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****** DATA-MEDICOS **********
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EL TRANILAST 
THE TRANILAST 
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***** DERMAGIC-EXPRESS No.30 ******** 
****** 19 ENERO DE 1.999 ******* 
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EDITORIAL ESPANOL
=================
Amigos dermatólogos, DERMAGIC de nuevo con ustedes. EL TRANILAST (Acido
antranilico)
producto nuevo que esta siendo usado por los Japoneses, en numerosas
patologías dermatologicas y no dermatologicas. Les traigo estas 31
referencias que ilustran las bondades del producto. Nombre comercial RIZABEN. 
Entre las enfermedades dermatologicas donde esta siendo usado figuran:
queloides, cicatrices hipertróficas, esclerodermia localizada,
pseudoainhum, sarcoidosis, mastocitosis, granoloma anular, penfigo vulgar y
dermatitis atópica.

!!! EL SINGULAIR (montelukast sodico) llego a VENEZUELA, !!!precio 29.500
bs UNA CAJA DE 30 TABS (5MGRS), 32.950 (TABS 10 MGRS), PRECIO FARMACIAS
MACRO,,,LABORATORIO MERCK SHARP AND DOHME, !!!, en la proxima edición una
corta REVISON DEL MONTELUKAST !!! 

Saludos,,, 

Dr. Jose Lapenta R.

EDITORIAL ENGLISH
=================
Friends dermatologist, DERMAGIC again with you. THE TRANILAST (anthranilic
acid) 
new product that is being used by Japaneses, in numerous pathologies
dermatologic and non dermatologic. I bring these 31 references that
illustrate the kindness of the product. Commercial name, RIZABEN. 
Among the illnesses dermatologics where this being used they figure:
keloid and hypertrophic scars, localized scleroderma, pseudoainhum,
sarcoidosis, mastocytoma, granuloma annulare, pemphigus vulgaris and atopic
dermatitis. 

Greetings, 

Dr. José Lapenta R. 

================================================================
DERMAGIC/EXPRESS(30)
================================================================
EL TRANILAST // THE TRANILAST 
================================================================
1.) Treatment of keloid and hypertrophic scars by iontophoretic
transdermal delivery of tranilast.
2.) Topical delivery of keloid therapeutic drug, tranilast, by combined use
of oleic acid and propylene glycol as a penetration enhancer: evaluation by
skin microdialysis in rats.
3.) In vitro release of tranilast from oily gels and penetration of the
drug into Yucatan micropig skin.
4.) Successful treatment of pemphigus vulgaris with prednisolone and
tranilast [letter]
5.) Solitary mastocytoma treated with tranilast.
6.) Treatment of granuloma annulare with tranilast.
7.) A case of atypical localized scleroderma presenting with pseudoainhum:
treatment with tranilast, an anti-fibrotic agent [letter]
8.) Tranilast inhibits collagen synthesis in normal, scleroderma
and keloid fibroblasts at a late passage culture but not at an
early passage culture.
9.) Treatment of linear localized scleroderma with the anti-allergic drug,
tranilast.
10.) Treatment of cutaneous sarcoidosis with tranilast.
11.) Tranilast antagonizes angiotensin II and inhibits its biological
effects in vascular smooth muscle cells. 
12.) Inhibition of interferon-gamma and interleukin-2 production from
lymphocytes stimulated with food antigens by an anti-allergic drug,
Tranilast, in patients with food-sensitive atopic dermatitis.
13.) In-vivo calibration of microdialysis probe by use of endogenous
glucose as an internal recovery marker: measurement of skin distribution of
tranilast in rats.
14.) Inhibitory effects of tranilast on expression of transforming growth
factor-beta isoforms and receptors in injured arteries. 
15.) [Eosinophilic cystitis induced by tranilast: a case report]
16.) Inhibition by tranilast of vascular endothelial growth factor
(VEGF)/vascular permeability factor (VPF)-induced increase in vascular
permeability in rats.
17.) Tranilast inhibits the proliferation, chemotaxis and tube formation of
human microvascular endothelial cells in vitro and angiogenesis in vivo.
18.) [The effect of tranilast on subepithelial corneal opacity after
excimer laser keratectomy]
19.) Effectiveness of tranilast on restenosis after directional coronary
atherectomy.
20.) Inhibition of proliferation of MCF-7 breast cancer cells by a
blocker of Ca(2+)-permeable channel. Cell Calcium
21.) Effects of pemirolast and tranilast on intimal thickening after
arterial injury in the rat.
22.) Effect of topical tranilast and corticosteroids on subepithelial
haze after photorefractive keratectomy in rabbits.
23.) Tranilast inhibits contraction of rat aortic smooth muscle.
24.) Suppressive effects of tranilast on the expression of inducible
cyclooxygenase (COX2) in interleukin-1beta-stimulated fibroblasts.
25.) Tranilast inhibits the growth of rat mesangial cells.
26.) Tranilast inhibits contraction and Ca2+ movement of porcine
coronary arteries.
27.) Tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) down-regulates
the growth of scirrhous gastric cancer.
28.) Inhibitory effect of tranilast on activation and transforming growth
factor beta 1 expression in cultured rat stellate cells.
29.) Blockade of DNA synthesis induced by platelet-derived growth factor by
tranilast, an inhibitor of calcium entry, in vascular smooth muscle cells.
30.) Inhibition by tranilast of collagen accumulation in hypersensitive
granulomatous inflammation in vivo and of morphological changes and
functions of fibroblasts in vitro.
31.) Suppressive effects of tranilast on pulmonary fibrosis and activation
of alveolar
macrophages in mice treated with bleomycin: role of alveolar macrophages in
the fibrosis. 
========================================================================
========================================================================
1.) Treatment of keloid and hypertrophic scars by iontophoretic
transdermal delivery of tranilast.
========================================================================
Scand J Plast Reconstr Surg Hand Surg 1997 Jun;31(2):151-8 (ISSN: 0284-4311)

Shigeki S; Murakami T; Yata N; Ikuta Y [Find other articles with these
Authors]

Department of Orthopedic Surgery, Hiroshima University School of Medicine,
Japan.

