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Abstracts

Scleroderma
(Systemic Sclerosis)

ABSTRACTS

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Influence of asiatic acid, madecassic acid, and asiaticoside on human collagen I synthesis.

Bonte F, Dumas M, Chaudagne C, Meybeck A. LVMH Recherche, Colombes, France.

Planta Med 1994 Apr;60(2):133-5

Asiatic acid, madecassic acid, and asiaticoside, terpenoids with an ursane skeleton, were tested separately and in combination on skin human fibroblast collagen I synthesis in vitro. In the absence of ascorbic acid, the mixture as well as each individual component stimulated collagen I synthesis to a similar extent. In the presence of ascorbic acid, the level of collagen I secretion was higher for each individual component and for the mixture. A comparison of asiaticoside and asiatic acid shows that the sugar moiety of the molecule does not seem to be necessary for this biological activity.

Increased susceptibility to oxidation of low-densitylipoproteins isolated from patients with systemic sclerosis.

Bruckdorfer KR; Hillary JB; Bunce T; Vancheeswaran R; Black CM Department of Rheumatology, Royal Free Hospital School of Medicine, London, England.

Arthritis Rheum (United States) Aug 1995, 38 (8) p1060-7

OBJECTIVE. To examine the resistance to oxidation of low-density lipoproteins (LDL) from patients with systemic sclerosis (SSc) and primary Raynaud's phenomenon (RP) compared with healthy controls.

METHODS. Plasma LDL were isolated from patients with diffuse cutaneous and limited cutaneous SSc (dcSSc and lcSSc, respectively), patients with primary RP, and healthy control subjects. The lipoproteins were assessed for their resistance to oxidation in the presence of cupric ions, using spectrophotometric assays.

RESULTS. LDL from patients with dcSSc and lcSSc were more susceptible to oxidation than were those from healthy control subjects or patients with RP.

CONCLUSION. Our findings suggest that free radicals may play a role in the pathology of SSc.

Fish - oil dietary supplementation in patients withRaynaud's phenomenon: a double-blind, controlled, prospective study.

DiGiacomo RA; Kremer JM; Shah DM Division of Rheumatology, Albany Medical College, New York 12208.

Am J Med (United States) Feb 1989, 86 (2) p158-64

PURPOSE: The ingestion of omega -3 fatty acids could benefit patients with Raynaud's phenomenon because, among other effects, these fatty acids induce a favorable vascular response to ischemia. The aim of our study was to investigate, in a double-blind, placebo-controlled manner, the effects of fish - oil fatty-acid dietary therapy in patients with rheumatic disease.

PATIENTS AND METHODS: Thirty-two patients with primary or secondary Raynaud's phenomenon were randomly assigned to olive-oil placebo or fish-oil groups. Patients ingested 12 fish-oil capsules daily containing a total of 3.96 g eicosapentaenoic acid and 2.64 g docosahexaenoic acid or 12 olive-oil capsules and were evaluated at baseline and after six, 12, and 17 weeks. All patients ingested olive oil between Weeks 12 to 17. Digital systolic blood pressures and blood flow were measured at room air and water baths of 40 degrees C, 25 degrees C, 15 degrees C, and 10 degrees C using strain gauge plethysmography. Onset of Raynaud's phenomenon was timed with a stop watch and defined as plethysmographic evidence of cessation of blood flow and blood pressure in the study finger.

RESULTS: In the fish-oil group, the median time interval before the onset of Raynaud's phenomenon increased from 31.3 +/- 1.3 minutes baseline to 46.5 +/- 2.1 minutes at six weeks (p = 0.04). Patients with primary Raynaud's phenomenon ingesting fish oil had the greatest increase in the time interval before the onset of the condition. Five of 11 patients (45.5 percent) with primary Raynaud's phenomenon ingesting fish oil in whom the phenomenon was induced at baseline could not be induced to develop Raynaud's at the six- or 12-week visit compared with one of nine patients (11 percent) with primary Raynaud's ingesting olive oil (p = 0.05). The mean digital systolic pressures were higher in the patients with primary Raynaud's phenomenon ingesting fish oil than in patients with primary Raynaud's ingesting olive oil in the 10 degrees C water bath (+32 mm Hg, p = 0.02).

