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Transient receptor potential (TRP) channels are Ca 2+ permeable non-selective cation channels which play a pivotal role in diabetes and diabetic complications. Among diabetic complications, diabetes-induced cognitive impairment is a major CNS complication. The role of several TRP channels has been investigated extensively for their diverse Ca 2+ regulating mechanism, and recently their role has been postulated in the progression of neurodegenerative disorders. However, the role of TRPV2 has not been investigated yet. Therefore, in the present study, the involvement of TRPV2 channels was investigated in diabetes-induced cognitive impairment using TRPV2 inhibitor, tranilast. High glucose exposure in rat C6 glial cells enhances the Ca 2+ -entry through TRPV2 channels. In our in-vivo study, diabetic rats showed increased gene and protein expression of TRPV2 in the hippocampus. Subsequent increase in the acetylcholinesterase activity in the cortex, as well as decrease in the phosphorylation of Ca 2+ /calmodulin-dependent protein kinase II (p-CaMKII-Thr-286), p-GSK-3β (Ser-9), p-CREB (Ser-133) and postsynaptic density protein 95 (PSD-95) in the hippocampus were also observed this led to the impairment in the learning and memory as evident from behavioral parameters such as Morris water maze test, passive avoidance and Y-maze test paradigm. Three-week treatment with tranilast (30 and 100 mg/kg, p.o.) showed improvement in learning and memory associated behaviours (Morris water maze test, passive avoidance, and Y-maze test) by increasing the p-CaMKII (Thr-286), p-GSK-3β (Ser-9), p-CREB (Ser-133) and PSD-95 in the hippocampus. Cortical acetylcholinesterase activity was also reduced by the tranilast. These findings depicted that TRPV2 inhibition may be an effective treatment strategy in diabetes-induced cognitive deficits., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background/aim: Transforming growth factor β1 (TGF-β1) is an important epithelial-mesenchymal transition (EMT) activator that regulates the expression of E-cadherin and vimentin through Smad signalling. Tranilast is an anti-allergic drug that inhibits TGF-β1, and is used in the treatment of keloids and hypertrophic scars. We investigated whether tranilast inhibits TGF-β1-induced EMT and invasiveness in human non-small cell lung cancer cell lines., Materials and Methods: We examined the effects of tranilast treatment on EMT markers, TGF-β1/Smad signalling, and cell invasiveness in A549 and PC14 cells. Tumours from a mouse orthotopic lung cancer model with or without tranilast treatment were also immunohistochemically evaluated., Results: Tranilast increased E-cadherin expression via Smad4 suppression and inhibited cell invasion in TGF-β1-stimulated cells. Tranilast treatment of the in vivo mouse model reduced the pleural dissemination of cancer cells and suppressed vimentin and Smad4 expression., Conclusion: Tranilast inhibited TGF-β1-induced EMT and cellular invasion/metastasis by suppressing Smad4 expression in cancer cells., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

TGFβ signaling plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial-mesenchymal transition. As a conventional nonsteroidal anti-inflammation drugs, tolfenamic acid (TA) has been previously reported to exhibit anti-cancer activity. Herein, we investigated the effect of TA on TGFβ-mediated pro-metastatic activity and the underlying mechanisms in hepatocellular carcinoma (HCC). As a result, TA suppresses TGFβ-induced migration and glycolysis in HCC cells, which is accompanied with reduced Smad phosphorylation and subsequent nuclear transcription activity. Mechanistically, TA promotes lipid raft-caveolar internalization pathway of TGFβ receptor, therefore leading to its rapid turnover. Consistently, TA inhibits constitutively active TGFβ type I receptor induced Smad phosphorylation and EMT markers, whereas ectopic expression of TGFβ type II receptor could partially rescue TGFβ-mediated Smad2 phosphorylation and downstream genes expression in the presence of TA. Furthermore, TA inhibited HCC cells invasion in nude mice, associated with the alteration of characteristics related with EMT and glycolysis of cancer cells. Our study suggests TA could activate lipid raft pathway and modulate TGFβ mediated metastasis, implicating the potential application of TA as a modulator of tumor microenvironment in HCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Renal interstitial fibrosis is a final pathway that is observed in various types of kidney diseases, including diabetic kidney disease (DKD). The present study investigated the effect of tranilast on renal interstitial fibrosis and the association between its role and mast cell infiltration in a rat model of DKD. A total of 30 healthy 6‑week‑old male Sprague‑Dawley rats were randomly divided into the following four groups: Normal control group; DKD model group; low‑dose tranilast group (200 mg/kg/day); and high‑dose tranilast group (400 mg/kg/day). The morphological alterations of tubulointerstitial fibrosis were evaluated by Masson's trichrome staining, while mast cell infiltration into the renal tubular interstitium was measured by toluidine blue staining and complement C3a receptor 1 (C3aR) immunohistochemical staining (IHC). The expression of fibronectin (FN), collagen I (Col‑I), stem cell factor (SCF) and proto‑oncogene c‑kit (c‑kit) was detected by IHC, western blotting and reverse transcription‑quantitative‑polymerase chain reaction. The results demonstrated that tubulointerstitial fibrosis and mast cell infiltration were observed in DKD model rats, and this was improved dose‑dependently in the tranilast treatment groups. The expression of FN, Col‑I, SCF and c‑kit mRNA and protein was upregulated in the tubulointerstitium of DKD model rats compared with the normal control rats, and tranilast inhibited the upregulated expression of these markers. Furthermore, the degree of SCF and c‑kit expression demonstrated a significant positive correlation with C3aR‑positive mast cells and the markers of renal interstitial fibrosis. The results of the present study indicate that mast cell infiltration may promote renal interstitial fibrosis via the SCF/c‑kit signaling pathway. Tranilast may prevent renal interstitial fibrosis through inhibition of mast cell infiltration mediated through the SCF/c-kit signaling pathway.

