in patients with RA (P < 0.05). In contrast, patients given a placebo showed no change in disease. Overall clinical responses (significant change in four measures) were no better in the treatment group than in the placebo group. No patients withdrew from BCSO treatment because of adverse reactions. However, many patients withdrew because BCSO and its placebo had to be administered in 15 large capsules daily. Nonetheless, the study indicates that BCSO is a potentially effective treatment for active RA. However, means must be found to reduce the size and number of capsules taken, so that larger studies of longer duration in RA patients can be done

The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection.

Licinio J, Wong ML.

Mol Psychiatry. 1999 Jul; 4(4):317-27.

Depression represents a major public health problem. It is estimated that 13-20% of the population has some depressive symptoms at any given time and about 5% of the population is assumed to suffer from major depression. Known pathological processes include ischemia, neoplasia, necrosis, apoptosis, infection, and inflammation. Of those, inflammation is the most compatible with the waxing and waning course of depression, and could explain the biology of this disorder that has a fluctuating course with severe episodes that can be followed by partial or complete remission. Over the years a body of evidence has been accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Major depression commonly co-occurs with ischemic heart disease and decreased bone mineral density. Depressive symptoms are known to have a negative impact on cardiovascular prognosis, increasing the mortality rate of coronary artery disease. Several lines of evidence indicate that brain cytokines, principally interleukin-1beta (IL-1beta) and IL-1 receptor antagonist may have a role in the biology of major depression, and that they might additionally be involved in the pathophysiology and somatic consequences of depression as well as in the effects of antidepressant treatment. A particularly unique and novel aspect of the studies and views discussed here is their potential to lead to interventions which may reduce the morbidity and mortality risks for osteoporosis, cardiovascular disease, and behavioral symptoms in patients with major depression. We also discuss the emerging concept of peripheral and central cytokine compartments: their integration and differential regulation is a key element for the optimal functioning of the immune and nervous systems

S-Adenosylmethionine: molecular, biological, and clinical aspects--an introduction.

Lieber CS, Packer L.

Am J Clin Nutr. 2002 Nov; 76(5):1148S-50S.

In clinical research, a novel approach has emerged: some of the essential nutrients are being used to treat pathologic conditions. Many of these nutrients, including methionine, must first be activated in the liver or in other tissues before they can exert their key functions. However, this activating process is impaired in disease states and, as a consequence, nutritional requirements change. For instance, for methionine to act as the main cellular methyl donor, it must first be activated to S-adenosylmethionine (SAMe; also known as ademethionine). SAMe is required and is of fundamental importance for the metabolism of nucleic acids and polyamines, the structure and function of membranes, and as a precursor of glutathione. These processes are often seriously altered in various pathologic states addressed in this symposium, but they cannot be restored by simply administering methionine. For instance, in liver disease associated with impairment of the enzyme that activates methionine to SAMe, supplementation with methionine is useless and may even become toxic as it accumulates because it is not used. Accordingly, one must correct the lack of SAMe by bypassing the deficiency in enzyme activation; this is done by providing the product of the defective reaction, namely SAMe. Under these pathologic conditions, SAMe becomes crucial for the functioning of the cell. Thus SAMe, which is found in all living organisms, becomes the essential nutrient instead of methionine. This symposium reviewed the biological and corresponding molecular aspects of SAMe metabolism and the clinical consequences of its deficiency or supplementation in various tissues

Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis.

Maccagno A, Di Giorgio EE, Caston OL, et al.

Am J Med. 1987 Nov 20; 83(5A):72-7.

A double-blind, randomized, 84-day controlled clinical trial was carried out to compare orally administered S-adenosylmethionine (SAMe) (1,200 mg per day) with oral piroxicam therapy (20 mg per day) in the management of unilateral knee osteoarthritis. The ability of each drug to maintain the results achieved at the end of the treatment period was also evaluated during a 56-day follow-up period. Forty-five patients completed the study, 22 in the SAMe group and 23 in the piroxicam group. Both SAMe and piroxicam proved effective in inducing a significant improvement in the total pain score after 28 days of treatment. With regard to the other clinical parameters (i.e., morning stiffness, the distance walked before the onset of pain, active and passive motility), improvement started from about Day 56 in both groups. No significant difference was found between the two treatments in terms of efficacy and tolerability. Patients treated with SAMe maintained clinical improvement achieved at the end of treatment longer than did patients receiving piroxicam

Dietary fish oil and fish and borage oil suppress intrapulmonary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neutrophil accumulation in endotoxic rats.

Mancuso P, Whelan J, DeMichele SJ, et al.

Crit Care Med. 1997 Jul; 25(7):1198-206.

OBJECTIVE: Proinflammatory eicosanoids and cytokines are important mediators of local inflammation in acute lung injury. We determined if enteral nutrition with anti-inflammatory fatty acids, eicosapentaenoic acid, and gamma-linolenic acid would reduce the intrapulmonary synthesis of proinflammatory eicosanoids and cytokines and pulmonary neutrophil accumulation in a rat model of acute lung injury. DESIGN: Prospective, randomized, controlled, double-blind study. SETTING: Research laboratory at a university medical center. SUBJECTS: Male Long-Evans rats (250 g). INTERVENTIONS: Rats were randomly assigned to three dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day) containing 55.2% of the total calories from fat with either 97% corn oil, 20% fish oil, or 20% fish and 20% borage oil for 21 days. On day 22, bronchoalveolar lavage was performed 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg) or saline. Bronchoalveolar lavage fluid was analyzed for leukotriene B4, leukotriene C4/D4, thromboxane B2, prostaglandin E2, 6 keto-prostaglandin F1alpha, tumor necrosis factor (TNF)-alpha, and macrophage inflammatory protein-2 (MIP-2). Lung myeloperoxidase activity (a marker for neutrophil accumulation) and phospholipid fatty acid composition were also determined. MEASUREMENTS AND MAIN RESULTS: Lung phospholipid concentrations of arachidonic acid were lower and the concentrations of eicosapentaenoic acid and docosahexaenoic acid were higher with fish oil and fish and borage oil as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, increased with fish and borage oil as compared with fish oil and corn oil. The levels of leukotriene B4, leukotriene C4/D4, 6-keto-prostaglandin F1alpha, and thromboxane B2 with corn oil were significantly increased with endotoxin as compared with saline. In contrast to the corn oil group, endotoxin did not significantly increase bronchoalveolar lavage levels of leukotriene B4, leukotriene C4/D4, and thromboxane B2 above those of saline-treated rats with fish oil and fish and borage oil. Lung myeloperoxidase activity was significantly increased in endotoxin-treated rats compared with those rats given saline in all dietary treatment groups. However, lung myeloperoxidase activity was significantly lower with either fish oil or fish and borage oil as compared with corn oil after endotoxin. Although endotoxin increased the levels of TNF-alpha and MIP-2 with all dietary treatment groups as compared with saline-treated rats, there were no significant differences in the levels of either cytokine between the dietary treatment groups. CONCLUSIONS: These results indicate that dietary fish oil and fish and borage oil as compared with corn oil may ameliorate endotoxin-induced acute lung injury by suppressing the levels of proinflammatory eicosanoids (but not TNF-alpha or MIP-2) in bronchoalveolar lavage fluid and reducing pulmonary neutrophil accumulation

Platelet resistance to prostacyclin. Enhancement of the antiaggregatory effect of prostacyclin by pentoxifylline.

Manrique RV, Manrique V.

Angiology. 1987 Feb; 38(2 Pt 1):101-8.