CONCLUSION: We conclude that the ingestion of fish oil improves tolerance to cold exposure and delays the onset of vasospasm in patients with primary, but not secondary, Raynaud's phenomenon. These improvements are associated with significantly increased digital systolic blood pressures in cold temperatures.

[Madecassol treatment of systemic and localized scleroderma]. [Article in Russian]

Guseva NG, Starovoitova MN, Mach ES.

Ter Arkh 1998;70(5):58-61

AIM: The trial of efficacy of 6-month therapy with madecassol (tablets, ointment, powder) of patients with systemic and focal scleroderma (SS and FS).

MATERIALS AND METHODS: 54 patients (49 females and 5 males) aged 15 to 70 years with scleroderma running from 3 months to 15 years entered the study. 30 patients had typical SS, 24 patients had FS. Tablets were given to 18 patients, ointment was applied in 42 patients, powder in 3 and tablets + ointment in 9 patients. Madecassol 10 mg tablets were taken 3 times a day by patients with SS and advanced FS. The ointment was preferred in ulcers and scars on fingers and toes in SS and vascular trophic lesions in FS. In active focal scleroderma the ointment was applied to the skin lesions. The ointment was used 2 times a day (in the morning and evening) for 1-6 months. Madecassol powder was employed rarely, primarily of anal and vulval lesions.

RESULTS: 6-month oral course (30 mg/day) in 12 SS patients brought about a decrease of indurative lesions, hyperpigmentation (8), vascular trophic disorders (6) and improvement of general condition (5). Subjective response was good in 10 patients and corresponded to absence of progression. In progressive disease and diffuse skin lesions the drug was ineffective. The best response was obtained in local application of madecassol ointment on digital ulcers in SS.

CONCLUSION: Madecassol is effective and well tolerated and therefore recommended for oral and local use in combined treatment of SS adn FS. Indications for per os utelization are: chronic or subchronic SS with limited skin involvement, advanced and/or prone to progression FS in which combined administration of the tablets and ointment is proposed.

Dietary intake of micronutrient antioxidants in relation to blood levels in patients with systemic sclerosis.

Herrick AL; Worthington H; Rieley F; Clarke D; Schofield D; Braganza JM; Jayson MI University of Manchester Rheumatic Diseases Centre, Hope Hospital, Salford, UK.

J Rheumatol (Canada) Apr 1996, 23 (4) p650-3

OBJECTIVE. To document habitual intakes of micronutrient antioxidants in patients with systemic sclerosis (SSc) in light of studies reporting subnormal levels of ascorbate and selenium in this patient group.

METHODS. Dietary intakes of vitamin C , selenium, alpha-tocopherol, beta-carotene, and sulfur amino acid precursors of glutathione were assessed using the 7 day weighed record in 12 patients with SSc and in 12 healthy control subjects. The intakes of the first 4 substances were examined in relation to plasma/serum levels, while intakes of sulfur amino acids were examined in relation to urinary inorganic sulfate.

RESULTS. Antioxidant and sulfur amino acid intakes were similar in patients and controls, although the patients had lower levels of selenium (median 74 compared to 87 milligrams in controls; p = 0.014) and of vitamin C in plasma (median 6.0 compared to 11.1 milligrams/l in controls; p = 0.08). Inorganic sulfate concentration in urine was similar in patients and controls.

CONCLUSION. Our results suggest that reduced blood levels of the water soluble antioxidants selenium and ascorbic acid in patients with SSc are not due to dietary deficiency. Other explanations must therefore be sought.

Essential fatty acid metabolism in diseases of connective tissue with special reference to scleroderma and to Sjogren's syndrome.