Tolfenamic acid is one of the fenamic acid-derived non-steroid anti-inflammatory drugs (NSAIDs) and has been shown to exhibit anti-cancer activities in several types of cancer. Both mutations and aberrant expression of β-catenin are highly associated with progression of cancer. Therefore, β-catenin is considered to be a promising molecular target for cancer prevention and treatment. The current study investigates the role of tolfenamic acid on β-catenin expression in colon cancer. Treatment with tolfenamic acid led to inhibition of cell growth and down-regulation of β-catenin expression in a dose- and time-dependent manner in human colon cancer cell lines. Reduction of β-catenin upon tolfenamic acid treatment was associated with ubiquitin-mediated proteasomal degradation, without affecting mRNA level and promoter activity of β-catenin. In addition, treatment with tolfenamic acid downregulated Smad2 and Smad3 expression, while overexpression of Smad2, but not Smad3, blocked tolfenamic acid-induced suppression of β-catenin expression. Tolfenamic acid also decreased expression of β-catenin target genes, including vascular endothelial growth factor (VEGF). Compared to adjacent normal tissue, intestinal tumor tissues of Apc(Min/+) mice exhibited increased expression of β-catenin, Smad2, Smad3, and VEGF, which were down-regulated with tolfenamic acid treatment at a dose of 50mg/kg body weight. In conclusion, our findings suggest that tolfenamic acid inhibits growth of colon cancer cells through downregulation of Smad2 and, subsequently, facilitating ubiquitin-proteasome-mediated β-catenin degradation in colon cancer., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, is known to exhibit antitumor effects in various cancers apart from nasopharyngeal cancer (NPC). NPC exhibits high invasiveness, as well as metastatic potential, and patients continue to suffer from residual, recurrent, or metastatic disease even after chemoradiation therapy. Therefore, new treatment strategies are needed for NPC. In this study, we investigated the efficacy and molecular mechanisms of TA in NPC treatment., Materials and Methods: TA-induced cell death was detected by cell viability assay in the NPC cell lines, HNE1 and HONE1. Wound healing assay, invasion assay, and Western blot analysis were used to evaluate the antitumor effects of TA in NPC cell lines., Results: Treatment with TA suppressed the migration and invasion of HNE1 and HONE1 cells. Hepatocyte growth factor enhanced the proliferation, migration, and invasion abilities of NPC cells. This enhancement was successfully inhibited by TA treatment. Treatment with TA increased phosphorylation of p38, and the inhibition of p38 with SB203580 reversed the cytotoxic, anti-invasive, and anti-migratory effects of TA treatment in NPC cell lines. Moreover, inhibition of p38 also reversed the decrease in expression of Slug that was induced by TA treatment., Conclusion: In conclusion, the activation of p38 plays a role in mediating TA-induced cytotoxicity and inhibition of invasion and migration via down-regulation of Slug.

We propose the acute, local suppression of transforming growth factor beta (TGF-ß), a major profibrotic cytokine, to reduce fibrosis around silicone implants. To this end, we prepared silicone implants that were able to release tranilast, a TGF-ß inhibitor, in a sustained manner for 5 days or 15 days. We performed histologic and immunohistochemical analyses for 12 weeks after the implantation of the implants in living rats. The capsule thicknesses and collagen densities significantly decreased compared with those around the non-treated silicone implants. Notably, early suppression of TGF-ß affected the fibrogenesis that actually occurs at the late stage of wound healing. This change may be ascribed to the decrease in monocyte recruitment mediated by early TGF-ß during the acute inflammatory reaction. Thus, a significant decrease in differentiated macrophages was observed along with a decrease in the quantity of TGF-ß and fibroblasts during the subsequent inflammation stage; these changes led to a diminished fibrotic capsule formation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We have previously reported that tolfenamic acid treatment decreases the amyloidogenic proteins in C57BL/6 and in old hemizygous R1.40 transgenic mice via the degradation of the transcription factor specificity 1 protein (Sp1). The lowering of amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in hemizygous R1.40 transgenic mice was accompanied by reversal of the identified spatial reference and working memory deficits observed in the mouse model. In this study, we examined the ability of tolfenamic acid to reduce the amyloid plaque burden, as well as to ameliorate spatial learning and memory deficits in homozygous R1.40 mice. Results from immunohistochemical analysis indicated that tolfenamic acid treatment resulted in a profound decrease in cerebral Aβ plaque burden that was accompanied by improvements in spatial working memory assessed by spontaneous alternation ratio in the Y-maze. These results provide further evidence that tolfenamic acid could be utilized as a repurposed drug to modify Alzheimer's disease pathogenesis.