With regard to existence of high prostacyclin (PGI2) levels during atheromatosis and thrombus formation, resistance of platelets to prostacyclin and its analogues seems to play an important pathophysiologic key role for the clarifying of vasoocclusive phenomena. Platelet resistance to prostacyclin was studied in vitro and ex vivo in 160 atherosclerotic patients (assessed by objective diagnostic criteria) with and without thrombotic complications and in 50 controls. Prostacyclin resistance phenomena were more pronounced and frequent in patients with occlusive complications, the difference from controls being statistically significant. However, there was no significant difference between the controls and the nonthrombotic patient sample. The intraplatelet cAMP levels might be the metabolic basis of the PGI2 resistance phenomenon, because in the patient group, platelet cAMP levels were decreased by 50% after Ca2+ stimulation. Compared to controls beta-thromboglobulin and thromboxane B2 plasma levels were significantly increased (30 +/- 9 to 87 +/- 26 ng/ml and 9 +/- 5 to 54 +/- 21 pg/ml, respectively), confirming the hyperreactivity state of resistant platelets. From the therapeutic point of view, patients with resistant platelets require PGI2 doses that cause, however, increased side effects. We were able to demonstrate in vivo that IV pretreatment with pentoxifylline--a known stimulator of cAMP formation in platelets--followed by a simultaneous and continuous IV infusion of PGI2 + pentoxifylline, permitted us to reduce significantly the mean PGI2 doses needed for triggering an antiplatelet effect, without inducing side effects. In ex vivo studies, PGI2 resistant platelets of atherosclerotic patients pretreated with pentoxifylline showed normalized stimulation response, and platelet cAMP levels increased from 7.8 +/- 2.7 to 15.2 +/- 1.9 pmol/10(8) platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for the role of an altered redox state in hyporesponsiveness of synovial T cells in rheumatoid arthritis.

Maurice MM, Nakamura H, van der Voort EA, et al.

J Immunol. 1997 Feb 1; 158(3):1458-65.

In rheumatoid arthritis (RA), T cells isolated from the synovial fluid (SF) show impaired responses to mitogenic stimulation compared with T cells from the peripheral blood (PB). Here it is reported that hyporesponsiveness of SF T cells correlated with a significant decrease in the levels of the intracellular redox-regulating agent glutathione (GSH). GSH was decreased in both CD4+ (p = 0.0022) and CD8+ (p = 0.0010) SF T cell subsets compared with PB CD4+ and CD8+ T cells in RA patients. Levels of thioredoxin (TRX), another key redox mediator, previously found to be secreted under conditions of oxidative stress, were found to be significantly increased in SF compared with plasma samples of RA patients (p = 0.005). Increased levels of TRX in the SF of inflamed joints was found to be associated with RA when compared with other arthritides (p = 0.007). Restoration of GSH levels in SF T cells with N-acetyl-L-cysteine (NAC), enhanced mitogenic induced proliferative responses and IL-2 production. Collectively, these data impute an important role to an altered redox state in the hyporesponsiveness of joint T cells in patients with RA

The role of tumor necrosis factor alpha in the pathophysiology of congestive heart failure.

McTiernan CF, Feldman AM.

Curr Cardiol Rep. 2000 May; 2(3):189-97.

A variety of clinical and experimental investigations have suggested that tumor necrosis factor alpha (TNF-alpha) may play a role in the pathophysiology of heart failure. Serum levels of TNF-alpha are elevated in patients with heart failure, and both cardiac and infiltrating cells of the myocardium can produce this proinflammatory cytokine. Both cardiac myocytes and nonmyocytes also express receptors for TNF-alpha, and experimental studies on isolated cells, muscles, and transgenic models demonstrate the ability of TNF-alpha to recapitulate functional and biochemical alterations resembling that observed in human congestive heart failure. The intracellular pathways affected by TNF-alpha include production of ceramide and an alteration in calcium metabolism. Recent studies in both animal models and clinical investigations suggest that anti-TNF-alpha therapies may limit the pathophysiologic consequences of congestive heart failure

Triene prostaglandins: prostacyclin and thromboxane biosynthesis and unique biological properties.

Needleman P, Raz A, Minkes MS, et al.

Proc Natl Acad Sci U S A. 1979 Feb; 76(2):944-8.

Uncooked, lactobacilli-rich, vegan food and rheumatoid arthritis.

Nenonen MT, Helve TA, Rauma AL, et al.

Br J Rheumatol. 1998 Mar; 37(3):274-81.

We tested the effects of an uncooked vegan diet, rich in lactobacilli, in rheumatoid patients randomized into diet and control groups. The intervention group experienced subjective relief of rheumatic symptoms during intervention. A return to an omnivorous diet aggravated symptoms. Half of the patients experienced adverse effects (nausea, diarrhoea) during the diet and stopped the experiment prematurely. Indicators of rheumatic disease activity did not differ statistically between groups. The positive subjective effect experienced by the patients was not discernible in the more objective measures of disease activity (Health Assessment Questionnaire, duration of morning stiffness, pain at rest and pain on movement). However, a composite index showed a higher number of patients with 3-5 improved disease activity measures in the intervention group. Stepwise regression analysis associated a decrease in the disease activity (measured as change in the Disease Activity Score, DAS) with lactobacilli-rich and chlorophyll-rich drinks, increase in fibre intake, and no need for gold, methotrexate or steroid medication (R2=0.48, P=0.02). The results showed that an uncooked vegan diet, rich in lactobacilli, decreased subjective symptoms of rheumatoid arthritis. Large amounts of living lactobacilli consumed daily may also have positive effects on objective measures of rheumatoid arthritis

Pentoxifylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha by human peripheral blood mononuclear cells.

Neuner P, Klosner G, Schauer E, et al.

Immunology. 1994 Oct; 83(2):262-7.

Pentoxifylline (PTX) is a methylxanthine compound known to inhibit the production of tumour necrosis factor-alpha (TNF-alpha), which is an important inflammatory mediator. There is also recent evidence that PTX may influence other inflammatory cytokines, such as interleukin-1 (IL-1) and IL-6. Due to the therapeutic implications, the present study addressed the in vivo effects of PTX on the release of TNF-alpha, IL-1 beta, IL-6 and IL-8 by human peripheral blood mononuclear cells (PBMC). When PBMC were obtained from healthy volunteers ingesting 5 x 400 mg PTX orally for 2 days, the ability of PBMC cultured for 24 hr to release TNF-alpha was significantly reduced, while secretion of IL-1 beta, IL-6 and IL-8 was not affected. However, when PBMC were obtained from the same individuals 5 days after PTX had been stopped, the release of all four cytokines was significantly suppressed. This effect appeared to be exerted at the transcriptional level, since Northern blot analysis revealed reduced cytokine transcripts. In order to gain more insight into the effect of PTX on cytokine release, PBMC were obtained from normal volunteers, either stimulated with lipopolysaccharide (LPS) or left unstimulated, and subsequently incubated in vitro with PTX for 48 hr. Under these conditions, only TNF-alpha was found to be reduced by PTX, while IL-1 beta and IL-8 were not affected, IL-6 was even enhanced. However, when PBMC were incubated with PTX for 24 hr, PTX removed thereafter by medium change and cells further cultured, the production not only of TNF-alpha but also of IL-1 beta, IL-6 and IL-8 was reduced, demonstrating that PTX exerts diverse (inhibitory) effects on cytokine release by PBMC

Acetabular bone destruction related to non-steroidal anti-inflammatory drugs.

Newman NM, Ling RS.

Lancet. 1985 Jul 6; 2(8445):11-4.

