EDITORIAL ESPANOL:

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Amigos dermatólogos, DERMAGIC de nuevo con ustedes. EL TRANILAST (Ácido antranílico) producto nuevo que esta siendo usado por los Japoneses, en numerosas patologías dermatológicas y no dermatológicas. Les traigo estas 31 referencias que ilustran las bondades del producto. Nombre comercial RIZABEN. 

Entre las enfermedades dermatológicas donde esta siendo usado figuran: queloides, cicatrices hipertróficas, esclerodermia localizada, pseudoainhum, sarcoidosis, mastocitoma, granuloma anular, pénfigo vulgar y dermatitis atópica.

 EDITORIAL ENGLISH:

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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. 

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DERMAGIC/EXPRESS(30)

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EL TRANILAST // THE TRANILAST 

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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. 

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1.) Treatment of keloid and hypertrophic scars by iontophoretic

transdermal delivery of tranilast.

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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. 

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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.

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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. 

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3.) In vitro release of tranilast from oily gels and penetration of the

drug into Yucatan micropig skin.

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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. 

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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] 

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5.) Solitary mastocytoma treated with tranilast.

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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. 

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6.) Treatment of granuloma annulare with tranilast.

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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. 

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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 

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8.) Tranilast inhibits collagen synthesis in normal, scleroderma

and keloid fibroblasts at a late passage culture but not at an

early passage culture.

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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. 

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9.) Treatment of linear localized scleroderma with the anti-allergic drug,

tranilast.

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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. 

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10.) Treatment of cutaneous sarcoidosis with tranilast.

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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. 

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11.) Tranilast antagonizes angiotensin II and inhibits its biological

effects in vascular smooth muscle cells. 

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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). 

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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.

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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. 

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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.

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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. 

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14.) Inhibitory effects of tranilast on expression of transforming growth

factor-beta isoforms and receptors in injured arteries. 

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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.

mward@baker.edu.au.

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. 

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15.) [Eosinophilic cystitis induced by tranilast: a case report]

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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. 

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16.) Inhibition by tranilast of vascular endothelial growth factor

(VEGF)/vascular permeability factor (VPF)-induced increase in vascular

permeability in rats.

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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. 

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17.) Tranilast inhibits the proliferation, chemotaxis and tube formation of

human microvascular endothelial cells in vitro and angiogenesis in vivo.

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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. 

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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. 

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19.) Effectiveness of tranilast on restenosis after directional coronary

atherectomy.

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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.

ikedam@cc.utsunomiya-u.ac.jp.

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-MÉDICOS/DERMAGIC-EXPRESS No (30) 19/01/99 DR. JOSE LAPENTA R. 

======================================================================

Produced by Dr. José Lapenta R. Dermatologist
Venezuela 1.998-2.024

Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.0024

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