Purpose: The purpose of this study was to determine the effect of a synthetic tryptophan metabolite, tranilast [N-(3,4-dimethoxycinnamoyl)-anthranilic acid], on inflammatory and hemorrhagic areas after pulmonary radiofrequency ablation (RFA) in rabbits., Materials and Methods: Percutaneous RFA using a 17-gauge LeVeen electrode was performed in normal rabbit lungs. The rabbits were divided into tranilast-treated (300 mg/kg/day, orally) and control groups (n = 24/group). The effects of tranilast were evaluated using multidetector-row computed tomography (CT), histology, and immunohistochemistry immediately after RFA on days 1, 7, 14, and 28., Results: Oral administration of tranilast significantly reduced the size of ablated lesions assessed using CT and histology on days 7 and 14. Furthermore, it reduced the hemorrhagic areas on day 7 and inflammatory areas on day 14, but did not affect the areas of coagulation necrosis on days 1, 7, 14, and 28. Immunohistochemical analysis showed an increase in the ratio of CD163-positive macrophage areas to rabbit macrophage (RAM11)-positive pan-macrophage areas and a decrease in the number of nuclear factor-κB-positive nuclei and CD31-positive microvessels in the tranilast group on days 7 and/or 14., Conclusions: The results suggest that tranilast modulates the repair process after pulmonary RFA through macrophage accumulation, suppression of inflammation, and angiogenesis.

Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) that inhibits lung, esophageal, breast and pancreatic cancer cell and tumor growth, and this study investigated the anticancer activity of TA in colon cancer. TA inhibited growth and induced apoptosis in RKO, SW480, HT-29, and HCT-116 colon cancer cells, and TA (50 mg/kg/d) also inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. TA downregulated expression of Sp proteins (Sp1, Sp3, and Sp4) in colon cancer cells and this was accompanied by decreased expression of several Sp-regulated growth promoting (cyclin D1, hepatocyte growth factor receptor), angiogenic (vascular endothelial growth factor (VEGF) and its receptor 1), survival (survivin and bcl-2), and inflammatory (NFκBp65/p50) gene products. The mechanism of TA-mediated effects on Sp proteins was due to activation of caspases. These results now extend the number of NSAIDs that may have clinical potential for colon cancer chemotherapy and show that the anticancer activity of TA is due, in part, to targeting Sp transcription factors., (© 2013 Wiley Periodicals, Inc.)

Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5-50 μg/ml), and cell viability was measured at 1-3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 μg/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c-PARP), and survivin was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ~40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin.

Small intestinal tuberculosis is a rare disorder of the small intestine. We report the development of deep small bowel tuberculosis in a rheumatoid arthritis patient who was taking methotrexate. The diagnosis of small bowel tuberculosis was ascertained by typical endoscopic findings and production of interferon gamma in the peripheral blood. The patient was successfully treated with antituberculous chemotherapy combined with an antifibrotic agent, tranilast, to suppress the progression of intestinal stenosis toward symptomatic stricture., (© 2012 The Authors. Digestive Endoscopy © 2012 Japan Gastroenterological Endoscopy Society.)

Background: Tranilast has been shown to inhibit TGFβ1-related fibrosis and organ failure in various disease models. We sought to examine the effects of tranilast on left ventricular (LV) remodelling post-MI., Methods: Following coronary artery ligation, Sprague Dawley rats were randomised to receive tranilast (300mg/kg/d, p.o.) or vehicle control over one of two treatment periods: (1) from 24h until seven days post-MI, (2) from seven days to 28 days post-MI. Cardiac tissue was harvested for molecular, immunohistochemical and cell culture analyses., Results: Tranilast treatment of MI rats from 24h until seven days post-MI reduced myocardial collagen content, α1 (I) procollagen, TGFβ1 and CTGF mRNA transcripts, monocyte/macrophage infiltration and exacerbated infarct expansion compared with vehicle-treatment. Delaying the commencement of tranilast treatment to seven days post-MI attenuated myocardial fibrosis, gene expression of α1(I) procollagen, α1(III) procollagen, fibronectin, TGFβ1 and CTGF mRNA transcripts, and monocyte/macrophage infiltration at 28d compared to vehicle-treatment, without detriment to infarct healing. Extended post-MI also preserved LV infarct size. In cultures of rat cardiac fibroblasts, tranilast attenuated TGFβ1-stimulated fibrogenesis., Conclusion: Tranilast inhibits myocardial TGFβ1 expression, fibrosis in rat post-MI and collagen production in cardiac fibroblasts. While tranilast intervention from 24h post-MI exacerbated infarct expansion, delaying the commencement of treatment to seven days post-MI impeded LV remodelling., (Copyright © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Tranilast (TL), an antiallergic agent, has been clinically used in the treatment of bronchial asthma, although the clinical use of TL is limited because of its poor solubility and systemic side effects. To overcome these drawbacks, a novel respirable powder (RP) of TL for inhalation therapy was developed using nanocrystal solid dispersion of TL (CSD/TL). In the CSD/TL, wet-milled crystalline TL particles with a mean diameter of 122 nm were dispersed, and there was a marked improvement in dissolution behavior of the CSD/TL-RP compared with that of a physical mixture of TL and carrier. Laser diffraction and cascade impactor analyses on the CSD/TL-RP demonstrated high dispersibility and deposition in the respiratory organs with emitted dose and fine particle fraction of ca. 98 and 60%, respectively. Inhaled CSD/TL-RP could attenuate antigen-induced inflammatory events in rats, as evidenced by histochemical analyses and inflammatory biomarkers such as lactate dehydrogenase, eosinophil peroxidase, and myeloperoxidase. The CSD/TL-RP seemed to be more potent than the physical mixture in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Systemic exposure of TL after intratracheal administration of CSD/TL-RP at a pharmacologically effective dose (100 μg of TL/rat) was found to be fivefold less than that of the oral TL dosage form at clinical dose (1.67 mg/kg). Given the improved pharmacodynamics and lower systemic TL concentration, the inhalable TL formulation might provide an interesting alternative to oral therapy with a better safety margin for the treatment of asthma and other airway inflammatory diseases., (Copyright © 2010 Wiley-Liss, Inc.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used for the treatment of acute or chronic conditions with pain and inflammation. Evidence from a wide range of sources suggested that chronic administration of NSAIDs reduced the risk of cancer incidences. Both the epidemiological and animal studies showed an inverse association between the incidence of various cancers and the use of aspirin or other NSAIDs. The chemopreventive and therapeutic interventions of NSAIDs in cancer are obvious; however, the instigation of drug and treatment period depends on the study objective. Typically, prevention involves initiating the medication before the appearance of clinical symptoms and lasts long-term; while treatment could be short-term and contingent to the response of patient to the medication. Recent studies from our laboratories provided substantial evidence on the anti-cancer activity of tolfenamic acid, a NSAID for the potential applications in pancreatic, esophageal and lung cancers. In this review, we provide a summary on the potential benefits of NSAIDs in a variety of human cancers with more emphasis on tolfenamic acid.