The feasibility of iontophoretic transdermal delivery of tranilast
(N-(3,4-dimethoxycinnamoyl)
anthranilic acid) for the treatment of keloid and hypertrophic scars was
evaluated in hairless rats
and humans. A drug electrode containing tranilast 1.5 ml (8 mg/ml in
ethanol/water (8/2, v/v)
mixture) was placed on the dorsal skin surface of anaesthetised rats or the
affected parts of patients,
and connected to the negative pole; an electric current (0.5-4 mA for rats,
2 mA for people) was
pulsed through at one minute intervals. Tranilast was effectively delivered
transdermally
iontophoretically into the restricted skin tissues of hairless rats and the
affected parts of four patients
with hypertrophic scars with no skin damage. In four other patients
tranilast given iontophoretically
for a period of 30 minutes a week reduced the patients' complaints of pain
and itching after only one
or two treatments although there were some variations among patients. These
results indicate that
the transdermal iontophoretic delivery of tranilast is a useful treatment
for keloid and hypertrophic
scars, particularly for relieving pain and itching, and is more beneficial
than tranilast given orally. 

========================================================================
2.) Topical delivery of keloid therapeutic drug, tranilast, by combined use
of oleic acid and propylene glycol as a penetration enhancer: evaluation by
skin microdialysis in rats.
========================================================================
J Pharm Pharmacol 1998 Jan;50(1):49-54 (ISSN: 0022-3573)

Murakami T; Yoshioka M; Yumoto R; Higashi Y; Shigeki S; Ikuta Y; Yata N
[Find other articles
with these Authors]

Department of Biopharmaceutics, Institute of Pharmaceutical Sciences,
Hiroshima University School
of Medicine, Japan.

Topical delivery of tranilast (N-(3,4-dimethoxycinnamoyl)anthranic acid),
an inhibitor of collagen
synthesis and a therapeutic drug for keloid and hypertrophic scar, was
examined, in rats, with oleic
acid alone or a combination of oleic acid and propylene glycol as
penetration enhancer. Evaluation
was by measurement of the concentration of tranilast in plasma and in the
dialysate from skin
microdialysis. When tranilast at a dose of 1.5 mg was applied topically as
an ethanol solution
containing 5% polyvinylpyrrolidone on a dorsal skin surface (2.25 cm2), the
maximum
concentration of tranilast in skin dialysate was approximately 2 microM.
When 10 or 20% oleic
acid was added to the same ethanol solution the maximum concentration of
tranilast in the
dialysate increased to 10-20 microM, and this value was further increased
to 60 microM by the
addition of a combination of oleic acid (10 or 20%) and propylene glycol
(10%) to the solution.
With the combination of oleic acid and propylene glycol the area under the
plot of the concentration
of tranilast in skin dialysate against time between 0 and 4 h (AUC0-4) was
more than 400-fold
that after intravenous administration. The transdermal bioavailability of
tranilast as assessed by the
AUC0-4 of tranilast in plasma, was 0.2% of the dose applied in the ethanol
solution, 3-5% of that
applied in the ethanol solution containing oleic acid, and 14-16% of that
applied in the ethanol
solution containing both oleic acid and propylene glycol. These results
suggest that the topical
delivery of tranilast with an absorption enhancer such as a mixture of
oleic acid and propylene
glycol might be a more effective medication than oral administration of
tranilast for the treatment of
keloid and hypertrophic scar. 

========================================================================
3.) In vitro release of tranilast from oily gels and penetration of the
drug into Yucatan micropig skin.
========================================================================
Biol Pharm Bull 1998 Mar;21(3):300-3 (ISSN: 0918-6158)

Hori N; Fujii M; Yamanouchi S; Miyagi M; Saito N; Matsumoto M [Find other
articles with these
Authors]

Pharmaceutical Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.

For the transdermal delivery of tranilast (TL), a drug used for the
treatment of skin diseases such
as keloids and hypertrophic scars, its oily gels were prepared; its in
vitro release and penetration
into Yucatan micropig skin were evaluated. In the gels that consisted of
hydrogenated soybean
phospholipids (HSL) and octyl isononanoate (IOIN), a fatty-acid ester, the
release of TL from the
gels was proportional to the drug content, and the extent of TL released up
to 6 h from them was
approximately 70% of the amount of applied TL. On the other hand, with the
gels consisting of HSL
and isocetyl isostearate (ICIS), the release of TL from the gels was about
half of that from IOIN
gels, even at the same drug concentration. When oily gels were used, the TL
skin concentration was
rapidly increased compared with the level obtained with suspensions. With
0.1% IOIN gel, a high
concentration of TL (ca. 160 microg/g) in the dermis was obtained and
continued until at least 48 h.
These results suggest that oily gels may be useful for the topical
application of TL. 

========================================================================
4.) Successful treatment of pemphigus vulgaris with prednisolone and
tranilast [letter]
Acta Derm Venereol 1997 Jan;77(1):87-8 (ISSN: 0001-5555)

Miyamoto H; Takahashi I [Find other articles with these Authors] 
========================================================================

========================================================================
5.) Solitary mastocytoma treated with tranilast.
========================================================================
J Dermatol 1996 May;23(5):335-9 (ISSN: 0385-2407)

Katoh N; Hirano S; Yasuno H [Find other articles with these Authors]

Department of Dermatology, Kyoto Prefectural University of Medicine, Japan.

Two infants with solitary mastocytoma were treated with 5 mg/kg/day of
tranilast
[N-(3',4'-dimethoxycinnamoyl)anthranilic acid], a mast cell stabilizing
compound extracted from
Nandina domestica. Tranilast was administered orally in three divided
doses. In one infant, a
topical corticosteroid was also applied in combination with the oral
tranilast. Patients experienced
symptomatic relief, and nodules resolved almost completely after eight
weeks of treatment.
Tranilast therapy was continued for six months. No relapses were observed
after discontinuation
of therapy. We speculated that tranilast not only inhibited mast cell
degranulation but also reduced
the number of mast cells. 

========================================================================
6.) Treatment of granuloma annulare with tranilast.
========================================================================
J Dermatol 1995 May;22(5):354-6 (ISSN: 0385-2407)

Yamada H; Ide A; Sugiura M; Kurihara S; Tajima S


Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Three cases of granuloma annulare which did not exhibit a self-limited
course were treated with
tranilast at the dose of 300 mg/daily. The treatment resulted in the
resolution of skin lesions within
three months of administration. Although spontaneous resolution is often
observed in granuloma
annulare, tranilast may provide an alternative therapy for the treatment of
cases resistant to
spontaneous healing. 

