tranilast and Keloid

Keloids and hypertrophic scars occur anywhere from 30 to 90% of patients, and are characterized by pathologically excessive dermal fibrosis and aberrant wound healing. Both entities have different clinical and histochemical characteristics, and unfortunately still represent a great challenge for clinicians due to lack of efficacious treatments. Current advances in molecular biology and genetics reveal new preventive and therapeutical options which represent a hope to manage this highly prevalent, chronic and disabling problem, with long-term beneficial outcomes and improvement of quality of life. While we wait for these translational clinical products to be marketed, however, it is imperative to know the basics of the currently existing wide array of strategies to deal with excessive scars: from the classical corticotherapy, to the most recent botulinum toxin and lasers. The main aim of this review paper is to offer a useful up-to-date guideline to prevent and treat keloids and hypertrophic scars.

Topics: Adjuvants, Immunologic; Adrenal Cortex Hormones; Aminoquinolines; Anti-Inflammatory Agents; Antineoplastic Agents; Bleomycin; Botulinum Toxins, Type A; Cicatrix, Hypertrophic; Cryotherapy; Disease Management; Fluorouracil; Humans; Imiquimod; Injections, Intralesional; Interferons; Keloid; Lasers, Dye; Low-Level Light Therapy; Neuromuscular Agents; ortho-Aminobenzoates

To report a case of bilateral idiopathic corneal keloid.. Retrospective review of clinical features, histopathological findings, clinical management, and outcome.. A 2-year-old boy with bilateral corneal keloid was treated with lamellar keratoplasty and tranilast eye drops. Peripheral localized white corneal nodules had been present bilaterally since the age of approximately 6 months in the absence of any history of trauma, inflammatory disease, or relevant family history. Pathological examination of the excised corneal buttons revealed myofibroblast proliferation (positive staining for α-smooth muscle actins), a haphazard arrangement of collagen bundles, and the absence of inflammatory cells. On the basis of these findings, a diagnosis of corneal keloid was assigned. The size of the corneal lesion in the right eye decreased in response to therapy with tranilast eye drops. Lamellar keratoplasty resulted in improved bilateral visual acuity, which was maintained at the 12-year follow-up.. This report describes a very rare case of bilateral corneal keloid in the absence of trauma or inflammation that was diagnosed by histological and immunohistochemical examination and electron microscopy. Good visual acuity was maintained over an extended period of postsurgery follow-up. Tranilast may represent a novel adjuvant therapy for corneal keloid.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Child, Preschool; Corneal Diseases; Corneal Transplantation; Follow-Up Studies; Humans; Keloid; Male; ortho-Aminobenzoates; Treatment Outcome

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.

Topics: Administration, Cutaneous; Administration, Oral; Adolescent; Adult; Aged; Animals; Child; Cicatrix; Female; Humans; Iontophoresis; Keloid; Male; Middle Aged; ortho-Aminobenzoates; Pain; Pruritus; Rats

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.

Topics: Anti-Allergic Agents; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Enzyme Induction; Fibroblasts; Humans; Immunohistochemistry; Interleukin-1; Isoenzymes; Keloid; Membrane Proteins; ortho-Aminobenzoates; Prostaglandin-Endoperoxide Synthases

Even after successful operations on children, unattractive postoperative scars are often distressing to patients and their parents. There are no reports about the factors affecting keloid or hypertrophic scar (HS) development after congenital cardiac surgery.. Postoperative scars were studied in 75 patients 3 months after congenital cardiac surgery by median skin incision. The mean age of the 51 males and 24 females was 2.7 +/- 2.3 years (range, 2 days-12 years). The scars were evaluated according to degree of redness, expressed as redness score, and skin blood flow, as measured by laser Doppler imaging. Skin blood flow ratio was calculated as blood flow at the scar divided by blood flow below the navel. After surgery, 40 patients received 5 mg/kg/day of tranilast, which inhibits the collagen synthesis of keloid fibroblasts.. None of the 75 patients had keloid formation and 21 (28%) developed HS after operation. Mean age of patients with HS (HS (+) group) was 4.4 +/- 3.3 years and that of patients with no HS development (HS (-) group) was 1.5 +/- 1.9 years (p < 0.01). There were no significant differences between these two groups in gender or in pre- or postoperative cyanosis. Hypertrophic scar (+) patients exhibited significantly higher skin blood flow ratios than HS (-) patients (2.7 +/- 1.3 versus 1.4 +/- 0.6; p < 0.001). Hypertrophic scar was seen in 11 of 40 tranilast administered patients (28%) and in 10 of 34 patients not receiving tranilast (29%) (NS). Hypertrophic scar was less apparent in the patients who received tranilast versus those who did not; redness scores were 29.5 +/- 16.5 and 51.6 +/- 14.9, respectively (p < 0.01).. These data suggest that age and skin blood flow ratio were the factors affecting HS development. Postoperative use of tranilast did not affect the frequency of HS development but did reduce its redness.

Topics: Age Factors; Anti-Inflammatory Agents, Non-Steroidal; Child; Child, Preschool; Cicatrix, Hypertrophic; Female; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Keloid; Male; ortho-Aminobenzoates; Risk Factors; Skin; Sternum; Treatment Outcome

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.