Unlabelled: Our aim was to explore the effects of the anti-allergic and antifibrotic agent tranilast on chronic cyclosporine (CsA) nephrotoxicity in rats., Methods: Eighteen Sprague-Dawley rats were randomized to be given the following daily treatments by gavage for 4 weeks: (1) controls, olive oil; (2) CsA group, CsA 25 mg/kg; (3) CsA plus tranilast group, CsA 25 mg/kg and tranilast 400 mg/kg. We examined the body weights and the effects of tranilast on histopathology, macrophage (Mvarphi) infiltration, and expression of osteopontin (OPN)., Results: The administration of tranilast improved body weight gain by CsA-treated rats (232 +/- 24 vs 203 +/- 6 g; P < .05). This treatment reduced the expression of OPN protein and infiltration of macrophages (9.14 +/- 2.7 vs 22.44 +/- 5.68 ED-1 positive cells per high power field, P < .05). Furthermore compared with the CsA alone group, it ameliorated tubulointerstitial fibrosis scores (1.18 +/- 0.08 vs 2.57 +/- 0.21, P < .05)., Conclusion: Tranilast attenuated tubulointerstitial fibrosis through decreased expression of OPN protein and macrophage infiltration, showing renal protective effects in rats with chronic CsA nephrotoxicity.

Tolfenamic acid (TA) is a nonsteroidal anti-inflammatory drug that inhibits pancreatic cancer cell and tumor growth through decreasing expression of specificity protein (Sp) transcription factors. TA also inhibits growth of erbB2-overexpressing BT474 and SKBR3 breast cancer cells; however, in contrast to pancreatic cancer cells, TA induced down-regulation of erbB2 but not Sp proteins. TA-induced erbB2 down-regulation was accompanied by decreased erbB2-dependent kinase activities, induction of p27, and decreased expression of cyclin D1. TA also decreased erbB2 mRNA expression and promoter activity, and this was due to decreased mRNA stability in BT474 cells and, in both cell lines, TA decreased expression of the YY1 and AP-2 transcription factors required for basal erbB2 expression. In addition, TA also inhibited tumor growth in athymic nude mice in which BT474 cells were injected into the mammary fat pad. TA represents a novel and promising new anticancer drug that targets erbB2 by decreasing transcription of this oncogene.

Aim: To assess the welfare impact of lameness on dairy cattle in New Zealand by measuring the duration of allodynia (decreased nociceptive threshold) and increased locomotion score, and to evaluate the influence of treatment on that duration., Methods: After lame cows were treated using corrective paring by a veterinarian, they were allocated to one of six treatment groups. If the veterinarian determined that additional elevation of the lesion was not required the cow was randomly allocated to receive one of four treatments, viz 2 mg/kg tolfenamic acid, a plastic shoe to elevate the lesion, both treatments, or no further treatment. Cows that required additional elevation were treated using a plastic shoe and then randomly allocated to two separate treatment groups, either 2 mg/kg tolfenamic acid or no further treatment. Assessments of locomotion score (based on posture and gait) and mechanical nociceptive threshold (using a pneumatically actuated blunt pin) were made prior to treatment, and 3, 8, 28 and 100 days later., Results: Data were collected from 149 lame cows from nine dairy farms. There were significant improvements in mean locomotion score and nociceptive threshold in all treatment groups. At all time-points after treatment, locomotion score and nociceptive threshold were significantly improved when compared with the previous time-point. Thus, in these cows, the deleterious effects of lameness persisted for longer than 28 days, despite treatment, as the mean locomotion scores and nociceptive threshold on Day 100 were better than those on Day 28. No significant long-term benefit of using tolfenamic acid at the time of treatment was observed on either locomotion score or nociceptive threshold, nor was there any benefit in using a plastic shoe in cases where it had been determined that such treatment was not necessary., Conclusions: This study demonstrated that the welfare impact of lameness on dairy cattle in New Zealand is of long duration even when treated effectively. In contrast to previous studies, no significant long-term benefit of using non-steroidal anti-inflammatory drugs (NSAID) at the time of treatment was observed, probably because unlike those previous studies the nociceptive threshold improved in the cattle which did not receive an NSAID, perhaps because treated cattle were kept on pasture rather than housed., Clinical Relevance: The long duration of increased allodynia after treatment demonstrates that prevention of lameness rather than therapeutic treatment is the key to reducing its impact on the welfare of dairy cows.