========================================================================
7.) A case of atypical localized scleroderma presenting with pseudoainhum:
treatment with tranilast, an anti-fibrotic agent [letter]
Acta Derm Venereol 1996 Mar;76(2):162 (ISSN: 0001-5555)

Tajima S; Suzuki Y; Inazumi T 
========================================================================
========================================================================
8.) Tranilast inhibits collagen synthesis in normal, scleroderma
and keloid fibroblasts at a late passage culture but not at an
early passage culture.
========================================================================
J Dermatol Sci 1995 Jan;9(1):45-7 (ISSN: 0923-1811)

Yamada H; Tajima S; Nishikawa T [Find other articles with these Authors]

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

We have previously reported that tranilast, an anti-allergic agent,
specifically suppresses collagen
synthesis in normal skin fibroblasts and to a greater extent in keloid
fibroblasts. We found in this
study that the specific suppression of collagen synthesis by tranilast was
limited to the fibroblasts
with a high passage number (passage 8-10). In normal skin fibroblasts with
a low passage number
(passage 1-2), tranilast exerted no significant effect on collagen
synthesis. This was also observed
with scleroderma and keloid fibroblasts. This result suggests that
inhibition of collagen by tranilast
will be dependent on in vitro cellular aging and that serial cell passages
result in the loss of the cell
phenotype resistant to tranilast effect. 


========================================================================
9.) Treatment of linear localized scleroderma with the anti-allergic drug,
tranilast.
========================================================================
Clin Exp Dermatol 1994 Sep;19(5):391-3 (ISSN: 0307-6938)

Taniguchi S; Yorifuji T; Hamada T 

Department of Dermatology, Osaka City University Medical School, Japan.

A 14-year-old boy with linear localized scleroderma had a dramatic
improvement in contractures
after treatment with N-(3',4'-dimethoxycinnamoyl) anthranilic acid
(tranilast, Rizaben). The
observation that this anti-allergic drug was effective in localized
scleroderma lends further support to
the concept that mast cells play a role in increased collagen synthesis in
this disease. 


========================================================================
10.) Treatment of cutaneous sarcoidosis with tranilast.
========================================================================
J Dermatol 1995 Feb;22(2):149-52 (ISSN: 0385-2407)

Yamada H; Ide A; Sugiura M; Tajima S


Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Tranilast is an anti-allergic drug clinically used for the treatment of
atopy or urticaria. The drug has
been shown to have an anti-fibrotic effect as well. We treated two
cutaneous sarcoidosis patients
with tranilast, resulting in remission within three months of
administration. This drug should be an
excellent tool for the treatment of other granulomatous diseases. 

========================================================================
11.) Tranilast antagonizes angiotensin II and inhibits its biological
effects in vascular smooth muscle cells. 
========================================================================
Author 
Miyazawa K; Fukuyama J; Misawa K; Hamano S; Ujiie A 
Address 
Pharmacological Laboratories, Kissei Pharmaceutical Co. Ltd., Hotaka,
Nagano 399-83,
Japan. 
Source 
Atherosclerosis, 121(2):167-73 1996 Apr 5 
Abstract 
Recent studies have been reported indicating that angiotensin II may
potentiate neointimal
formation. In the present study, we examined the antagonistic effect
of tranilast on
angiotensin II. Losartan was used as the reference compound. First,
tranilast inhibited the
angiotensin II-induced contraction of rabbit aortic strips in a
noncompetitive manner (pD'(2)
= 3.7), whereas it had little effect on the contraction induced by
noradrenaline or endothelin-l.
Second, tranilast inhibited the binding of (125)I-labeled angiotensin
II to angiotensin AT1
receptors in rat liver membranes with an IC(50) value of 289 mu M.
Finally, functional
antagonism of tranilast (100 and 300 mu M) was demonstrated by its
blockade of
angiotensin II (10(-8)M)-induced (45)Ca(2+) -efflux from human
vascular smooth muscle
cells (VSMC). However, tranilast (30-300 mu M) exerted no influence on
PDGF-induced
formation of inositol triphosphates which cause an increase in
[Ca(2+)]i in human VSMC.
The antagonistic activity of tranilast towards angiotensin II may be
involved in part in
preventing restenosis after percutaneous transluminal coronary
angioplasty (PTCA). 

========================================================================
12.) Inhibition of interferon-gamma and interleukin-2 production from
lymphocytes stimulated with food antigens by an anti-allergic drug,
Tranilast, in patients with food-sensitive atopic dermatitis.
========================================================================
Biotherapy 1994;8(1):19-22 (ISSN: 0921-299X)

Kondo N; Fukutomi O; Shinbara M; Orii T [Find other articles with these
Authors]

Department of Pediatrics, Gifu University School of Medicine, Japan.

N(3',4'-dimethoxycinnamoyl) anthranilic acid (Tranilast) inhibits
antibody-mediated
hypersensitivity reactions, and is an effective drug for patients with
bronchial asthma or allergic
rhinitis. Interferon-gamma (IFN-gamma) production of ovalbumin
(OA)-stimulated peripheral blood
mononuclear cells (PBMCs) from hen's egg-sensitive patients with atopic
dermatitis (AD) was
significantly higher than those of healthy controls. Tranilast inhibited
this IFN-gamma production.
Moreover, interleukin-2 (IL-2) production of OA-stimulated PBMCs from hen's
egg-sensitive
patients with AD was also inhibited by Tranilast. Our results suggest that
Tranilast can be used to
the patients with food sensitive AD. 

========================================================================
13.) In-vivo calibration of microdialysis probe by use of endogenous
glucose as an internal recovery marker: measurement of skin distribution of
tranilast in rats.
========================================================================
J Pharm Pharmacol 1998 Jun;50(6):621-6 (ISSN: 0022-3573)

Hashimoto Y; Murakami T; Kumasa C; Higashi Y; Yata N; Takano M [Find other
articles with
these Authors]

Institute of Pharmaceutical Sciences, Hiroshima University School of
Medicine, Japan.