Horrobin DF

Med Hypotheses (England) Jul 1984, 14 (3) p233-47

Drugs which modify the conversion of essential fatty acids to prostaGLAndins and leukotrienes are the mainstays of treatment in rheumatology. Yet these drugs have little or no action in scleroderma or Sjogren's syndrome and under some circumstances may have adverse effects. Patients with scleroderma have been shown to have very high levels of circulating prostaglandins, coupled with depletion of the prostaglandin precursors, dihomogammalinolenic acid and arachidonic acid. Levels of the metabolites of arachidonic acid, 22:4n-6 and 22:5n-6, which have major roles in maintaining normal cell membrane characteristics were exceptionally low in both plasma and red cell membranes. Others have observed that various functions are highly resistant to normal actions of PGs in scleroderma. This raises the possibility that the high rate of PG formation in scleroderma may be beneficial, in compensation, and that clinical symptoms develop when PG precursors begin to be depleted. Red cell membrane fatty acids patterns in Sjogren's syndrome are almost identical to those in scleroderma. Placebo-controlled trials of supplementation with essential fatty acids have been found to be beneficial in both scleroderma and Sjogren's syndrome.

Essential fatty acid and prostaglandin metabolism in Sjogren's syndrome, systemic sclerosis and rheumatoid arthritis.

Horrobin DF

Scand J Rheumatol Suppl (Sweden) 1986, 61 p242-5

Evidence from biochemical studies and from experimental animals indicates that abnormalities of essential fatty acid (EFA) and eicosanoid metabolism could lead to salivary and lacrimal GLAnd atrophy and to immunological and cardio-vascular defects. Measurements of EFA levels in erythrocytes from patients with primary Sjogren's syndrome have shown that abnormalities are indeed present. Controlled clinical trials of supplementation with gamma-linolenic acid (GLA) as evening primrose oil (Efamol) in both primary Sjogren's syndrome and systemic sclerosis have given positive results. There are strong arguments to indicate that sophisticated manipulation of EFA metabolism may have a role to play, not only in Sjogren's syndrome but also in other rheumatological disorders. (16 Refs.)

Biomechanical stimulation therapy. A novel physiotherapy method for systemic sclerosis.

Klyscz T, Rassner G, Guckenberger G, Junger M. Department of Dermatology, University Hospital of Tubingen, Germany.

Adv Exp Med Biol 1999;455:309-16

To improve the mobility of joints, particularly of the finger joints and the mandibular joint, and to reduce the edema of the skin, various physical therapies have to be used in patients with SSc. As the quality of patients' life depends on the use of their fingers and of their mouth, these therapeutics belong to the basic measures in the treatment of SSc. In addition to the manually performed lymph drainage a new method, the biomechanical stimulation therapy, has proven to be efficacious to improve the mobility of the joints and to reduce the edema in SSc-patients. By devices of various size, longitudinal vibrations are transduced to patients' body: finger, hand, face, mandibular joint, the oral mucosa, the legs and the trunk. In 6 patients we found: significant (p < 0.05) increase of skin score, grip strength, mobility of joints (10-30%). No side effects were observed. We conclude from these data, that skin, mucosa, joints and patients' quality of life are improved by the biomechanical stimulation therapy in a clinical relevant degree.

Management of severe scleroderma with long-term extracorporeal photopheresis.

Krasagakis K, Dippel E, Ramaker J, Owsianowski M, Orfanos CE. Department of Dermatology, University Medical Center Benjamin Franklin, Free University of Berlin, Germany.

Dermatology 1998;196(3):309-15

BACKGROUND: The management of systemic sclerosis remains unsatisfactory. Thus far, the action of extracorporeal photopheresis (ECP) in severe systemic scleroderma has been evaluated in short-term studies, and only limited experience has been obtained with long-term application.

OBJECTIVE: The aim of the present study was to evaluate prospectively the long-term effect of ECP in a group of 16 patients suffering from severe scleroderma, showing visceral involvement and progressive clinical course.