Objectives: The degradation of tryptophan by indoleamine 2,3-dioxygenase yields a number of immunomodulatory metabolites, including 3-hydroxyanthranilic acid, 3-hydroxykynurenic acid and quinolinic acid. N-(3',4'-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is a synthetic anthranilic acid derivative that has been used therapeutically in Japan for many years as an anti-allergic drug and has recently been shown to be effective in a murine model of multiple sclerosis., Methods: In the present study, we tested the efficacy of 3,4-DAA in collagen-induced arthritis, a mouse model of rheumatoid arthritis, and analysed its mechanism of action., Results: Administration of 3,4-DAA after arthritis onset reduced clinical and histological severity of arthritis and reduced pain. It completely abrogated thermal and mechanical hyperalgesia. 3,4-DAA also suppressed Th1 cell activity in lymph node cell cultures and raised serum levels of IL-10. In vitro, 3,4-DAA suppressed IFNgamma production and proliferation of both T and B lymphocytes in a manner comparable with the endogenous tryptophan metabolite, 3-hydroxyanthranilic acid, suggesting similar mechanisms of action., Conclusion: It is concluded that 3,4-DAA has both anti-inflammatory and analgesic properties, and may therefore be useful in filling an unmet need, in the treatment of rheumatoid and other forms of arthritis, especially in the light of its analgesic properties.

Peritoneal fibrosis (PF) is invariably observed in patients undergoing long-term peritoneal dialysis (PD). The condition is thought to occur in response to a variety of insults, including bioincompatible dialysates (acidic solution, high glucose, glucose degradation products, or a combination), peritonitis, uremia, and chronic inflammation. Recently, the pathophysiologic mechanisms that contribute to the fibrosing process have been intensively studied. Transforming growth factor-beta has been shown to be a key mediator of PF. Loss of the mesothelial cell layer has been identified in several studies and shown to correlate with submesothelial thickening and vasculopathy. An association has also been identified between increased submesothelial thickness in the peritoneal membrane and increased solute transport, suggesting a relationship between PF and loss of ultrafiltration capacity. Thus, to maintain long-term PD and improve quality of life for patients, it is important to develop interventions for prevention and treatment of PF. Several strategies for peritoneal fibrosis intervention have been reported, including developing biocompatible dialysate, targeting mediators responsible for inflammation and fibrosis, and reconstituting the peritoneum using mesothelial or bone marrow-derived cells. Recent experimental trials in animal models and clinical studies are presented in this review.

Unlabelled: Many cardiologists consider it reasonable to assume in clinical practice that percutaneous coronary intervention using drug-eluting stents ought to be considered equivalent, if not superior, to bypass surgery. In the absence of a definitive clinical trial to support this view, how should the prudent, cutting-edge cardiologist proceed?, Objectives: This study assessed the geographical differences in target vessel revascularization (TVR) after percutaneous coronary intervention (PCI) in the Prevention of Restenosis With Tranilast and its Outcomes (PRESTO) trial., Background: An aggressive approach to PCI is more common in the U.S. than in other countries. The impact of this approach on restenosis outcomes has not been studied., Methods: Using the PRESTO trial, we compared nine-month ischemic TVR after PCI in U.S.-treated patients (n = 5,026) with rates in other countries (n = 6,458). We defined TVR as repeat intervention for chest pain/positive stress test. Additionally, angiographic restenosis (> or =50% narrowing or > or =50% loss of gain at nine-month follow-up) was compared between U.S. and non-U.S. patients within the prespecified angiographic subset (n = 2,823). Regression models were developed to adjust for clinical and lesion-related characteristics., Results: Higher rates of TVR (18% vs. 11%), and angiographic restenosis (65% vs. 48%) were observed in patients treated in the U.S. as compared with the other patients (p < 0.01 for both comparisons). Patients treated in the U.S. were more likely to be female, diabetic, not currently smoking, to have unstable angina, and to have a prior PCI. In U.S. patients, lesions tended to be longer, but less likely to be American College of Cardiology/American Heart Association class C. After adjusting for clinical and angiographic variables, PCI in the U.S. was still associated with increased angiographic restenosis and ischemic TVR., Conclusions: Angiographic restenosis and ischemia-driven TVR rates were higher in patients treated in the U.S. The difference could only partially be explained by the higher prevalence of measured adverse clinical and angiographic features.