In a retrospective investigation of the relation between use of non-steroidal anti-inflammatory drugs (NSAIDs) and acetabular destruction in primary osteoarthritis of the hip, 70 hips were studied in 64 patients. Cranial acetabular migration, a measure of acetabular destruction, was present in 37 hips and absent in 33. Migrators and non-migrators did not differ in age, sex, hip pain score, walking ability score, femoral neck-shaft angle, or distribution of atrophic and hypertrophic types of osteoarthritis. Regular intake of NSAIDs was noted for 31 of the 37 migrating hips and irregular intake for a further 3. Among the 33 non-migrating hips, the corresponding numbers were 7 and 5, respectively. This highly significant association between NSAID use and acetabular destruction gives cause for concern, not least because of the difficulty in achieving satisfactory hip replacements in patients with severely damaged acetabula

Proinflammatory cytokines and arthroscopic findings of patients with internal derangement and osteoarthritis of the temporomandibular joint.

Nishimura M, Segami N, Kaneyama K, et al.

Br J Oral Maxillofac Surg. 2002 Feb; 40(1):68-71.

This study investigated the correlations between the concentrations of proinflammatory cytokines in synovial fluid and the degree of synovitis on the one hand, and the degree of degeneration of articular cartilage on the other hand, in patients with internal derangement and osteoarthritis of the temporomandibular joint. We measured the concentrations of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 in synovial fluid and the degree of arthroscopic synovitis and degeneration of articular cartilage in 37 joints with internal derangement and osteoarthritis. The correlations between the concentration of each cytokine and the score of each arthroscopic feature were analysed statistically. The detection rates of IL-1beta,TNF-alpha, IL-6 and IL-8 were 57%, 78%, 89% and 70%, respectively. There was a positive correlation between the IL-6 concentration and the synovitis score (P = 0.02). Measurement of IL-6 in synovial fluid might be useful as an indicator of the extent of synovitis

Ex-vivo in-vitro inhibition of lipopolysaccharide stimulated tumor necrosis factor-alpha and interleukin-1 beta secretion in human whole blood by extractum urticae dioicae foliorum.

Obertreis B, Ruttkowski T, Teucher T, et al.

Arzneimittelforschung. 1996 Apr; 46(4):389-94.

An extract of Urtica dioica folium (IDS 23, Rheuma-Hek), monographed positively for adjuvant therapy of rheumatic diseases and with known effects in partial inhibition of prostaglandin and leukotriene synthesis in vitro, was investigated with respect to effects of the extract on the lipopolysaccharide (LPS) stimulated secretion of proinflammatory cytokines in human whole blood of healthy volunteers. In the assay system used, LPS stimulated human whole blood showed a straight increase of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion reaching maximum concentrations within 24 h following a plateau and slight decrease up to 65 h, respectively. The concentrations of these cytokines was strongly positively correlated with the number of monocytes/macrophages of each volunteer. TNF-alpha and IL-1 beta concentration after LPS stimulation was significantly reduced by simultaneously given IDS 23 in a strictly dose dependent manner. At time 24 h these cytokine concentrations were reduced by 50.8% and 99.7%, respectively, using the highest test IDS 23 assay concentration of 5 mg/ml (p < 0.001). After 65 h the corresponding inhibition was 38.9% and 99.9%, respectively (p < 0.001). On the other hand IDS 23 showed no inhibition but stimulated IL-6 secretion in absence of LPS alone. Simultaneously given LPS and IDS 23 resulted in no further increase. In contrast to described effects on arachidonic acid cascade in vitro, tested Urtica dioica phenol carbon acid derivates and flavonoides such as caffeic malic acid, caffeic acid, chlorogenic acid, quercetin and rutin did not influence LPS stimulated TNF-alpha, IL-1 beta and IL-6 secretion in tested concentrations up to 5 x 10(-5) mol/l. These further findings on the pharmacological mechanism of action of Urticae dioica folia may explain the positive effects of this extract in the treatment of rheumatic diseases

Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. The Cooperative Systematic Studies of Rheumatic Diseases Group.

Paulus HE, Egger MJ, Ward JR, et al.

Arthritis Rheum. 1990 Apr; 33(4):477-84.

A composite index for estimating improvement in individual rheumatoid arthritis (RA) patients during trials of slow-acting, disease-modifying antirheumatic drugs (DMARDs) was developed by analyzing the responses of 130 placebo-treated participants in Cooperative Systematic Studies of Rheumatic Diseases studies. If responses in 4 of 6 selected measures were required for improvement (by greater than or equal to 20% for morning stiffness, Westergren erythrocyte sedimentation rate, joint pain/tenderness score, and joint swelling score, and by greater than or equal to 2 grades on a 5-grade scale, or from grade 2 to grade 1 for patient's and physician's overall assessments of current disease severity), few placebo-treated patients qualified as improved, whereas significantly more DMARD-treated patients demonstrated improvement. The proposed index appears to be useful in estimating the probability that an RA patient will improve if taking a placebo during a DMARD trial, and may be a useful tool for analysis of DMARD studies

Trental (Generic Name Pentoxifylline).

PDR.

2001;Physicians Desk Reference 2001; Physicians Desk Reference 2001

Changes of faecal flora in rheumatoid arthritis during fasting and one-year vegetarian diet.

Peltonen R, Kjeldsen-Kragh J, Haugen M, et al.

Br J Rheumatol. 1994 Jul; 33(7):638-43.

The beneficial effect of a 1-yr vegetarian diet in RA has recently been demonstrated in a clinical trial. We have analysed stool samples of the 53 RA patients by using direct stool sample gas-liquid chromatography of bacterial cellular fatty acids. Based on repeated clinical assessments disease improvement indices were constructed for the patients. At each time point during the intervention period the patients in the diet group were then assigned either to a group with a high improvement index (HI) or a group with a low improvement index (LI). Significant alteration in the intestinal flora was observed when the patients changed from omnivorous to vegan diet. There was also a significant difference between the periods with vegan and lactovegetarian diets. The faecal flora from patients with HI and LI differed significantly from each other at 1 and 13 months during the diet. This finding of an association between intestinal flora and disease activity may have implications for our understanding of how diet can affect RA

The role of tumor necrosis factor (TNF) in arthritis: studies in transgenic mice.

Plows D.

Rheumatol Eur. 1995; Suppl.(2):51-4.

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.

Plummer SM, Holloway KA, Manson MM, et al.

Oncogene. 1999 Oct 28; 18(44):6013-20.

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention

Oral pentoxifylline inhibits release of tumor necrosis factor-alpha from human peripheral blood monocytes : a potential treatment for aseptic loosening of total joint components.

Pollice PF, Rosier RN, Looney RJ, et al.

J Bone Joint Surg Am. 2001 Jul; 83-A(7):1057-61.