To estimate the absolute concentration of substrates surrounding a
microdialysis probe in-vivo, we
developed a simple calibration method using endogenous glucose as an
internal recovery marker
and determined the skin distribution of tranilast
(N-(3,4-dimethoxy-cinnamoyl)anthranic acid), an
anti-allergic agent, in rats. This calibration method was based on the
assumption that the
concentration of glucose in the extracellular fluid of skin tissues is the
same as that in plasma and that
the in-vivo recovery ratio of glucose to tranilast by microdialysis is the
same as that estimated
in-vitro. Based on these assumptions, the dialysate concentrations of
tranilast and glucose
recovered from cutaneous microdialysis, glucose concentration in plasma,
and in-vitro recovery
ratio of tranilast to glucose by microdialysis were determined for the
estimation of absolute
unbound concentration of tranilast in the extracellular fluid of skin
tissues. In an in-vitro study
employing plasma containing tranilast, the unbound concentration of
tranilast in plasma estimated
from the dialysate concentration was just comparable with that determined
by ultrafiltration
methods. Also in an in-vivo study under steady-state plasma concentration
of tranilast in rats, the
estimated concentration of tranilast in the skin extracellular fluid was
the same level as the unbound
concentration of tranilast in plasma. Using the present calibration method,
the skin distribution of
tranilast administered into the intestinal loop or transdermally was
continuously monitored in a
quantitative manner. 

========================================================================
14.) Inhibitory effects of tranilast on expression of transforming growth
factor-beta isoforms and receptors in injured arteries. 
========================================================================
Atherosclerosis 1998 Apr;137(2):267-75 (ISSN: 0021-9150)

Ward MR; Sasahara T; Agrotis A; Dilley RJ; Jennings GL; Bobik A [Find other
articles with these
Authors]

Cell Biology Laboratory, Baker Medical Research Institute, Prahran, VIC,
Australia.
[email protected].

Tranilast (N(3,4-dimethoxycinnamoyl)anthranilic acid), an agent which in
cell culture inhibits
transforming growth factor-beta (TGF-beta) secretion and antagonises the
effects of TGF-beta and
platelet-derived growth factor (PDGF) on cell migration and proliferation,
has been reported to
reduce the incidence of restenosis after angioplasty in angiographically
validated human clinical trials.
We investigated in a rat model of balloon angioplasty whether tranilast's
effects in vivo could be
attributed to inhibition of expression of TGF-beta and/or its receptor
types. Using a standardised
reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we examined
the effects of three
doses of tranilast (25, 50 and 100 mg/kg) on the expression of two TGF-beta
isoforms, the types
I and II TGF-beta receptors and two putative TGF-beta responses, induction
of integrins alpha(v)
and beta3 mRNA, 2 h after oral administration and 26 h after vessel injury.
Tranilast attenuated in
a dose-dependent and reversible manner the injury-induced increases in mRNA
levels encoding
TGF-beta1, TGF-beta3, two type I TGF-beta receptors ALK-5 and ALK-2, and
the type II
receptor TbetaRII. At the highest dose mRNA levels encoding TGF-beta1 and
TbetaRII were
attenuated to levels approaching or below those observed in uninjured
vessels. Messenger RNAs
encoding TGF-beta3, ALK-5 and ALK-2 were all attenuated by between 70 and
74% (all P
0.05). Tranilast also attenuated in a reversible manner the elevations in
mRNA levels for integrins
alpha(v) and beta3 observed after vessel injury, by 90 and 72%,
respectively. We also investigated,
in cultured smooth muscle cells derived from injured carotid arteries, the
extent to which tranilast
(300 mg/l) attenuated any increases in expression of type I and type II
receptors stimulated by
PDGF-BB and TGF-beta1, growth factors implicated in smooth muscle cell
migration and
proliferation in injured vessels. Increases in mRNA levels of the type I
receptors ALK-5 and
ALK-2 induced by PDGF-BB and TGF-beta1 were almost completely prevented by
tranilast.
Tranilast also prevented the PDGF-BB induced increases in TbetaRII but only
partially inhibited
the TGF-beta1 induced upregulation of TbetaRII. We conclude that tranilast
can inhibit
transcriptional mechanisms associated with the upregulation of TGF-beta and
its receptor types in
balloon catheter injured vessels. It is possible that these mechanisms
contribute to its ability to
reduce the frequency of restenosis after angioplasty. 

========================================================================
15.) [Eosinophilic cystitis induced by tranilast: a case report]
========================================================================
Hinyokika Kiyo 1998 Jan;44(1):45-7 (ISSN: 0018-1994)

Sakai N; Yamada T; Murayama T [Find other articles with these Authors]

Department of Urology, Sagamihara National Hospital.

We report a patient with tranilast-induced eosinophilic cystitis who had no
allergies, but had been
administered tranilast to reduce prednisolone. A 62-year-old man presented
with macroscopic
hematuria and bladder irritative symptoms. The patient had a past medical
history of idiopathic
thrombocytopenic purpula and had been treated with 15 mg of prednisolone
since 1980. He had
been receiving 300 mg of tranilast for the past 18 months. Urinalysis
revealed a marked increase in
eosinophils (4 x 10(4)/ml). A cystoscopic examination revealed reddish
mucosa throughout the
bladder. A retrograde cystogram showed incomplete bilateral vesicoureteral
reflux. Histological
examinations of biopsied bladder specimens revealed a marked increase in
the number of
eosinophils (1,126/mm2), but not of mast cells (12/mm2). The symptoms
resolved within one week
after cessation of tranilast. 

========================================================================
16.) Inhibition by tranilast of vascular endothelial growth factor
(VEGF)/vascular permeability factor (VPF)-induced increase in vascular
permeability in rats.
========================================================================

Life Sci 1998;63(4):PL71-4 (ISSN: 0024-3205)

Isaji M; Miyata H; Ajisawa Y; Yoshimura N [Find other articles with these
Authors]

Discovery Research Laboratories, Kissei Pharmaceutical Co., Ltd.,
Minamiazumi, Nagano-Pref.,
Japan.

We studied the effects of tranilast, an anti-allergic and
anti-proliferative drug in clinical use, on
VEGF/VPF-induced vascular permeability in a rat air pouch model. A large
increase in vascular
permeability was induced by injection of 4 ml of a 100 ng/ml VEGF/VPF
solution into the
preformed air pouch. Over a 15-min period, tranilast inhibited the
VEGF/VPF-induced vascular
permeability in a dose-dependent manner. This result suggests that
tranilast, which we recently
found to inhibit VEGF/VPF-induced angiogenesis, could also improve
VEGF/VPF-dependent
increases in vascular permeability. 