Local catabolism of the amino acid tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. We show that IDO transcription was increased when myelin-specific T cells were stimulated with tolerogenic altered self-peptides. Catabolites of Trp suppressed proliferation of myelin-specific T cells and inhibited production of proinflammatory T helper-1 (T(H)1) cytokines. N-(3,4,-Dimethoxycinnamoyl) anthranilic acid (3,4-DAA), an orally active synthetic derivative of the Trp metabolite anthranilic acid, reversed paralysis in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Trp catabolites and their derivatives offer a new strategy for treating T(H)1-mediated autoimmune diseases such as MS.

New derivatives related to floctafenine were synthesized and representative examples were screened for their anti-inflammatory and analgesic activities. All compounds tested were found to exhibit anti-inflammatory and analgesic activities and some were more potent than the references, floctafenine and indomethacin, in carragenan-induced rat's paw edema. None of the tested compounds showed an ulcerogenic effect on the p-benzoquinone-induced writhing test in mice.

Oxidative stress and inflammatory cytokines such as monocyte chemoattractant protein 1 (MCP-1), TGF-beta, and IL-2 are supposed to play crucial roles in the pathogenesis of insulin resistance (IR). Tranilast is an anti-allergic drug which exerts anti-inflammatory and anti-angiogenesis effects through inhibition of expression of MCP-1, TGF-beta, and antigen-induced IL-2 lymphocyte responsiveness. It also possesses a certain antioxidant activity. Considering the above facts and in view of its safety, tranilast may prove invaluable in the treatment of IR.

Background: Rizatriptan is an effective and fast acting drug for the acute treatment of migraine. Some nonsteroidal anti-inflammatory drugs (NSAID) have also demonstrated efficacy in treating migraine attacks. There is evidence that the combination of a triptan and a NSAID decreases migraine recurrence in clinical practice. The primary aim of this randomized open label study was to assess the recurrence rates in migraine sufferers acutely treated with rizatriptan (RI) alone vs. rizatriptan plus a COX-2 enzyme inhibitor (rofecoxib, RO) vs. rizatriptan plus a traditional NSAID (tolfenamic acid, TO). We were also interested in comparing the efficacy rates within these three groups., Methods: We assessed 45 patients from a headache clinic in Rio de Janeiro (35 women and 10 men, ages 18 to 65 years, mean 37 years). Patients with IHS migraine were randomized to one out of 3 groups, where they had to treat 6 consecutive moderate or severe attacks in counterbalanced order. In group 1, patients treated the first two attacks with 10 mg RI, the third and fourth attacks with RI + 50 mg RO and the last attacks with RI + 200 mg of TA. In group 2, we began with RI + TA, followed by RI, and RI + RO. Group 3 treated in the following order: RI + RO, RI + TA, RI alone. The presence of headache, nausea and photophobia at 1, 2 and 4 hours, as well as recurrence and side effects were compared., Results: A total of 33 patients finished the study, treating 184 attacks. The pain-free rates at 1 hour were: RI: 15.5%; RI + RO: 22.6%; RI + TA: 20.3%(NS). Pain-free rates at 2 h were: RI: 37.9%; RI + RO: 62.9%, and RI + TA: 40.6% (p = 0.008 for RI vs. RI + RO; p = 0.007 for RI + RO vs. RI + TA, NS for RI vs RI + TA). At 4 h, pain-free rates were: RI: 69%; RI + RO: 82.3%; RI + TA: 78.1% (NS for all comparisons). The combination of RI + RO was superior to RI and to RI + TA in regard of the absence of nausea and photophobia at 4 hours. Recurrence (after being pain-free at 2 h) was observed in 50% of patients treated with RI, in 15,4% of those treated with RI + RO, and in 7,7% of those treated with RI + TA., Conclusions: Despite the methodological limitations of this study, the combination of RI and RO revealed a higher response rate at 2 hours. Recurrence was also clearly decreased with both combinations in relation to the use of RI alone. Controlled studies are necessary to provide additional evidence.

Background/aims: Tubulointerstitial pathology with the accumulation of extracellular matrix are pathological hallmarks of diabetic nephropathy that are directly related to declining renal function. Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic acid), an inhibitor of transforming growth factor-beta (TGF-beta), used to treat hypertrophic scars has recently been shown in pilot studies to exert a beneficial effect in advanced diabetic nephropathy in humans. However, its effects on diabetic renal pathology are unknown., Methods: Studies were conducted using a transgenic model, the diabetic (mRen-2)27 rat, which develops many of the structural and functional characteristics of human diabetic nephropathy when diabetes is induced with streptozotocin (STZ). An experimental design was chosen to mimic, in part, the clinical context with drug therapy (tranilast 400 mg/kg/ day) initiated in established disease (8 weeks after STZ) and in the presence of persistent hyperglycaemia and hypertension., Results: At 16 weeks, diabetes was associated with progressive albuminuria, tubulointerstitial fibrosis and tubular atrophy. Without affecting blood pressure or blood glucose, tranilast treatment was associated with a 83% reduction in tubulointerstitial fibrosis (p < 0.001), a 58% reduction in tubular atrophy (p < 0.01) and near normalization of albuminuria (p < 0.05) in diabetic Ren-2 rats. In vitro studies in primary cultures of human renal cortical fibroblasts demonstrated a reduction in TGF-beta-induced hydroxyproline incorporation and fibronectin synthesis with tranilast 100 microM., Conclusion: Tranilast, when administered during the course of experimental diabetic nephropathy, attenuates tubulointerstitial pathology and albuminuria. These findings are consistent with the antagonist effects of tranilast on TGF-beta actions in the diabetic kidney., (Copyright 2003 S. Karger AG, Basel)