METHODS: Fourteen patients with systemic scleroderma involving several organs, 1 with CREST syndrome and another with scleroderma-myositis overlap syndrome were treated with ECP over a period of 6-45 months. In 3 cases, gamma-IFN was additionally administered. Skin and visceral involvement were assessed by evaluating a series of clinical criteria and results from laboratory, imaging and functional tests.

RESULTS: Overall, clear improvement was encountered in 6 patients, mixed response in 2, stable disease in 3 and continuing progressive course in 5 patients. Four out of 6 patients with improvement were treated with ECP early after onset of scleroderma (< or = 2 years), whereas all patients with a progressive course under ECP had had scleroderma for longer than 2 years. Immunosuppressive drugs previously administered could be reduced or fully withdrawn under ECP treatment in 5 patients, but additional oral medication was introduced in 4 patients due to disease progression. Addition of gamma-IFN to ECP did not reveal further benefit. No side-effects were recorded under ECP treatment.

CONCLUSIONS: Based on this observation, we believe that long-term ECP represents an effective treatment modality in severe scleroderma particularly when started early, with stabilization of the disease course and partial remission of the cutaneous findings, whereas visceral involvement, if present, may rarely improve.

Triterpenes from Centella asiatica stimulate extracellular matrix accumulation in rat experimental wounds.

Maquart FX, Chastang F, Simeon A, Birembaut P, Gillery P, Wegrowski Y. Laboratory of Biochemistry, UPRESA CNRS 6021, IFR-53 Biomolecules, Faculty of Medicine, Reims, France. fmaquart@chu-reims.fr

Eur J Dermatol 1999 Jun;9(4):289-96

Titrated Extract from Centella asiatica (TECA) is a drug which has been used for many years in Europe for the treatment of wound healing defects. It is a reconstituted mixture of 3 triterpenes extracted from the plant, asiatic acid, madecassic acid and asiaticoside. In this report, we studied the effects of TECA and its separated components in the wound chamber model described by Schilling et al. Stainless steel wound chambers were surgically inserted under the skin of rats and received serial injections of either TECA or its purified components. Chambers were collected at days 7, 14, 21 or 28 for biochemical analysis or histological examination. TECA-injected wound chambers were characterized by increased dry weight, DNA, total protein, collagen and uronic acid contents. Peptidic hydroproline was also increased, showing an increased remodeling of the collagen matrix in the wound. The 3 purified components of TECA were all able to reproduce the effects of the complete drug, with some differences depending on the product. Asiatic acid and asiaticoside were the most active of the 3 triterpenes. Asiaticoside exerted a preferential stimulation of collagen synthesis and was active at low doses only. In addition to collagen, the 3 components were also able to stimulate glycosaminoglycan synthesis.

[The effect of dimethyl sulfoxide on the thromboelastographic indices and the microcirculation in patients with rheumatic diseases]

Murav'ev IuV; Loskutova TT; Anikina NV; Shcherbakov AB; Sokolov VB

Ter Arkh (USSR) 1989, 61 (12) p106-9

Using a blind method for assessing the results, a study was made of the effect of dimethylsulfoxide (DMSO) on fibrin formation and microcirculation in 42 patients with rheumatic diseases (rheumatoid arthritis, systemic scleroderma, Raynaud's syndrome). It has been shown that the therapeutic effect of DMSO in rheumatic diseases is determined to a definite degree by its normalizing action on fibrin formation and microcirculation.

Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase.

Safayhi H, Mack T, Sabieraj J, Anazodo MI, Subramanian LR, Ammon HP. Department of Pharmacology, University of Tuebingen, FRG.