BACKGROUND: Pentoxifylline (Trental) is a methylxanthine-derivative drug that has been used for more than twenty years in the treatment of peripheral vascular disease. Pentoxifylline is also a potent inhibitor of tumor necrosis factor-alpha (TNF-alpha) secretion, both in vitro and in vivo, and has demonstrated efficacy in the treatment of certain animal and human inflammatory diseases. Pentoxifylline has a potential therapeutic role in the treatment of aseptic loosening of total joint replacement components because it inhibits TNF-alpha secretion by particle-stimulated human peripheral blood monocytes. The purpose of our study was to determine whether the particle-stimulated secretion of TNF-alpha by peripheral blood monocytes was inhibited in volunteers who had received pentoxifylline orally. METHODS: Human peripheral blood monocytes were harvested from eight healthy volunteers and were exposed to three different concentrations of titanium particles or to 500 ng/mL of lipopolysaccharide as a positive control. The same volunteers were then given pentoxifylline (400 mg, five times per day) for seven days. Their peripheral blood monocytes were again isolated and exposed to experimental conditions, and the TNF-alpha levels were measured. RESULTS: The peripheral blood monocytes from all eight volunteers showed a significant reduction in TNF-alpha release following oral treatment with pentoxifylline. This reduction was observed at exposures of 10(7) and 10(6) titanium particles/mL and in the lipopolysaccharide-treated group, but not at 10(5) particles/mL. CONCLUSIONS: To our knowledge, this is the first study to demonstrate the ability of an oral drug to decrease the release of TNF-alpha from human peripheral blood monocytes exposed ex vivo to particle debris. TNF-alpha is involved in the pathogenesis of osteolysis and subsequent loosening of total joint arthroplasty components. The ability to suppress the release of TNF-alpha in patients with a total joint replacement may help to control osteolysis and to reduce the development of aseptic loosening. This effect could increase implant longevity and decrease the need for revision arthroplasty

The total costs of drug therapy for rheumatoid arthritis. A model based on costs of drug, monitoring, and toxicity.

Prashker MJ, Meenan RF.

Arthritis Rheum. 1995 Mar; 38(3):318-25.

OBJECTIVE. We created a model to estimate the total medication costs of treating patients with rheumatoid arthritis with 6 second-line agents for the first 6 months of treatment. METHODS. Drug costs were obtained from a survey of pharmacies; monitoring costs were calculated from utilization information obtained in a survey of rheumatologists; toxicity costs were obtained using decision trees to represent the evaluation and treatment of potential toxicities. Monitoring and toxicity costs were estimated using costs from the Boston University Medical Center or, for hospitalizations, using appropriate diagnosis-related group categories. The sum of the 3 components determined the total medication costs. RESULTS. The least expensive medication was penicillamine, at $10.62/week, and the most expensive was injectable gold, at $30.89/week. In terms of monitoring costs, methotrexate had the highest costs associated with necessary laboratory tests and office visits. Hydroxychloroquine had the lowest monitoring costs for office visits, and oral gold had the lowest for laboratory costs. Hematologic toxicities were the largest component of toxicity costs for all 6 medications, and renal toxicities were costly for patients taking oral gold, penicillamine, and injectable gold. Total medication costs revealed oral gold as the least expensive medication and injectable gold as the most expensive. The combination of monitoring and toxicity costs accounted for more than 60% of the total costs for all medications except injectable gold. In all cases, the cost of treating toxicities was the smallest of the 3 components. CONCLUSION. When calculating the costs of drug therapy, it is important to consider not only the price of the drug, but also the costs of monitoring and treating the toxicities that might occur. Failure to do so will result in underestimating the true costs of treatment with these medications

Modulation of cytokine production in vivo by dietary essential fatty acids in patients with colorectal cancer.

Purasiri P, Murray A, Richardson S, et al.

Clin Sci (Lond). 1994 Dec; 87(6):711-7.

1. The effects of essential fatty acids (gamma-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid), at a dose of 4.8 g/day, given in combination as dietary supplements, on cytokine production were investigated in patients with colorectal cancer. 2. Total serum cytokines--interleukin (interleukin-1 beta, 2, 4 and 6), tumour necrosis factor-alpha and interferon-gamma--were analysed using the enzyme-linked immunosorbent assay technique at different time intervals during the course of essential fatty acid supplementation. 3. Fatty acid uptake and patient compliance were confirmed by a significant increase in serum levels of gamma-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid in all three fractions: tricylglycerol, cholesterol and phospholipid. 4. There was no significant alteration in total serum cytokine concentration/levels in the first 2 months of essential fatty acid ingestion, but the levels of serum cytokines steadily declined thereafter, reaching minimum levels after 6 months of essential fatty acid supplementation. 5. Essential fatty acids, at the dose and duration (6 months) used in this study, reduced total serum interleukin-1 beta levels by 61% (P = 0.044), interleukin-2 by 63% (P = 0.05), interleukin-4 by 69% (P = 0.025), interleukin-6 by 83% (P = 0.030), tumour necrosis factor-alpha by 73% (P = 0.040) and interferon-gamma by 67% (P = 0.050). 6. Three months after cessation of essential fatty acid intake, however, these cytokine levels returned to presupplementation values. 7. This present study has shown that long-term n-3 and n-6 EFA ingestion results in a significant reduction in circulating key cytokines. The precise mechanism of this reduction is unclear

Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis.

Qiu GX, Gao SN, Giacovelli G, et al.

Arzneimittelforschung. 1998 May; 48(5):469-74.

A double-blind therapeutic investigation was performed on 178 Chinese patients suffering from osteoarthritis of the knee randomized into two groups, one treated for 4 weeks with glucosamine sulfate (GS, CAS 29031-19-4, Viartril-S) at the daily dose of 1,500 mg and the other with ibuprofen (IBU, CAS 15687-27-1) at the daily dose of 1,200 mg. Knee pain at rest, at movement and at pressure, knee swelling, improvement and therapeutic utility as well as adverse events and drop-outs were recorded after 2 and 4 weeks of treatment. The variables were recorded also after 2 weeks of treatment discontinuation in order to appreciate the remnant therapeutic effect. Both GS and IBU significantly reduced the symptoms of osteoarthritis with the trend of GS to be more effective. After 2 weeks of drug discontinuation there was a remnant therapeutic effect in both groups, with the trend to be more pronounced in the GS group. GS was significantly better tolerated than IBU, as shown by the adverse drug reactions (6% in the patients of the GS group and 16% in the IBU group--p = 0.02) and by the drug-related drop-outs (0% of the patients in the GS group and 10% in the IBU group--p = 0.0017). The better tolerability of GS is explained by its mode of action, because GS specifically curbs the pathogenic mechanisms of osteoarthritis and does not inhibit the cyclo-oxygenases as the non-steroidal anti-inflammatory drugs (NSAIDs) do, with the consequent anti-inflammatory analgesic activities but also with the several adverse reactions due to this not targeted effect. The present study confirms that GS is a selective drug for osteoarthritis, as effective on the symptoms of the disease as NSAIDs but significantly better tolerated. For these properties GS seems particularly indicated in the long-term treatments needed in osteoarthritis

Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.

Reddi K, Henderson B, Meghji S, et al.

Cytokine. 1995 Apr; 7(3):287-90.

Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones

Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB.

Riehemann K, Behnke B, Schulze-Osthoff K.

FEBS Lett. 1999 Jan 8; 442(1):89-94.

Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases and is responsible for the enhanced expression of many proinflammatory gene products. Extracts from leaves of stinging nettle (Urtica dioica) are used as antiinflammatory remedies in rheumatoid arthritis. Standardized preparations of these extracts (IDS23) suppress cytokine production, but their mode of action remains unclear. Here we demonstrate that treatment of different cells with IDS23 potently inhibits NF-kappaB activation. An inhibitory effect was observed in response to several stimuli, suggesting that IDS23 suppressed a common NF-kappaB pathway. Inhibition of NF-kappaB activation by IDS23 was not mediated by a direct modification of DNA binding, but rather by preventing degradation of its inhibitory subunit IkappaB-alpha. Our results suggests that part of the antiinflammatory effect of Urtica extract may be ascribed to its inhibitory effect on NF-kappaB activation

Psychiatric Disorders in America: The Epidemiologic Catchment Area Study.

Robins LN.