Background: The Tranilast Restenosis Following Angioplasty Trial showed that oral administration of 600 mg/day of tranilast for 3 months markedly reduced the restenosis rate after percutaneous transluminal coronary angioplasty (PTCA) for de novo lesions., Methods: We conducted the second multicenter, randomized, double-blinded placebo-controlled trial. A total of 297 patients with 329 lesions were randomly assigned to treatment with tranilast or a placebo for 3 months after successful PTCA for both de novo and restenotic lesions. Angiographic follow-up examination was done at 3 months, and angiograms were interpreted with a quantitative approach., Results: Two hundred thirty-nine lesions (72.6%) in 216 of the patients (72.7%) met the criteria and were included in the assessment of restenosis. Lesion restenosis was defined as a loss of 50% or more of the initial gain, and the restenosis rates were 18.8% in the tranilast group (n = 112) and 44.1% in the placebo group (n = 127; P =.00005). The restenosis rate, defined as a percent stenosis of > or = 50% at follow-up examination, was also significantly lower in the tranilast group (25.9% versus 41.9%; P =.012). The numbers of restenotic lesions were 38 (33.9% of 112) in the tranilast group and 30 (23.6% of 127) in the placebo group. In restenotic lesions, the lesion restenosis rate was significantly lower in the tranilast subgroup (18.4% versus 53.3% with the first restenosis criterion; P =.004)., Conclusion: The oral administration of tranilast for 3 months markedly reduced the restenosis rate after PTCA, even in restenotic lesions.

The migraine prophylactic effect of tolfenamic acid 300 mg versus pizotifen 1.5 was evaluated in a prospective, randomized, double-blind, parallel group study. 192 patients were included with a frequency of 4-8 moderate to severe migraine attacks monthly, with or without aura, fulfilling the diagnostic criteria for migraine as defined by the International Headache Society. A four-week baseline period without medication was followed by 12 weeks of treatment with tolfenamic acid 300 mg or pizotifen 1.5 mg. In both periods patients were allowed to take escape medication (paracetamol and codeine) if the treatment was inefficient. All the patients had a headache diary before and during treatment. The primary criterion of efficacy was reduction in attack frequency per 4 weeks. Also reduction in intensity or duration of migraine attacks in hours at the end of 12 weeks treatment compared to the baseline period was measured. Both groups exhibited significant reduction in attack frequency (p < 0.001). Tolfenamic acid significantly reduced severity compared to the run-in period (p = 0.009). Patients treated with pizotifen needed more escape medication when compared to the run-in period (p < 0.01). Tolerance, especially weight gain, was a major drawback with pizotifen. Because of its high efficacy, excellent tolerability and low cost, tolfenamic acid is an interesting option for migraine prophylaxis.

Accelerated coronary arteriosclerosis remains a major problem for the long-term survival of cardiac transplant recipients. However, the pathogenesis of graft vasculopathy is poorly understood and there is no effective therapy. Tranilast is a promising drug that may prevent post-angioplasty restenosis. Here, we investigated whether orally administered tranilast inhibits the development of intima hyperplasia in a mouse model of cardiac transplantation. Cardiac allografts from BALB/c mice were transplanted heterotopically into C3H/He mice. Mice were administered either vehicle or tranilast everyday by gavage. Morphometrical analysis of the cardiac allografts harvested at 2 months revealed that the administration of tranilast significantly reduced the development of coronary atherosclerosis. In the mice treated with tranilast, up-regulation of the cyclin-dependent kinase inhibitor p21 was observed in the allografts, accompanied by a reduced number of proliferating cells. Tranilast also suppressed transforming growth factor-beta (TGF-beta) expression. Tranilast may be effective in preventing transplant-associated arteriosclerosis through its anti-inflammatory and anti-proliferative effects.

Background and Objectives: Triptans are effective drugs for the acute treatment of migraine. However, 30-40% of the patients commonly present recurrence before 24 hours therefore requiring another dose. Nonsteroidal anti-inflammatory drugs (NSAID) such as tolfenamic acid and naproxen sodium combined with sumatriptan have demonstrated efficacy in reducing recurrence observed with the single use of this drug. Steroids also have been suggested to treat refractory migraine and status migranosus. The aim of this study was to evaluate whether patients presenting frequent recurrence with the combination triptan plus NSAID, would decrease it with the association of dexamethasone., Method: Twenty three patients, 17 women and 6 men with migraine according to IHS criteria were prospectively studied. All patients presented frequent recurrence (> or= 60%, mean recurrence rate 74,8%) with the single use of sumatritpan 100 mg or zolmitriptan 2,5 mg or rizatriptan 10mg in at least 5 consecutive attacks, and didn't present a reduction of the recurrence rate superior than 20% with the combination of tolfenamic acid 200 mg or rofecoxib 25 mg in at least 5 other consecutive attacks (mean recurrence rate 60%). The patients had to treat 6 consecutive moderate or severe migraine attacks with their usual combination plus 4 mg of dexamathasone with a maximum of twice a week, and fill out a diary reporting headache parameters., Results: Twenty patients, 16 women and 4 men completed the study. Of those who completed the study, 11 took rizatriptan plus rofecoxib, 4 rizatriptan plus tolfenamic acid, 3 zolmitriptan plus rofecoxib, 1 zolmitriptan plus tolfenamic acid and 1 patient took sumatriptan plus tolfenamic acid, having the 20 patients taken as a third medication, a single tablet of 4 mg of dexamethasone. All patients took oral formulations and none presented vomiting after that. Among all 20 patients, one female and one male patient presented recurrence in 3 out of the 6 attacks (50%) while the remaining 18 patients revealed recurrence in 1 or 2 treated attacks (mean 23,4%) (p<0,001)., Conclusion: We concluded that the judicious use of oral dexamethasone might be useful for a limited population of migraine patients still presenting recurrence with the combination of a triptan and a NSAID. Case-control studies and studies with a randomized double-blind design are necessary to confirm these observations.