J Pharmacol Exp Ther 1992 Jun;261(3):1143-6

Isomers (alpha- and beta-) of boswellic acids (BAs), 11-keto-beta-BA and their acetyl derivatives were isolated from the gum resin of Boswellia serrata. BA and derivatives concentration dependently decreased the formation of leukotriene B4 from endogenous arachidonic acid in rat peritoneal neutrophils. Among the BAs, acetyl-11-keto-beta-BA induced the most pronounced inhibition of 5-lipoxygenase (5-LO) product formation with an IC50 of 1.5 microM. In contrast to the redox type 5-LO inhibitor nordihydroguaiaretic acid, BA in concentrations up to 400 microM did not impair the cyclooxygenase and 12-lipoxygenase in isolated human platelets and the peroxidation of arachidonic acid by Fe-ascorbate. The data strongly suggest that BAs are specific, nonreducing-type inhibitors of the 5-LO product formation either interacting directly with the 5-LO or blocking its translocation.

Novel functional sets of lipid-derived mediators with anti-inflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.

Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. cnserhan@zeau.bwh.harvard.edu

J Exp Med 2000 Oct 16;192(8):1197-204

Aspirin therapy inhibits prostaglandin biosynthesis without directly acting on lipoxygenases, yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive lipoxins (LXs) epimeric at carbon 15 (15-epi-LX, also termed aspirin-triggered LX [ATL]). Here, we report that inflammatory exudates from mice treated with omega-3 polyunsaturated fatty acid and aspirin (ASA) generate a novel array of bioactive lipid signals. Human endothelial cells with upregulated COX-2 treated with ASA converted C20:5 omega-3 to 18R-hydroxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15R-LX(5) and 5,12,18R-triHEPE. These new compounds proved to be potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue > 5,12,18R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HEPE and 15R-HEPE generation with recombinant COX-2 as well as omega-5 and omega-9 oxygenations of other fatty acids that act on hematologic cells. These findings establish new transcellular routes for producing arrays of bioactive lipid mediators via COX-2-nonsteroidal antiinflammatory drug-dependent oxygenations and cell-cell interactions that impact microinflammation. The generation of these and related compounds provides a novel mechanism(s) for the therapeutic benefits of omega-3 dietary supplementation, which may be important in inflammation, neoplasia, and vascular diseases.

Enhanced lipid peroxidation in systemic scleroderma

Sommerburg O.; Brenke A.; Muller G.-M.; Siems W.; Grune T. Abteilung fur Kindernephrologie, Medizinische Fakultat, Humboldt-Universitat, Schumannstrasse 20/21,10117 Berlin Germany

Zeitschrift fur Dermatologie (Germany) 1996, 182/3 (124+126-128)

Scleroderma, the aetiology of which remains uncertain, is a rare, autoimmunological disease of the vascular system and connective tissues often accompanied by joint pain. It has been shown that in patients with scleroderma, a considerable accumulation of free radicals, and massive lipid peroxidation occurs. The serum of these patients contains levels of 4-hydroxynonenal - an aldehydic product of lipid peroxidation which is toxic at lowdoses - that are three times as high as those seen in healthy subjects. Under treatment with the antioxidant, vitamin E, the concentrations of 4-hydroxynonenal decrease by more than two-thirds, and the subjective feeling of well-being clearly improves.

New innovations in scar management.

Widgerow AD, Chait LA, Stals R, Stals PJ.