1991;

Dietary marine lipids suppress murine autoimmune disease.

Robinson DR, Tateno S, Knoell C, et al.

J Intern Med Suppl. 1989; 225(731):211-6.

Dietary marine lipids reduce both mortality and the severity of glomerulonephritis in inbred murine strains which develop spontaneous autoimmune disease. The protective effects of marine lipids appear to be accounted for by the major n-3 fatty acids in these preparations, 20:5 and 22:6. The n-3 fatty acids in dietary fish oil are extensively incorporated into several lipid classes in the spleen of autoimmune mice, including phosphatidylinositol, phosphatidylethanolamine, plasmalogens and saturated ether-linked phospholipids as well as diacylphosphoglycerides. The effects of dietary marine lipids on autoimmune disease in experimental models are highly specific. Careful controlled trials will be required to establish the role of dietary marine lipids in the therapy of human autoimmune disease

Indomethacin treatment in osteoarthritis of the hip joint. Does the treatment interfere with the natural course of the disease?

Ronningen H, Langeland N.

Acta Orthop Scand. 1979 Apr; 50(2):169-74.

The course of osteoarthritis in 294 hips of 186 patients was evaluated by examining their radiographs. The development of the disease in patients treated with indomethacin was compared with that in a control material. In the indomethacin group the disease progressed more frequently and in one parameter the progress was more severe. The results support previous reports indicating that indomethacin might have a deleterious effect on osteoarthritic hip joints. Some possible explanations for this adverse effect of indomethacin treatment are discussed

Botanical lipids: effects on inflammation, immune responses, and rheumatoid arthritis.

Rothman D, DeLuca P, Zurier RB.

Semin Arthritis Rheum. 1995 Oct; 25(2):87-96.

OBJECTIVE: This review discusses the rationale and experimental data that led to clinical trials of certain botanical lipids, mainly gammalinolenic acid (GLA), for the treatment of rheumatoid arthritis (RA). DATA SOURCES: Pertinent articles and reviews, and a bibliographic database in English using the following indexing terms: rheumatoid arthritis, fatty acids, gammalinolenic acid, lymphocytes, and monocytes, were used. STUDY SELECTION: All clinical trials in which GLA was used to treat arthritis are included in this review. Data from appropriately peer reviewed in vitro and animal experiments evaluating the effects of botanical lipids as regulators of cell activation and immune responses are also reviewed. DATA SYNTHESIS: GLA treatment is associated with clinical improvement in patients with RA, as evaluated by duration of morning stiffness, joint pain and swelling, and ability to reduce other medications. However, studies vary in terms of duration, GLA dose, whether or not they were placebo controlled, and, if so, what placebo was used, criteria for evaluation, and use of concomitant medication. Studies done in vitro generally indicated that GLA reduces lymphocyte activation and production of mediators of inflammation. CONCLUSIONS: A small number of studies suggest that GLA is effective treatment for RA patients. Further controlled studies of its use in RA seem warranted

A large, randomized, placebo-controlled, double-blind study of glucosamine sulfate vs. piroxicam and vs. their association, on the kinetics of the symptomatic effect in knee osteoarthritis.

Rovati LC.

Osteoarthritis Cartilage. 1994;(2(Suppl. 1)):56.

Large-dose ascorbic acid administration suppresses the development of arthritis in adjuvant-infected rats.

Sakai A, Hirano T, Okazaki R, et al.

Arch Orthop Trauma Surg. 1999; 119(3-4):121-6.

We performed animal experiments to test the hypothesis that active oxygen species (AOS) play a major role in adjuvant-induced arthritis in rats and to determine whether large-dose ascorbic acid administration would suppress the development of arthritis, reducing the level of damaging AOS in the same animal model. Arthritis was induced in male Lewis rats by adjuvant injection into the base of the tail. Ascorbic acid at doses of 0.5, 1.0, and 2.0 g/kg body weight (BW) was injected intraperitoneally twice each week for 3 weeks (9 rats per group). The BW, hind paw edema, and arthritis score of the extremities were monitored during the period. On day 21, synovial tissues obtained from the ankle joints were examined histologically and for the activity of superoxide dismutase (SOD). The SOD activity in the red blood cells (RBC) was also measured. The arthritic control rats showed significant increases in paw volume and arthritis score from day 11. These changes were dose-dependently reduced by ascorbic acid administration. The infiltration of inflammatory cells into the synovial tissues was markedly decreased by ascorbic acid. The increases in SOD activities produced by the adjuvant injection were significantly reduced in both the synovium and the RBC at ascorbic acid doses of 1.0 and 2.0 g/kg BW. In conclusion, large-dose ascorbic acid administration reduced the increases in hind paw inflammatory edema, arthritis in the extremities, and infiltration of the inflammatory cells into the synovial tissue in the adjuvant-induced arthritis rats. Since these anti-arthritic effects were associated with a decrease in SOD activities in both the synovium and RBC, the decrease in SOD activity could be one of the mechanisms underlying the suppressive effects of large-dose ascorbic acid on the development of arthritis in this animal model, inhibiting the damaging AOS

Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage.

Saklatvala J.

Nature. 1986 Aug 7; 322(6079):547-9.

During inflammatory reactions, activated leukocytes are thought to produce a variety of small proteins (cytokines) that influence the behaviour of other cells (including other leukocytes). Of these substances, which include the interleukins, interferons and tumour necrosis factors (TNFs), interleukin-1 (IL-1) has been considered potentially a most important inflammatory mediator because of its wide range of effects. In vivo it is pyrogenic and promotes the acute phase response; in vitro it activates lymphocytes and stimulates resorption of cartilage and bone. Cartilage resorption is a major feature of inflammatory diseases such as rheumatoid arthritis, and IL-1 is the only cytokine hitherto known to promote it. TNFs are characterized by their effects on tumours and cytotoxicity to transformed cells, but share some actions with IL-1. I report here that recombinant human TNF alpha stimulates resorption and inhibits synthesis of proteoglycan in explants of cartilage. Its action is similar to and additive with IL-1, and it is a second macrophage-derived cytokine whose production in rheumatoid arthritis, or inflammation generally, could contribute to tissue destruction

[Parkinsonism or Parkinson's disease unmasked by pentoxifylline?].

Serrano-Duenas M.

Neurologia. 2001 Jan; 16(1):39-42.

Pentoxifylline is a synthetic derivative of xantine which stimulates adenosine receptors, inhibit phosphodiesterase and increases cyclic monophosphate adenosine. It is also considered a dopaminergic D1 receptor agonist. Worsening of patients with Parkinson's disease when taking this product has been reported. On the other hand, it is considered that adenosine A2A receptors antagonists have antiparkinsonian properties. Four cases of patients with a mean age of 77 years who developed a rigid akinetic syndrome following therapy with a mean dose of 1100 mg/day of pentoxifylline over a mean period of 32 days are presented. Two of these patients presented clinical characteristics of drug-induced parkinsonism and the other two showed Parkinson's disease. The possibility of pentoxifylline causing an imbalance between D1 and D2 receptor stimulation and producing pharmacologic parkinsonism, or rather, the possibility of pentoxifylline unmasking subclinical Parkinson's disease are discussed

Anti-inflammatory drugs and their effects on cartilage synthesis and renal function.

Shield MJ.

Eur J Rheumatol Inflamm. 1993; 13(1):7-16.