========================================================================
17.) Tranilast inhibits the proliferation, chemotaxis and tube formation of
human microvascular endothelial cells in vitro and angiogenesis in vivo.
========================================================================
Br J Pharmacol 1997 Nov;122(6):1061-6 (ISSN: 0007-1188)

Isaji M; Miyata H; Ajisawa Y; Takehana Y; Yoshimura N [Find other articles
with these Authors]

Discovery Research, R & D, Kissei Pharmaceutical Co., Ltd, Nagano-Pref.,
Japan.

1. First developed as an antiallergic drug, tranilast inhibits chemical
mediator release from mast
cells. In the present study, we examine the effects of tranilast on
angiogenesis in vitro and in vivo
and discuss the application of tranilast for angiogenic diseases. 2.
Tranilast inhibited significantly
the proliferation (IC50: 136 microM, 95% confidence limits: 134-137 microM)
and vascular
endothelium growth factor (VEGF)-induced chemotaxis (IC50: 135 microM, 95%
confidence
limits: 124-147 microM) of human dermal microvascular endothelial cells
(HDMECs) at
concentrations greater than 25 micrograms ml-1. No toxicity to HDMECs
measuring by LDH
release and no inhibitory effects on metalloproteinase (MMP)-2 and MMP-9
activity were
observed even at 100 micrograms ml-1 (306 microM). 3. Tube formation of
HDMECs cultured on
the matrigel as an in vitro angiogenesis model was inhibited by tranilast in a
concentration-dependent manner. The IC50 value and 95% confidence limits
were 175 microM
and 151-204 microM, respectively. 4. In vivo angiogenesis was induced in
mice by the
subcutaneous injection of matrigel containing 30 ng ml-1 VEGF and 64
micrograms ml-1 heparin.
Tranilast was administered orally twice a day for 3 days. Tranilast
dose-dependently suppressed
angiogenesis in the matrigel and a significant change was observed at a
dose of 300 mg kg-1. 5.
These results indicate that tranilast is an angiogenesis inhibitor which
may be beneficial for the
improvement of angiogenic diseases such as proliferative diabetic
retinopathy, age-related macular
degeneration, tumour invasion and rheumatoid arthritis. 


========================================================================
18.) [The effect of tranilast on subepithelial corneal opacity after
excimer laser keratectomy]
========================================================================
Nippon Ganka Gakkai Zasshi 1997 Oct;101(10):783-7 (ISSN: 0029-0203)

Sakai T; Okamoto S; Iwaki Y [Find other articles with these Authors]

Second Department of Ophthalmology, Toho University School of Medicine,
Tokyo, Japan.

Recent studies have reported that tranilast inhibited in vitro the
proliferation of keratocytes from
corneal subepithelial opacities (haze) and collagen synthesis in cultured
corneas after excimer laser
photorefractive keratectomy (PRK). In this study 0.5% tranilast eye drops,
0.1% betametazone
phosphate eyedrops, and a 0.5% tranilast base solution (control) were
administered four times
daily to rabbits which had undergone PRK. Weekly evaluation of the
inhibitory effect of these drugs
on haze began two weeks after surgery according to Fantes' classification.
0.5% tranilast
suppressed haze from six weeks to thirteen weeks after PRK (p 0.05). 0.1%
betametazone
phosphate showed no effect. These results suggested that 0.5% tranilast had
a satisfactory
therapeutic effect on haze after PRK. 


========================================================================
19.) Effectiveness of tranilast on restenosis after directional coronary
atherectomy.
========================================================================
Am Heart J 1997 Oct;134(4):712-8 (ISSN: 0002-8703)

Kosuga K; Tamai H; Ueda K; Hsu YS; Ono S; Tanaka S; Doi T; Myou-UW;
Motohara S;
Uehata H [Find other articles with these Authors]

Department of Cardiology, Shiga Medical Center for Adult Diseases, Japan.

Tranilast is an antiallergic drug used widely in Japan that also inhibits
the migration and proliferation
of vascular smooth muscle cells. This pilot study was undertaken to
determine the effectiveness of
tranilast on restenosis after successful directional coronary atherectomy.
After the procedure, 40
patients (56 lesions, tranilast group) were treated with oral tranilast for
3 months, and 152
patients (188 lesions, control group) did not receive tranilast.
Angiographic and clinical variables
were compared between the two groups. The minimal lumen diameter was
significantly larger in the
tranilast group than in the control group at both 3-month (2.08 vs 1.75 mm,
p = 0.004) and
6-month follow-up (2.04 vs 1.70 mm, p = 0.003). The diameter stenosis in
the tranilast group was
smaller than that in the control group both 3 months (28% vs 40%, p =
0.0007) and 6 months
(30% vs 43%, p = 0.0001) after the procedure, with a lower restenosis rate
(percent diameter
stenosis or =50) in the tranilast group at 3 months (11 % vs 26%, p =
0.03). The number of
clinical events over the 12-month period after the procedure was
significantly reduced by tranilast
administration (p = 0.013). These findings suggest that the oral
administration of tranilast strongly
prevents restenosis after directional coronary atherectomy. 

========================================================================
20.) Inhibition of proliferation of MCF-7 breast cancer cells by a
blocker of Ca(2+)-permeable channel. Cell Calcium
========================================================================

1997 Aug;22(2):75-82 (ISSN: 0143-4160)
Nie L; Oishi Y; Doi I; Shibata H; Kojima I [Find other articles with these
Authors]

Department of Cell Biology, Gunma University, Maebashi, Japan.

In MCF-7 breast cancer cells, insulin-like growth factor-1 (IGF-1)
increased the
calcium-permeability of the cells by activating a voltage-independent
calcium-permeable channel.
IGF-1 also induced oscillatory elevation of cytoplasmic free calcium
concentration in these cells. An
anti-allergic compound, tranilast, reduced the calcium-permeability
augmented by IGF-1 in a
dose-dependent manner and blocked the oscillatory elevation of cytoplasmic
free calcium
concentration. Tranilast did not affect early intracellular signals
activated by IGF-1, including
receptor autophosphorylation, activations of Ras, mitogen-activated protein
kinase and
phosphatidylinositol 3-kinase. Tranilast inhibited increases in
[3H]-thymidine incorporation, DNA
content and cell number induced by IGF-1. The ID50 for [3H]-thymidine
incorporation and DNA
content were about 10 microM. The inhibitory effect of tranilast was
reversible, and cell viability
was not affected. Treatment with tranilast increased the number of cells in
the G1 phase suggesting
that this compound induced G1 arrest. Tranilast also reduced the
phosphorylation of the
retinoblastoma protein. These results indicate that tranilast inhibits the
IGF-1-induced cell growth
in MCF-7 cells by blocking calcium entry. 