Topics: Cells, Cultured; Cellular Senescence; Collagen; Fibroblasts; Humans; Keloid; ortho-Aminobenzoates; Scleroderma, Localized

Effects of tranilast, N-(3,4-dimethoxycinnamoyl)anthranilic acid, on collagen synthesis in cultured human skin fibroblasts were studied. Tranilast was found to inhibit collagen synthesis in a dose-dependent manner to a maximum of 55% at 300 microM during 48 h of treatment; the synthesis of type I and type III collagens was equally affected. Administered simultaneously or subsequently, tranilast reduced the stimulatory effect of transforming growth factor beta 1 (2.5 ng/ml) on collagen synthesis without affecting the accompanying stimulation of noncollagen protein synthesis. It did not affect prolyl or lysyl hydroxylase activity in vitro and in cells. The content of pro alpha 1(I) collagen mRNA was decreased 60% by tranilast. Tranilast prevented the TGF beta 1-mediated increase in pro alpha 1(I) collagen mRNA. These results indicate that tranilast specifically inhibits collagen production at a pretranslational level by interfering with TGF beta 1 effects. Tranilast also inhibited collagen synthesis in scleroderma fibroblasts to the same extent and in keloid fibroblasts to a greater extent than in normal fibroblasts, attesting to its therapeutic potential as an antifibrotic drug.

Topics: Adolescent; Adult; Aged; Cells, Cultured; Collagen; Female; Fibroblasts; Histamine H1 Antagonists; Humans; Keloid; Male; Middle Aged; ortho-Aminobenzoates; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; Procollagen-Proline Dioxygenase; RNA, Messenger; Scleroderma, Localized; Skin

We studied the inhibitory effects of tranilast, an anti-allergic drug, on the human keloid tissues implanted into the dorsal skin of athymic nude mice and on the growth of keloid fibroblast in vitro. In the keloid tissue-implanted model, tranilast (50-200 mg/kg, p.o.) decreased the weight of the keloid tissue as triamcinolone (25 mg/kg, p.o.) did. Tranilast (200 mg/kg, p.o.) reduced the hydroxyproline content of implanted tissues. Tranilast (3-300 microM) also inhibited the collagen synthesis by keloid fibroblast in vitro. Only a high concentration of tranilast (300 microM) suppressed the glycosaminoglycan synthesis and cell proliferation of keloid fibroblasts. Moreover, tranilast scarcely affected the fibronectin production. Triamcinolone (10 microM) also inhibited glycosaminoglycan synthesis and cell proliferation. These results suggest that the inhibitory effect of tranilast on the keloid tissues is related to its inhibition of the collagen synthesis of fibroblasts. Tranilast would be useful as a therapeutic drug for the treatment of keloids.

Topics: Animals; Cell Division; Cells, Cultured; Collagen; Disease Models, Animal; Extracellular Matrix; Fibroblasts; Histamine H1 Antagonists; Humans; Hydroxyproline; Keloid; Male; Mice; Mice, Inbred BALB C; Mice, Nude; ortho-Aminobenzoates; Tissue Transplantation; Triamcinolone

We studied the effect of tranilast on the growth of carrageenin-induced granulation and the increase in capillary permeability induced by inflammatory agents in rats. In the carrageenin-induced granulation model, tranilast (50 or 100-200 mg/kg, p.o.) decreased significantly and dose-dependently the weight and the hydroxyproline content of the granulation tissue. Tranilast, however, showed no effect on the healing day of locally wounded dorsal skin of rats. Triamcinolone (10 mg/kg, p.o.) also showed an inhibitory effect on the carrageenin-induced granulation model. Tranilast (50-400 mg/kg, p.o.) dose-dependently inhibited the enhancement of capillary permeability induced by the Ca ionophore A23187, bradykinin and xanthine oxidase. Moreover, tranilast (30 and 300 microM) suppressed superoxide production induced by FMLP in human neutrophils, but did not act as a superoxide scavenger. Considering that hypertrophic scar and keloid are conditions characterized by abnormal cell proliferation and excessive collagen accumulation accompanied with itch and pain, these results suggest that tranilast is useful as a therapeutic drug for hypertrophic scars and keloids.

Topics: Adult; Animals; Capillary Permeability; Carrageenan; Cicatrix; Disease Models, Animal; Dose-Response Relationship, Drug; Granulation Tissue; Histamine H1 Antagonists; Humans; Keloid; Male; Neutrophils; ortho-Aminobenzoates; Rats; Rats, Inbred Strains; Superoxides

The clinical effects of tranilast, an antiallergic drug, become clear at 1 to 4 weeks after the start of drug treatment. In fundamental studies its absorption into blood is smooth and it is known to inhibit degranulation in mast cells promptly after administration. Thus tranilast's delayed onset of clinical effects has remained unknown. The author studied whether this could be caused by a delay in absorption of the drug into tissues. We examined the drug's concentrations in keloid tissues sampled from keloid patients of four groups. In each group the tranilast treatment was started 3 days, 2, 4, or 8 weeks before surgical operation of keloid. As a result there were no significant differences noted between or among each group in view of the drug's tissue concentrations. This suggests that the reason of such delayed onset of clinical effects in tranilast treatment is not the slow elevation in its tissue concentration as has been thought of.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Humans; Keloid; Male; Middle Aged; ortho-Aminobenzoates; Skin; Time Factors