Growing evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs), while able to alleviate inflammation, may damage articular cartilage, though both chondrodestructive and chondroprotective activities have been observed with different NSAIDs. Experiments conducted on explants of normal and osteoarthritic human cartilage have shown that certain NSAIDs at pharmacologic concentrations achievable in man consistently inhibit glycosaminoglycan (GAG) synthesis. The addition of the prostaglandin E1 analogue misoprostol consistently reversed these inhibitory effects in a dose-related manner. Paradoxically, with some NSAIDs, such as diclofenac and aspirin, misoprostol was also able to enhance GAG synthesis above control levels, especially in osteoarthritic cartilage. This supports findings from other work that NSAIDs exert effects other than through inhibition of cyclooxygenase, direct action on cell membranes being one of these alternative mechanisms of action. Additionally it is interesting to note and may be of clinical relevance that misoprostol on its own also stimulates GAG synthesis in explants of human osteoarthritic cartilage whilst exerting no apparent effect on healthy cartilage with a normal GAG turnover. With regard to renal aspects, the effects of NSAIDs are readily explicable in terms of interference with prostanoid synthesis. The consequent inhibition exerted on vasodilatory prostaglandins (PGs), which oppose vasoconstrictor action induced by substances such as thromboxane or leukotrienes, upsets the balance that maintains renal function. In situations in which there is reduced renal reserve, reduction of renal PG synthesis by NSAIDs will adversely affect maintenance of renal blood flow and glomerular filtration rate and excretion of sodium, potassium, and water. Patients with alcoholic cirrhosis manifest this type of compromised renal function and in them misoprostol reverses the adverse effects of indomethacin on renal hemodynamics and partially reverses indomethacin-induced renal sodium retention. Although the clinical significance of these data is not yet established, exogenous administration of specific PGs may be able to minimize the deleterious actions of NSAIDs

Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.

Shoba G, Joy D, Joseph T, et al.

Planta Med. 1998 May; 64(4):353-6.

The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects

Effect of six months of fish oil supplementation in stable rheumatoid arthritis. A double-blind, controlled study.

Skoldstam L, Borjesson O, Kjallman A, et al.

Scand J Rheumatol. 1992; 21(4):178-85.

Therapeutic effects of fish oil (10 g/day) in rheumatoid arthritis were investigated in a randomized, controlled, double-blind study. Forty-three patients completing the study were evaluated at 0, 3 and 6 months. The nutrient intake in the fish oil group and in the control group was essentially similar. In the fish oil group, the percentage of n-3 fatty acids in serum phosphatidylcholine increased by 9.6 (range 2.6-16.1). Patients in the fish oil group reported a significantly decreased consumption of NSAID at 3 and 6 months, and the status of global arthritic activity improved at 3 months in physician's assessment. Control patients reported an increased global arthritic activity at 6 months. No change was found in patient assessment of pain, duration of morning stiffness or functional capacity. Essentially no change occurred in biochemical markers of inflammation. We conclude that fish oil has small anti-inflammatory effects with at most a NSAID-saving potential. The value of prolonged supplementation remains to be evaluated

Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina.

Smith DA, Irving SD, Sheldon J, et al.

Circulation. 2001 Aug 14; 104(7):746-9.

BACKGROUND: Proinflammatory cytokines play a role in acute coronary events. However, the potential role of antiinflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10, which is expressed in human atherosclerotic plaques, has potent deactivating properties in macrophages and T cells. The aim of this study was to assess whether serum concentrations of IL-10 differed between patients with unstable and stable angina pectoris. METHODS AND RESULTS: A total of 95 patients with angina pectoris and angiographically documented coronary artery disease were studied. Of these, 50 patients had chronic stable angina (with stable symptoms over 3 months), and 45 patients had Braunwald class IIIB unstable angina with ST-segment changes. Serum IL-10 and IL-6 concentrations were measured on admission using commercially available immunoassays. Serum IL-10 concentrations were lower in unstable angina patients compared with those who had chronic stable angina (28.4 versus 14.0 pg/mL; 95% CI, 9.8 to 19.0; P

Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis.

Soeken KL, Lee WL, Bausell RB, et al.

J Fam Pract. 2002 May; 51(5):425-30.

OBJECTIVE: We assessed the efficacy of S-adenosylmethionine (SAMe), a dietary supplement now available in the Unites States, compared with that of placebo or nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis (OA). STUDY DESIGN: This was a meta-analysis of randomized controlled trials. DATA SOURCES: We identified randomized controlled trials of SAMe versus placebo or NSAIDS for the treatment of OA through computerized database searches and reference lists. OUTCOMES MEASURED: The outcomes considered were pain, functional limitation, and adverse effects. RESULTS: Eleven studies that met the inclusion criteria were weighted on the basis of precision and were combined for each outcome variable. When compared with placebo, SAMe is more effective in reducing functional limitation in patients with OA (effect size [ES] =.31; 95% confidence interval [CI],.099-.520), but not in reducing pain (ES =.22; 95% CI, -.247 to.693). This result, however, is based on only 2 studies. SAMe seems to be comparable with NSAIDs (pain: ES =.12; 95% CI, -.029 to.273; functional limitation: ES =.025; 95% CI, -.127 to.176). However, those treated with SAMe were less likely to report adverse effects than those receiving NSAIDs. CONCLUSIONS: SAMe appears to be as effective as NSAIDs in reducing pain and improving functional limitation in patients with OA without the adverse effects often associated with NSAID therapies

Drug-induced arthropathy and necrosis of the femoral head.

Solomon L.

J Bone Joint Surg Br. 1973 May; 55(2):246-61.

Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in rheumatoid arthritis.

Sperling RI, Weinblatt M, Robin JL, et al.

Arthritis Rheum. 1987 Sep; 30(9):988-97.

Twelve patients with active rheumatoid arthritis supplemented their usual diet with 20 gm of Max-EPA fish oil, daily, for 6 weeks. Following this supplementation, the ratio of arachidonic acid to eicosapentaenoic acid in the patients' neutrophil cellular lipids decreased from 81:1 to 2.7:1, and the mean generation of leukotriene B4 (with calcium ionophore stimulation) significantly declined by 33%. The mean neutrophil chemotaxis to both leukotriene B4 and FMLP significantly increased toward the normal range at week 6. The generation of 5-lipoxygenase products by calcium ionophore-stimulated monocytes was not significantly suppressed, but a significant decline (37%) in platelet-activating factor generation was noted at week 6. The modulation of these measures of leukocyte inflammatory potential suggests that fish oil supplementation may have an antiinflammatory effect

Ginger (Zingiber officinale) and rheumatic disorders.

Srivastava KC, Mustafa T.

Med Hypotheses. 1989 May; 29(1):25-8.

Oxygenation of arachidonic acid is increased in inflamed tissues. In this condition products of two enzymic pathways--the cyclooxygenase and the 5-lipoxygenase producing respectively prostaglandins and leukotrienes--are elevated. Of the cyclooxygenase products, PGE2 and of the lipoxygenase products, LTB4 are the strongest candidates for mediating inflammation. Non-steroidal anti-inflammatory drugs which inhibit the cyclooxygenase, and corticosteroids are used to treat such disorders. Both types of drugs produce adverse side-effects on prolonged use. Ginger is reported in Ayurvedic and Tibb systems of medicine to be useful in rheumatic disorders. Seven patients suffering from such disorders reported relief in pain and associated symptoms on ginger administration

[Better AVK treatment with self monitoring. Dosage can be regulated in time].

Stigendal L, Andre U, Christenson B.

Lakartidningen. 1999 May 19; 96(20):2482, 2485-2, 2487.