========================================================================
21.) Effects of pemirolast and tranilast on intimal thickening after
arterial injury in the rat.
========================================================================
J Cardiovasc Pharmacol 1997 Aug;30(2):157-62 (ISSN: 0160-2446)

Miyazawa N; Umemura K; Kondo K; Nakashima M [Find other articles with these
Authors]

Department of Pharmacology, Hamamatsu University School of Medicine,
Handa-cho, Japan.

We previously reported that tranilast, an antiallergic agent, reduced
intimal thickening after
endothelial injury in rats. In this study, to verify whether or not
antiallergic agents inhibit intimal
thickening, we investigated the effect of pemirolast on intimal thickening
after endothelial injury and
compared its effect with that of tranilast. Administration of two
antiallergic agents, pemirolast (0.1,
1, and 10 mg/kg, p.o.) and tranilast (300 mg/kg, p.o., daily), was begun 2
days before endothelial
injury and continued until the animals were killed. Endothelial injury in
the rat femoral artery was
induced by a photochemical reaction between localized irradiation by green
light and intravenously
administered rose bengal. To evaluate intimal hyperplasia, we measured the
cross-sectional area of
the intima 21 days after endothelial damage. Pemirolast at doses of 0.1, 1,
and 10 mg/kg reduced
the intimal area to 2.10 +/- 0.33, 1.36 +/- 0.19, and 1.35 +/- 0.18 (x0.01
mm2), respectively, and
tranilast showed a tendency to reduce the intimal area, which was 1.86 +/-
0.35 x 0.01 mm2,
compared with findings for controls (2.83 +/- 0.49 x 0.01 mm2). In rat A10
vascular
smooth-muscle cells, we investigated the effects of antiallergic agents on
migration by using a
modified Boyden chamber assay and on proliferation by using the
bromodeoxyuridine-incorporation
assay. Two antiallergic agents inhibited in a concentration-dependent
manner both migration and
proliferation of smooth muscle cells stimulated by platelet-derived growth
factor. These results
suggest that antiallergic agents directly inhibit migration of
smooth-muscle cells to the intima from the
media and proliferation in the intima, and that pemirolast has more potent
antihyperplastic action
than does tranilast. Antiallergic agents may be effective in preventing
restenosis after coronary
angioplasty. 

========================================================================
22.) Effect of topical tranilast and corticosteroids on subepithelial
haze after photorefractive keratectomy in rabbits.
========================================================================
J Refract Surg 1997 Aug;13(5 Suppl):S457-8 (ISSN: 1081-597X)

Furukawa H; Nakayasu K; Gotoh T; Watanabe Y; Takano T; Ishikawa T; Kanai A
[Find other
articles with these Authors]

Kanai Juntendo University, Department of Ophthalmology, Tokyo, Japan.

BACKGROUND: Tranilast (trade name Rizaben), an anti-allergic drug with
anti-inflammatory
effects, is thought to inhibit synthesis of extracellular matrix of
fibroblasts through the suppression of
TGF-beta. We evaluated the effect of topical tranilast on the subepithelial
haze that developed
after excimer laser keratectomy and its effect was compared with that of
betamethasone eye drops
METHODS: Excimer laser keratectomy (phototherapeutic keratectomy mode) was
performed with
the Nidek EC-5000 excimer laser on 16 rabbit corneas (eight rabbits). From
the second
postoperative day, topical 2% tranilast was instilled in the right eye and
the control solution in the
left eye, four times daily. Until the fourth week after the operation, we
measured the densitometric
values of scattered light intensity of the subepithelial haze with an
anterior ocular analyzer,
EAS-1000 (Nidek). At the fifth postoperative week, light and electron
microscopy and
immunohistochemistry with an antibody to TGF-beta were also performed.
RESULTS:
Densitometric values of the subepithelial haze in the corneas treated with
2% tranilast were slightly
less than those of the subepithelial haze in the control corneas. However,
the values of the
subepithelial haze in the betamethasone-treated corneas were significantly
less than those in control
corneas. Histochemical examinations revealed that topical tranilast had a
small effect on the
subepithelial haze after excimer laser keratectomy in rabbits. CONCLUSION:
Topical 0.1%
betamethasone can limit the amount of subepithelial haze and tranilast may
inhibit development of
subepithelial haze by the suppression of TGF-beta. 

========================================================================
23.) Tranilast inhibits contraction of rat aortic smooth muscle.
========================================================================
Eur J Pharmacol 1997 Jun 18;329(1):43-8 (ISSN: 0014-2999)

Ihara T; Ikeda U; Ishibashi S; Shimada K [Find other articles with these
Authors]

Department of Cardiology, Jichi Medical School, Minamikawachi-Machi,
Tochigi, Japan.

Recently, the anti-allergic drug tranilast has been shown to reduce the
rate of coronary restenosis
after percutaneous transluminal coronary angioplasty. In this study, we
investigated the effect of
tranilast on contraction of and Ca2+ movement in vascular smooth muscle. We
measured the
isometric force and fura-2-estimated intracellular Ca2+ concentrations
([Ca2+]i) of rat aortic strips.
Exposure of aortic strips to tranilast (0-500 microM) dose-dependently
inhibited
endothelin-1-induced increases in tension and [Ca2+]i elevation of the
strips. Similar inhibition by
tranilast was observed in response to high K+ stimulation. These results
suggest that tranilast
inhibits the contraction of vascular smooth muscle by inhibiting Ca2+
mobilization, which might be
related to its preventive effect on coronary restenosis after percutaneous
transluminal coronary
angioplasty. 

========================================================================
24.) Suppressive effects of tranilast on the expression of inducible
cyclooxygenase (COX2) in interleukin-1beta-stimulated fibroblasts.
========================================================================
Biochem Pharmacol 1997 Jun 15;53(12):1941-4 (ISSN: 0006-2952)

Inoue H; Ohshima H; Kono H; Yamanaka M; Kubota T; Aihara M; Hiroi T; Yago
N; Ishida H
[Find other articles with these Authors]

Department of Plastic and Reconstructive Surgery, St. Marianna University
School of Medicine,
Miyamae, Kawasaki, Japan.

