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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.
SUGGESTED
READING
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.
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