Aesthetic Plast Surg 2000 May-Jun;24(3):227-34

As current aesthetic surgical techniques become more standardized and results more predictable, a fine scar may be the demarcating line between acceptable and unacceptable aesthetic results. With this in mind, a scar management program has been adopted based on the modalities of wound support, hydration, and hastened maturity, all factors gleaned from scientific evidence published over the past 25 years. Tension on a scar in one axis will result in a stretched scar, probably initiated by neutrophils and their neutral proteases [18,26]. Tension on a scar from many directions or intermittently will result in a hypertrophic scar, possibly initiated by lymphocytes but definitely related to a prolongation of the inflammatory process, with increased fibroblast activity and overabundant extracellular matrix secretion [24,26]. The common initiating factor is the tension on the scar, and the critical element needed to counteract this tension is scar support. Clinical experience has shown us that the most reliable way to support a scar is by using microporous tape. Hydration is a second beneficial influence on scar control and is the basis of the use of silicone sheeting and gel [7,29,36]. Alpha Centella cream has two main components. The first is an extract from the plant Bulbine frutescens. This increases hydration under the tape by leaving a layer of fatty vesicles of glycoprotein on the skin surface. This also has antibacterial properties. The second component is the principal terpenoids extracted from the Centella asiatica plant. These include asiatic acid, madecassic acid, and asiaticoside. Centella asiatica has been documented to aid wound healing in a large number of scientific reports [5,12,21,22,33,34,40]. The most beneficial effect appears to be the stimulation of maturation of the scar by the production of type I collagen [4,19] and the resulting decrease in the inflammatory reaction and myofibroblast production. Thus these components have been incorporated into the formulation of a scar management program. This publication reviews much of the available literature relating to scar management and describes the formulation and use of a scar management program based on this information.

The North American experience with photopheresis.

Zic JA, Miller JL, Stricklin GP, King LE Jr. Division of Dermatology, Vanderbilt University School of Medicine/Nashville Veterans Affairs Medical Center, Tennessee, USA.

Ther Apher 1999 Feb;3(1):50-62

Photopheresis or extracorporeal photochemotherapy (ECP) is a novel immunomodulatory therapy based upon pheresis of light-sensitive cells. Whole blood is removed from patients who have previously ingested the photosensitizing agent 8-methoxypsoralen (8-MOP) followed by leukapheresis and exposure of the 8-MOP containing white blood cells (WBCs) extracorporeally to an ultraviolet A (UVA) light source prior to their return to the patient. In 1988, the Food and Drug Administration (FDA) approved photopheresis for the treatment of cutaneous T-cell lymphoma (CTCL). Treatment of CTCL with photopheresis has been reported in over 300 patients worldwide. Photopheresis has also demonstrated encouraging results in the treatment of solid organ transplant rejection, graft versus host disease, scleroderma, and other autoimmune diseases although fewer patients have been studied. This review will focus on the North American experience with photopheresis.

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Effect of N-acetyl-L-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis.

Failli P, Palmieri L, D'Alfonso C, Giovannelli L, Generini S, Rosso AD, Pignone A, Stanflin N, Orsi S, Zilletti L, Matucci-Cerinic M. Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Firenze, Italy. failli@server1.pharm.unifi.it

Nitric Oxide. 2002 Dec;7(4):277-82.

Lung macrophages may play a relevant role in oxidative processes producing both superoxide anion (O(2)(-)) and NO. In this view, an antioxidant therapy can be useful in the treatment of systemic sclerosis (SSc) patients. N-Acetylcysteine (NAC) is able to expand natural antioxidant defenses by increasing intracellular gluthatione concentration and it has been proposed as an antioxidant therapy in respiratory distress syndromes. The aim of our study was to determine whether lung macrophages obtained from SSc patient bronchoalveolar lavage (BAL) express the inducible form of nitric oxide synthase (iNOS) and whether NAC can reduce the peroxynitrite (ONOO(-)) and O(2)(-) production of these cells. Alveolar macrophages were isolated from BAL of 32 patients and used for the immunocytochemical determination of iNOS, and the production of ONOO(-) and O(2)(-) was measured by fluorimetric or spectrophotometric methods, respectively. Lung macrophages obtained from SSc patients expressed a higher level of iNOS compared to healthy subject cells. NAC preincubation (5 x 10(-5)M, 24h) significantly reduced (-21%) the ONOO(-) production in formyl Met-Leu-Phe (fMLP)-activated cells and slightly reduced it under resting conditions, whereas NAC preincubation was unable to modify the release of O(2)(-) both in basal condition and in fMLP-stimulated cells. We conclude that since SSc lung macrophages express high levels of iNOS and produce a significant quantity of ONOO(-), NAC administration reduces ONOO(-) production and can be an useful treatment to alleviate SSc symptoms.