We investigated the effects of tranilast on inducible cyclooxygenase
(COX2)-mediated
prostaglandin E2 (PGE2) production and enzyme induction in interleukin-lbeta
(IL-1beta)-stimulated cultured dermal fibroblasts. IL-1beta enhanced PGE2
production in cultured
fibroblasts. Tranilast did not affect constitutive cyclooxygenase (COX1) or
COX2 activity in
non-stimulated or IL-lbeta-stimulated fibroblasts. However, the COX2
expression induced by
IL-1beta was inhibited by tranilast. This result, that IL-1beta-induced
COX2 expression was
suppressed by tranilast, was confirmed by immunohistochemical analysis.
Thus, it is possible for
tranilast to regulate PGE2 production by inhibiting COX2 induction. 

========================================================================
25.) Tranilast inhibits the growth of rat mesangial cells.
========================================================================
Eur J Pharmacol 1997 Apr 18;324(2-3):283-7 (ISSN: 0014-2999)

Ikeda M; Ikeda U; Shimada K; Fujita N; Okada K; Saito T; Minota S; Kano S
[Find other articles
with these Authors]

Department of Clinical Immunology, Jichi Medical School,
Minamikawachi-Machi, Tochigi, Japan.
[email protected].

We investigated the effects of tranilast on the growth of cultured rat
mesangial cells. The number of
mesangial cells increased fivefold during a 5-day incubation in RPMI 1640
with 20% fetal bovine
serum. The number of cells was significantly lower in the presence of
tranilast than in its abscence.
Tranilast (0 approximately 500 microM) inhibited platelet-derived growth
factor (PDGF)-induced
DNA synthesis of rat mesangial cells cultured in RPMI 1640 medium
containing 0.5% fetal bovine
serum in a dose-dependent manner. The inhibition of DNA synthesis by
tranilast was not affected
by the presence of indomethacin (1 microg/ml) or N(G)-monomethyl-L-arginine
(0.5 mM).
Tranilast did not stimulate nitrite oxide synthesis in PDGF-stimulated
cells. Mitogen-activated
protein kinase activity in mesangial cells was significantly increased by
exposure to PDGF, while the
effect was significantly suppressed in the presence of tranilast. The
present study revealed that
tranilast inhibits the growth of rat mesangial cells, independently of
nitric oxide or prostacycline
synthesis. 

========================================================================
26.) Tranilast inhibits contraction and Ca2+ movement of porcine
coronary arteries.
========================================================================
Atherosclerosis 1997 Apr;130(1-2):113-9 (ISSN: 0021-9150)

Ishibashi S; Ikeda U; Ihara T; Shimada K [Find other articles with these
Authors]

Department of Cardiology, Jichi Medical School, Tochigi, Japan.

In a recent clinical study, tranilast, an anti-allergic agent, was shown to
reduce the rate of coronary
restenosis after percutaneous transluminal coronary angioplasty, although
the mechanism of this
effect is unclear. The present study was undertaken to investigate the
effects of tranilast on
contraction and Ca2+ movement of the coronary arteries. We characterized
the effects of tranilast
on isometric force and aequorin-estimated intracellular Ca2+ concentrations
([Ca2+]i) of porcine
coronary artery strips. Tranilast concentration-dependently (10-500 microM)
inhibited histamine
(3 x 10(-5) M)-induced contraction of the coronary arteries. A similar
tendency was observed in
the response to high K+ (30 mM) stimulation. Histamine caused phasic and
tonic increases in
[Ca2+]i, and high K+ caused a tonic increase in [Ca2+]i of smooth muscle,
both of which were
significantly suppressed in the presence of tranilast. These results
suggest that tranilast inhibits the
contraction of coronary arteries by inhibiting both Ca2+ influx from
extracellular environment and
Ca2+ release from intracellular Ca2+ stores, which might be related to its
preventive effect on
restenosis after coronary angioplasty. 


========================================================================
27.) Tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) down-regulates
the growth of scirrhous gastric cancer.
========================================================================
Anticancer Res 1997 Mar-Apr;17(2A):895-900 (ISSN: 0250-7005)

Yashiro M; Chung YS; Sowa M [Find other articles with these Authors]

First Department of Surgery, Osaka City University Medical School, Japan.

BACKGROUND: Fibroblasts have been reported to play an important role in the
proliferation of
scirrhous gastric cancer cells. It would be an effective cancer therapy to
reduce the
cancer-stimulating activity of fibroblasts. The aim of the present
investigation was to define the
efficacy of Tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid), a drug
used clinically for the
treatment of excessive proliferation of fibroblasts, on the growth of
scirrhous gastric carcinoma both
in vitro and in vivo. Materials and Method: The human scirrhous gastric
cancer cell line,
OCUM-2M, and the human gastric fibroblasts, NF-8, were used. OCUM-2M cells
on the upper
well and NF-8 cells in the lower well were co-incubated with Tranilast at
the required
concentrations in vitro. The in vivo effect of Tranilast was examined by
measuring the size and the
apoptotic index of coinoculated tumor by OCUM-2M cells and NF-8 cells.
RESULTS: The
proliferation of OCUM-2M cells was significantly stimulated by co-culture
with NF-8 cells.
Tranilast significantly suppressed the proliferation of NF-8 cells and
subsequently decreased the
growth of OCUM-2M cells in vitro. Furthermore, Tranilast depressed gastric
carcinoma growth
and induced cancer cell apoptosis through its effect in blocking the
growth-interactions between
fibroblasts and scimbous gastric cancer cells in vivo. CONCLUSION:
Tranilast is a useful drug to
reduce the proliferation of scirrhous gastric carcinoma. 

========================================================================
28.) Inhibitory effect of tranilast on activation and transforming growth
factor beta 1 expression in cultured rat stellate cells.
========================================================================
Biochem Biophys Res Commun 1996 Oct 14;227(2):322-7 (ISSN: 0006-291X)

Ikeda H; Inao M; Fujiwara K [Find other articles with these Authors]

Department of Internal Medicine, Faculty of Medicine, University of Tokyo,
Japan.