As long-term anticoagulant treatment, with warfarin for instance, is associated with a risk of both thrombotic and thrombolytic complications, blood testing for dose regulation is necessary at 3-8-week intervals, which is expensive and inconvenient for patients who must take time off work and travel to and fro. A new technique, using small portable monitors designed for home use by patients, makes self-management of anticoagulant treatment possible. In Germany, over 25,000 patients had their own monitor by the end of 1998. After appropriate instruction, the German patients are able to monitor their prothrombin time and adjust their anticoagulant treatment accordingly. In case of problems they contact their GP. In a two-year pilot study conducted at the Anticoagulation Clinic of Sahlgrenska University Hospital, Gothenburg, in 1996-98, where 51 patients on long-term anticoagulant treatment were trained in self-management, the results of over 1,000 patient-hours of treatment showed self-management to be at least as safe as management by the clinic. The level of patient satisfaction is high, in terms of safety and freedom from regular hospital attendance during working hours, and the convenience of self-monitoring on holiday or business trips. As the patients do their testing once a week, the risk of complications is also reduced

Evaluation of S-adenosylmethionine in primary fibromyalgia. A double-blind crossover study.

Tavoni A, Vitali C, Bombardieri S, et al.

Am J Med. 1987 Nov 20; 83(5A):107-10.

The effect of S-adenosylmethionine (SAMe) and placebo was evaluated in a short-term crossover study of 17 patients with primary fibromyalgia. Eleven of 17 patients had a significant depressive state as assessed by either the Hamilton Depression Rating Scale or the Scala di Autovalutazione per la Depressione (SAD) rating scale. The number of trigger points plus painful anatomic sites decreased after administration of SAMe (p less than 0.02) but not after placebo treatment. In addition, scores on both the Hamilton and SAD rating scales improved after SAMe administration (p less than 0.05 and p less than 0.005, respectively), whereas they did not significantly change after placebo treatment. In all the patients, there was a good correlation between scores on the Hamilton rating scale and the number of trigger points. Thus, this preliminary study confirms the close relationship between primary fibromyalgia and psychologic disturbances, particularly with regards to a depressive state. SAMe treatment, by improving the depressive state and reducing the number of trigger points, seems to be an effective and safe therapy in the management of primary fibromyalgia

[Cytokine secretion in whole blood of healthy subjects following oral administration of Urtica dioica L. plant extract].

Teucher T, Obertreis B, Ruttkowski T, et al.

Arzneimittelforschung. 1996 Sep; 46(9):906-10.

Twenty healthy volunteers ingested for 21 days 2 capsules b.i.d. of an IDS 23/1 containing nettle leaf extract (Rheuma-Hek). Before and after 7 and 21 days the basal and the lipopolysaccharide (LPS) stimulated tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) concentrations were measured ex vivo. In vitro the effects of IDS 23/1 on the release of these cytokines were determined. Additionally basal interleukin-4 (IL-4) and interleukin-10 (IL-10) levels were recorded. Orally taken the test drug has ex vivo no effect on basal levels of TNF-alpha, IL-1 beta, IL-4, IL-6 or IL-10 which were always below detection limits. After 7 and 21 days ingestion ex vivo a decrease of LPS stimulated TNF-alpha release of 14.6 and 24.0%, respectively, was observed. IL-1 beta was reduced for 19.2 and 39.3%. In vitro IDS 23/1 added to whole blood resulted in an exceeded inhibition of LPS stimulated TNF-alpha and IL-1 beta secretion which correlated with the duration of the drug ingestion. Using the highest tested IDS 23/1 concentration the inhibition reached 50.5 (day 0) to 79.5% (day 21) for TNF-alpha and 90.0 (day 0) to 99.2% (day 21) for IL-1 beta, respectively. IDS 23/1 induced a pronounced release of IL-6 in absence of LPS only in vitro. The detected IL-6 concentrations were comparable to those after LPS stimulation, additive effects could not be observed. The absence of detectable IL-6 concentrations in whole blood ex vivo after oral ingestion of the tested drug as well as the differences in the inhibition patterns for TNF-alpha and IL-1 beta ex vivo and ex vivo in vitro suggest that the extract contains different pharmacological effective compounds with varying bioavailabilities

Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study.

Uebelhart D, Thonar EJ, Delmas PD, et al.

Osteoarthritis Cartilage. 1998 May; 6 Suppl A:39-46.

The aim of this study was to assess the clinical, radiological and biological efficacy and tolerability of the SYSADOA, chondroitin 4- and 6-sulfate (CS, Condrosulf, IBSA, Lugano, Switzerland), in patients suffering from knee osteoarthritis. This was a 1-year, randomized, double-blind, controlled pilot study which included 42 patients of both sexes, aged 35-78 years with symptomatic knee OA. Patients were treated orally with 800 mg chondroitin sulfate (CS) per day or with a placebo (PBO) administered in identical sachets. The main outcome criteria were the degree of spontaneous joint pain and the overall mobility capacity. Secondary outcome criteria included the actual joint space measurement and the levels of biochemical markers of bone and joint metabolism. This limited study confirmed that chondroitin sulfate was well-tolerated and both significantly reduced pain and increased overall mobility capacity. Treatment with CS was also associated in a limited group of patients with a stabilization of the medial femoro-tibial joint width, measured with a digitized automatic image analyzer, whereas joint space narrowing did occur in placebo-treated patients. In addition, the metabolism of bone and joint assessed by various biochemical markers also stabilized in the CS patients whereas it was still abnormal in the PBO patients. These results confirm that oral chondroitin 4- and 6-sulfate is an effective and safe symptomatic slow-acting drug for the treatment of knee OA. In addition, CS might be able to stabilize the joint space width and to modulate bone and joint metabolism. This is the first preliminary demonstration that a SYSADOA might influence the natural course of OA in humans

Characterization of extra cellular phospholipase A2 in human synovial fluids.

Vades P.

Life Sci. 1985;(36):579.

Soluble phospholipase A2 in human pathology: clinical-laboratory interface. In Biochemistry, Molecular Biology, and Physiology of Phospholipase A2 and Its Regulatory Factors 1990.

Vades P.

1990;

Chondroitin sulfate: S/DMOAD (structure/disease modifying anti-osteoarthritis drug) in the treatment of finger joint OA.

Verbruggen G, Goemaere S, Veys EM.

Osteoarthritis Cartilage. 1998 May; 6 Suppl A:37-8.

A total of 119 patients were included in a randomized, double-blind, placebo-controlled trial in order to assess the S/DMOAD properties in OA of chondroitin sulfate (CS 4&6, 3 x 400 mg/day, Condrosulf IBSA, Lugano, CH). Posteranterior roentgenographies of the interphalangeal (IP) joints were carried out at the start of the study and at yearly intervals. This enabled the investigators to document the radiological progression of the anatomical lesions in the pathological finger joints over a 3-year period. It was shown that the progression of OA in the IP finger joints in an individual can be determined by the evolution of his finger joints through previously described anatomical phases: 'N' (not affected), 'S' (classical OA), 'J' (loss of joint space), 'E' (erosive OA) and 'R' (remodeled joint). Structure/disease-modifying anti-OA drug (S/DMOAD) properties were searched for by assaying the number of patients developing OA in previously normal IP joints ('N' > 'S'), or progressing through the described anatomical phases of the disease ('S' > 'J', 'S' > 'E', 'J' > 'E', 'S' > 'R', 'J' > 'R', 'E' > 'R'). In the CS 4&6 group we observed a significant decrease in the number of patients with new 'erosive' OA finger joints. This result is particularly important since OA of the finger joints becomes a clinical problem (pain, functional loss) when 'S' joints progress to 'J' and especially 'E' phases. During and after these 'E' phases, joints will remodel and show the nodular deformities characteristic of Heberden's and Bouchard's nodes. Treated patients were protected against erosive evolution

Double-blind comparative clinical trial with S-adenosylmethionine and indomethacin in the treatment of osteoarthritis.