Activin, a grape seed-derived proanthocyanidin extract, reduces plasma levels of oxidative stress and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in systemic sclerosis.

Kalin R, Righi A, Del Rosso A, Bagchi D, Generini S, Cerinic MM, Das DK. Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington 06030-2110, USA.

Free Radic Res. 2002 Aug;36(8):819-25.

This study evaluated whether a new generation antioxidant Activin derived from the grape seed proanthocyanidins, could reduce the induction of the adhesion molecules as a result of inflammatory response in the plasma of systemic sclerosis (SSc) patients. SSc patients were divided into two groups: one group was treated with Activin, a grape seed-derived proanthocyanidins, while the other group served as control. Patients were given Activin 100 mg/day orally for one month after which the blood samples were withdrawn from both groups of the patients. Blood was also taken from normal human volunteers. Plasma was obtained in fasting state between 8 to 9 A.M. from two groups of SSc patients and controls. Soluble adhesion molecules including ICAM-1, VCAM-1, E-selectin and P-selectin as well as malonaldehyde, a marker for oxidative stress, were measured. The results of our study demonstrated up-regulation of these soluble adhesion molecules except for P-selectin, in the plasma of the SSc patients compared to those obtained from human volunteers. Activin significantly attenuated the increased expression of these adhesion molecules. In addition, there was a significant increase in the amount of malondialdehyde formation in the plasma of the SSc patients, which was also attenuated by Activin. The results of this study demonstrated that Activin could reduce the inflammatory response and the oxidative stress developed in SSc patients.

Emerging potentials for an antioxidant therapy as a new approach to the treatmentof systemic sclerosis.

Simonini G, Pignone A, Generini S, Falcini F, Cerinic MM, Gabriele S, Alberto P, Sergio G, Fernanda F, Marco MC. Department of Pediatrics, University of Florence, Institute of Internal Medicine, Italy.

Toxicology. 2000 Nov 30;155(1-3):1-15.

Oxidative stress, favoring disease progression by a rapid degeneration of endothelial cell function is deeply involved in Systemic Sclerosis (SSc) pathogenesis. Raynaud's phenomenon (RP), present in 90% of patients with SSc, provoking frequent daily episodes of hypoxia-reperfusion injury, produces several episodes of free radicals-mediated endothelial derangement. These events results in a positive feedback effect of luminal narrowing and ischemia and therefore to the birth of a vicious cycle of oxygen free radicals (OFR) generation, leading to endothelial damage, intimal thickening and fibrosis. Thus ischemia and reperfusion are two criticals events that may induce oxidative stress and inactivation of antioxidant enzymes. In RP and SSc, a reduced concentration of ascorbic acid, alpha-tocopherol and beta-carotene as well as low values of Selenium have been reported. This antioxidative potential deficiency increases the propensity to oxidative stress. favoring the development of injury mediated by OFR. We reviewed several antioxidant compounds, aiming at their capacity of reverting endothelial dysfunction and damage, scavenging lipid peroxidation and reducing multiple episodes of hypoxia-reperfusion injury. In order to interrupt SSc vicious cycle, we propose a main strategy for SSc treatment by a supplementation of antioxidants and different kind of drugs with antioxidant property, such as Lazaroids, Resveratrol, Melatonin and Probucol.

Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud's phenomenon.

Denton CP, Bunce TD, Darado MB, Roberts Z, Wilson H, Howell K, Bruckdorfer KR, Black CM. Academic Unit of Rheumatology, Royal Free Hospital School of Medicine, London, UK.

Rheumatology (Oxford). 1999 Apr;38(4):309-15.

OBJECTIVE: Reactive oxygen species have been implicated in the pathogenesis of inflammatory and vascular disease. We have undertaken a controlled trial to evaluate probucol, a synthetic antioxidant, as a potential therapy for Raynaud's phenomenon.