Stellate cells, the primary extracellular matrix-producing cells in the
liver, undergo activation
characterized by fibrogenesis, proliferation and smooth muscle alpha-actin
expression, in hepatic
fibrosis or when cultured on plastic. TGF beta 1 is known to have a pivotal
role in fibrogenesis.
Tranilast, a drug used for allergic diseases with anti-inflammatory
effects, is known to inhibit
collagen synthesis by cultured fibroblasts. Thus, effects of tranilast on
activation and TGF beta 1
expression in stellate cells was investigated in vitro. Tranilast reduced
collagen synthesis in a
dose-related manner up to 50.8% of the control. This effect was reversible
after tranilast
withdrawal. The mobility of procollagen on gel electrophoresis and the
ratio of intracellular
procollagen to extracellular collagen concentrations were not affected by
tranilast. Tranilast
decreased DNA synthesis and increased smooth muscle alpha-actin expression.
mRNA
expressions of procollagen and TGF beta 1 were reduced by tranilast.
Tranilast with
anti-fibrogenic and anti-inflammatory actions merits consideration as a
candidate for therapeutic
agent of hepatic fibrosis. 

========================================================================
29.) Blockade of DNA synthesis induced by platelet-derived growth factor by
tranilast, an inhibitor of calcium entry, in vascular smooth muscle cells.
========================================================================
Mol Pharmacol 1996 Oct;50(4):763-9 (ISSN: 0026-895X)

Nie L; Mogami H; Kanzaki M; Shibata H; Kojima I [Find other articles with
these Authors]

Department of Cell Biology, Gunma University, Maebashi, Japan.

The present study was conducted to establish a pharmacological method of
controlling growth of
vascular smooth muscle cells (VSMC) by blocking calcium entry. In cultured
rat VSMC, 1 nM
platelet-derived growth factor (PDGF) induced a biphasic elevation of
cytoplasmic free calcium
concentration, ([Ca2+]c). The second sustained phase of [Ca2+]c was
dependent on extracellular
calcium. At lower concentrations, PDGF induced oscillatory changes in
[Ca2+]c, and reduction of
extracellular calcium attenuated the oscillation. An antiallergic compound,
tranilast, abolished the
sustained phase of [Ca2+]c induced by 1 nM PDGF. Tranilast also inhibited
the oscillatory
changes in [Ca2+]c induced by 200 pM PDGF. In addition, PDGF-induced
calcium influx in the
late G1 phase, as assessed by measuring the initial uptake of 45Ca, was
inhibited by tranilast in a
concentration-dependent manner. Tranilast also inhibited PDGF-augmented DNA
synthesis; the
ID50 for the inhibition of DNA synthesis was nearly identical to that for
calcium influx. Although
tranilast blocked PDGF-induced calcium entry, it did not affect PDGF-mediated
autophosphorylation of the PDGF receptor, activation of
phosphatidylinositol 3-kinase, activation of
Ras or mitogen-activated protein kinase. Similarly, PDGF-induced elevation
of diacylglycerol was
not affected by tranilast. These results suggest that the antiallergic drug
tranilast inhibits
PDGF-induced DNA synthesis by blocking PDGF-mediated calcium entry.
Tranilast may be of
use in controlling PDGF-induced DNA synthesis in VSMC. 


========================================================================
30.) Inhibition by tranilast of collagen accumulation in hypersensitive
granulomatous inflammation in vivo and of morphological changes and
functions of fibroblasts in vitro.
========================================================================
Life Sci 1994;55(15):PL287-92 (ISSN: 0024-3205)

Isaji M; Aruga N; Naito J; Miyata H [Find other articles with these Authors]

Central Research Laboratories, Kissei Pharmaceutical Co., Ltd.,
Nagano-pref., Japan.

We examined the effects of tranilast, an anti-allergic agent, on
hypersensitive inflammation and on
morphology and functions of fibroblasts. In vivo, tranilast suppressed the
content of collagen in
granulation tissue of hypersensitive granulomatous inflammation induced by
methylated bovine serum
albumin (m-BSA) in rats. In culture, tranilast inhibited the
TGF-beta-independent inflammatory
exudate-induced stimulation of morphological changes of fibroblasts to
myofibroblast-like cells and
their proliferation. Collagen gel contraction by myofibroblast-like cells
and fibroblasts was also
inhibited by tranilast. Flow cytometric analysis revealed that tranilast
suspended the cell cycle of
fibroblasts at the G0/G1 phase. These results suggest that tranilast
modulates the fibrosis and
contraction of granulation tissue by inhibiting the growth of
myofibroblast-like cells and fibroblasts. 

========================================================================
31.) Suppressive effects of tranilast on pulmonary fibrosis and activation
of alveolar
macrophages in mice treated with bleomycin: role of alveolar macrophages in
the fibrosis. 
========================================================================
Author 
Mori H; Tanaka H; Kawada K; Nagai H; Koda A 
Address 
Department of Pharmacology, Gifu Pharmaceutical University, Japan. 
Source 
Jpn J Pharmacol, 67(4):279-89 1995 Apr 
Abstract 
We have reported that tranilast, an anti-allergic drug that inhibits
chemical mediator release
from mast cells, suppresses bleomycin (BLM)-induced pulmonary fibrosis
in mice through
mechanisms other than inhibiting chemical mediator release from mast
cells. The purpose of
this paper is to examine the effect of tranilast on alveolar
macrophage (AM) activation and
on the development of fibrosis in ICR mice instilled with BLM
intratracheally. Twenty eight
days after the BLM instillation (0.01 mg/mouse), AM often migrated
into alveolar spaces
surrounding the fibrotic areas. Flow cytometry analysis for the size
and density of AM
(MAC-1 positive cells) suggested that AM were activated not only in
the earlier acute
inflammatory phase, but also in the later chronic phase. The p.o.
administration of tranilast
suppressed an increase of AM activity to produce reactive oxygen
species in BLM-instilled
mice, and it inhibited the subsequent development of pulmonary
fibrosis. In vitro treatment
with tranilast suppressed the reactive oxygen species production from
murine peritoneal
macrophages. However, several different anti-oxidants failed to
inhibit the development of
fibrosis. These results suggest that the activation of AM plays an
important role in the
development of fibrosis, and it is likely that tranilast suppresses
fibrosis by inhibiting AM
activation but not by scavenging reactive oxygen species. 
======================================================================
DATA-MEDICOS/DERMAGIC-EXPRESS No (30) 19/01/99 DR. JOSE LAPENTA R. 
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