Vetter G.

Am J Med. 1987 Nov 20; 83(5A):78-80.

In a randomized double-blind study, 36 patients with osteoarthritis of the knee, hip, and/or spine were treated orally with a daily dose of S-adenosylmethionine (SAMe)(1,200 mg) or indomethacin (150 mg) over a period of four weeks. Pretreatment and posttreatment clinical parameters were determined and assessed according to a standard scoring system. SAMe therapy significantly improved the total score obtained by the sum of all clinical findings, as compared with pretreatment values. Similar improvement was evident in indomethacin-treated subjects. Two patients in the SAMe group reported slight nausea after two weeks of therapy, whereas adverse effects developed in seven patients in the indomethacin group

Salubrious effect of Semecarpus anacardium against lipid peroxidative changes in adjuvant arthritis studied in rats.

Vijayalakshmi T, Muthulakshmi V, Sachdanandam P.

Mol Cell Biochem. 1997 Oct; 175(1-2):65-9.

Oxygen derived free radicals are known to play an important role in the etiology of tissue injury in rheumatoid arthritis. The effect of milk extract of Semecarpus anacardium nuts at the dose level of 150 mg/kg body weight for 14 days on adjuvant arthritis was studied for gaining insight into the intrigue disease in relation to the lipid peroxidation and antioxidant defence system. Increased lipid peroxides' levels in both plasma and tissues (liver, kidney and heart) of adjuvant arthritis was significantly decreased by the administration of the drug. The antioxidant defence system studied in tissues of arthritic animals were altered significantly as evidenced by the decreased level of non-enzymatic antioxidants (GSH, vitamin E, vitamin C, NPSH and TSH) and enzymatic antioxidants (catalase and GPx except SOD). Administration of Semecarpus anacardium nut extract brings back the altered antioxidant defence components to near normal levels. These observations suggest that the diseased state of adjuvant arthritis may be associated with augmented lipid peroxidation and the administration of the drug may exert its antiarthritic effect by retarding lipid peroxidation and causing a modulation in cellular antioxidant defence system

Dietary docosahexaenoic acid but not eicosapentaenoic acid suppresses lipopolysaccharide-induced interleukin-1 beta mRNA induction in mouse spleen leukocytes.

Watanabe S, Katagiri K, Onozaki K, et al.

Prostaglandins Leukot Essent Fatty Acids. 2000 Mar; 62(3):147-52.

Mice were fed a diet supplemented either with beef tallow (BT), BT plus ethyl eicosapentaenoate (EPA) or BT plus ethyl docosahexaenoate (DHA) for 9 weeks. EPA and DHA supplementation increased the content of the respective fatty acid in spleen leukocyte lipids, which was associated with the reduction in the arachidonate content. IL-1beta mRNA induction upon lipopolysaccharide (LPS) stimulation in spleen leukocytes in the DHA diet group was significantly lower than in the BT diet group, but the EPA diet was without any significant effect. The amount of prostaglandin E2 (PGE2) released from LPS-stimulated spleen leukocytes was significantly lower in both the EPA and DHA groups than in the BT group. Thus, dietary EPA and DHA inhibited arachidonate metabolism similarly but had different effects on IL-1beta mRNA induction in mouse spleen leukocytes

Management of osteoporosis: is there a role for vitamin K?

Weber P.

Int J Vitam Nutr Res. 1997; 67(5):350-6.

Vitamin K is required for the biological activity of several coagulation factors, which is considered as the classical function of vitamin K. Recent research, however, suggests a role of vitamin K in bone metabolism. The metabolic role of vitamin K is to facilitate the carboxylation of glutamyl to gamma-carboxyglutamyl residues. Besides the hepatic tissue, in which the clotting factors are produced gamma-carboxyglutamyl-containing proteins are also abundantly available in bone tissue. Osteocalcin accounts for up to 80% of the total gamma-carboxyglutamyl content of mature bone. Human carboxylated osteocalcin contains 3 gamma-carboxyglutamyl residues which confer a highly specific affinity to the calcium ion of the hydroxyapatite molecule. Besides the gamma-carboxylation of osteocalcin vitamin K may also affect other parameters of bone metabolism, such as calcium hemostasis, and prostaglandin E2 and interleukin 6 production. Evidence from observational studies and first intervention trials indicate that vitamin K intakes much higher than the current recommendations improved biochemical markers of bone formation as well as bone density. In conclusion, the mechanistic data as well as the observational data and the results of the first controlled clinical trials in humans point to a beneficial effect of additional intakes of vitamin K in bone health

Home prothrombin time monitoring after the initiation of warfarin therapy. A randomized, prospective study.

White RH, McCurdy SA, von Marensdorff H, et al.

Ann Intern Med. 1989 Nov 1; 111(9):730-7.

STUDY OBJECTIVE: To evaluate the efficacy and accuracy of monitoring prothrombin times at home. DESIGN: Randomized, prospective cohort study. SETTING: Outpatients discharged from a university hospital or a community hospital. PATIENTS: Fifty patients started on warfarin for the first time who demonstrated an ability to use the monitor and who had not achieved a stable response to warfarin in the hospital. INTERVENTION: Oral anticoagulation therapy managed using a portable prothrombin time monitor compared with specialized anticoagulation clinic care. MEASUREMENTS AND MAIN RESULTS: In the 46 patients who completed the 8-week study, the median percentage of time that patients in the home-monitor group (n = 23) were within a range equal to the target prothrombin ratio +/- 0.3, but always above 1.25, was 93%, compared with 75% for patients in the clinic group (n = 23) (P = 0.003). There was no significant difference between groups in the percentage of time above the therapeutic range; however, the percentage of time that patients were subtherapeutic was significantly greater in the clinic group (P less than 0.001). There were no major thromboembolic or hemorrhagic complications in either group. Differences between home monitor measurements and corresponding clinical laboratory measurements using blood samples drawn within 4 hours of the home test were comparable to differences observed between measurements using two different clinical laboratory instruments.CONCLUSIONS: Use of a portable prothrombin time monitor by patients at home is feasible and provides accurate measurements. Patients doing home monitoring achieve superior anticoagulation control compared with those receiving standard anticoagulation clinic care

Free radicals in inflammation: second messengers and mediators of tissue destruction.

Winrow VR, Winyard PG, Morris CJ, et al.

Br Med Bull. 1993 Jul; 49(3):506-22.

In recent years it has become increasingly apparent that, in man, free radicals play a role in a variety of normal regulatory systems, the deregulation of which may play an important role in inflammation. As examples, we discuss the second messenger roles of: NO in the regulation of vascular tone, O2.- in fibroblast proliferation and H2O2 in the activation of transcription factors such as NF kappa B. Other control mechanisms, the physiological function of which may be perturbed in inflammation, include: the oxidative modification of low density lipoprotein, the oxidative inactivation of alpha-1-protease inhibitor, DNA damage/repair and heat shock protein synthesis. At sites of inflammation, increased free radical activity is associated with the activation of the neutrophil NADPH oxidase and/or the uncoupling of a variety of redox systems, including endothelial cell xanthine dehydrogenase. Although free radicals, thus produced, have the capacity to mediate tissue destruction, either alone or in concert with proteases, we argue that disturbances in the second messenger and regulatory activities of free radicals may also contribute significantly to the inflammatory process