METHODS: The study cohort included patients with systemic sclerosis (SSc; n = 20), primary Raynaud's phenomenon (n = 15) or 'autoimmune Raynaud's' (n = 5). Patients were allocated to receive either probucol (500 mg daily) or nifedipine (20 mg daily) for 12 weeks. Clinical and biochemical variables at baseline were compared with those at completion of treatment. Evaluation included assessment of Raynaud's attack frequency and severity by visual analogue scale, measurement of low-density lipoprotein (LDL) oxidation lag time, and plasma concentrations of cholesterol, triglyceride, vitamin E and vitamin C.

RESULTS: There was a significant reduction of both the frequency and severity of Raynaud's attacks in the patients who received probucol, but not in the control group. LDL oxidation lag time, reflecting in vitro susceptibility to oxidation, was also increased by probucol therapy and serum cholesterol levels were significantly reduced. Similar changes were observed in both SSc- and non-SSc-associated Raynaud's cases.

CONCLUSION: These data suggest that probucol may be useful for the symptomatic treatment of Raynaud's phenomenon and also reduces LDL oxidation susceptibility. Since oxidized lipoproteins may mediate vascular damage in SSc, the use of probucol could have additional disease-modifying benefits. Based upon the results of this pilot study, further evaluation of this novel form of therapy is warranted.

Effect of melatonin on normal and sclerodermic skin fibroblast proliferation.

Carossino AM, Lombardi A, Matucci-Cerinic M, Pignone A, Cagnoni M. Institute of Internal Medicine IV, University of Florence, Italy.

Clin Exp Rheumatol. 1996 Sep-Oct;14(5):493-8.

OBJECTIVE: We studied the effect of melatonin (MLT) (N-acetyl 5-methoxytryptamine) on the growth rate of normal skin fibroblasts and of fibroblasts from involved and apparently uninvolved skin of patients affected by systemic sclerosis (SSc).

METHODS: The growth rate was evaluated on the basis of growth curves and a 3H-thymidine incorporation assay.

RESULTS: Our results demonstrate that a dose of 200 micrograms/ml of MLT inhibits (> 80%) both control and SSc fibroblasts. Inhibition was dose-dependent and was greater than 70% for MLT concentrations of 100 micrograms/ml, 200 micrograms/ml and 400 micrograms/ml. 3H-thymidine incorporation was correlated with the effect on thegrowth curves (81% at 200 micrograms/ml of MLT). In contrast, at a low dosage of 6 micrograms/ml, MLT exerted a stimulatory effect on cell proliferation in all the cell lines analyzed. Cell viability was not affected by MLT at any of the concentrations tested. A recovery study indicated that replacement of MLT-containing medium with MLT-free medium resulted in a re-establishment of cell growth.

CONCLUSIONS: These results suggest that MLT, at higher dosages, is a potent inhibitor of the proliferation of fibroblasts derived from the skin of healthy and SSc patients.

Gastrointestinal function in patients with progressive systemic sclerosis.

Akesson A; Akesson B; Gustafson T; Wollheim F

Clin Rheumatol (Belgium) Dec 1985, 4 (4) p441-8

In 24 patients with progressive systemic sclerosis (PSS) the pentagastrin-stimulated gastric acid secretion was determined to investigate if acid hypersecretion is associated with reflux-oesophagitis--the most common complication to oesophageal involvement in PSS. Gastro-oesophageal reflux was observed in 12, reflux-oesophagitis in 9 and oesophageal mycosis in 8 patients. Gastric acid secretion was increased in 13 (54%) patients and tended to be higher in patients with oesophagitis. Patients with reflux and increased acid secretion seemed to be free from oesophageal mycosis. Bacterial overgrowth and malabsorption are known complications to intestinal scleroderma and these items were investigated using non-invasive methods. Four patients had increased bile acid deconjugation, 3 had increased (14C)xylose degradation indicating bacterial overgrowth and 7 patients had decreased fat absorption in the triolein breath test. Nutritional status with respect to selenium, folate, cobalamin and fat-soluble vitamins was essentially normal.