The adequacy of postoperative analgesia was assessed in 40 cats following ovariohysterectomy. At extubation, cats were given one dose of carprofen, ketoprofen, meloxicam or tolfenamic acid. Postoperative analgesia was assessed using visual analogue scale (VAS) scoring for pain and sedation; measurement of mechanical nociceptive thresholds at the wound; recognition of the requirement for rescue intervention analgesia; and an overall clinical assessment score at 18 hours. VAS pain scores were low throughout the trial, with no significant differences found between the groups. Postoperative mechanical nociceptive thresholds decreased significantly from baseline in all four groups, with no significant differences between the groups. One cat in each of the tolfenamic acid, ketoprofen and meloxicam groups required rescue intervention analgesia. Nine out of 10 cats in all four groups were classified as having desirable overall clinical assessment scores. In summary, all four drugs provided good postoperative analgesia, although none was able to prevent postoperative wound tenderness.

Objectives: We evaluated the effect of orally administered tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, on histologic and histomorphometric changes after angioplasty or stent implantation in pig coronary arteries., Background: Tranilast, which has antikeloid and antiallergic properties and therefore may modulate the fibrotic and inflammatory tissue responses to angioplasty and stenting, has been shown to inhibit angiographic restenosis in small clinical trials. However, its effect on histomorphometric changes in coronary arteries after angioplasty and stenting is unknown., Methods: Following initial pharmacokinetic studies in two pigs to determine desirable plasma levels of orally administered tranilast, 36 crossbred juvenile pigs were randomized to placebo or tranilast before undergoing balloon angioplasty in both the left anterior descending and left circumflex plus stent implantation in the right coronary artery. Oral tranilast was administered at 3 g/day starting 3 days before coronary injury and continued for 28 days until euthanasia. Injured vessels were harvested and sections analyzed by computer-assisted microscopic planimetry., Results: In balloon-injured vessels, tranilast was associated with a 37% reduction in neointimal area normalized to fracture length (0.47 +/- 0.01 vs. 0.74 +/- 0.03 mm; p < 0.001) and a 23% reduction in adventitial area normalized to vessel size (0.43 +/- 0.02 vs. 0.56 +/- 0.03; p = 0.003). In stented arteries, neointimal area normalized to injury score was 32% lower in the tranilast-treated group compared to control (1.94 +/- 0.17 vs. 2.86 +/- 0.29; p = 0.01)., Conclusions: In pig coronary arteries, tranilast was associated with a reduction in neointima formation and adventitial reaction after balloon injury. In stented vessels, tranilast was associated with a reduction in neointima formation normalized to injury score.

Background: 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., Study Design: 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., Results: 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)., Conclusions: 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.

A multicenter, double-blind, cross-over, random-order study compared the efficacy of floctafenin, 800 mg/day and acetaminophen, 3000 mg/day, in providing pain relief to 192 patients with chronic pain due to osteoarthritis in the lower limbs. Each drug was given for 12 days and the interval between the two treatment periods was two days. The primary evaluation criterion was pain relief as assessed using the visual analog scale developed by Huskisson (mean baseline score, 62.7 +/- 13.6 mm). Secondary criteria were the algofunctional index, the investigator's overall efficacy rating and patient preference. Floctafenin therapy was associated with significantly better results regarding the visual analog scale score (P = 0.036, 149 patients in the per protocol analysis) and the investigator's overall efficacy rating (P = 0.0001, 169 evaluable patients). Among the 169 evaluable patients, 68 had no preference for either treatment and 101 had a preference, which was for floctafenin therapy in 65% of cases (P = 0.001). Clinical tolerance was satisfactory with both drugs. Gastrointestinal symptoms were the most common side effects (13% and 11% of patients with floctafenin and acetaminophen, respectively).

The purpose of this study was to evaluate the antipyretic action of tolfenamic acid, as well as its possible adverse reactions, especially in children with severe or partial form of glucose-6-phosphate dehydrogenase (G6PD) deficiency. In the study 55 febrile children were included, whose mean age was +/- SD 3.5 +/- 3.3 years, range 0.5-15. Ten of them had severe or partial form of G6PD deficiency. Fifty-three of the patients responded with a decrease of temperature which lasted at least 6 hours, though in 2 of them the temperature decrease lasted less than 6 hours. The tolerance of the drug was good and no side-effects were noted. None of the patients with or without G6PD deficiency showed symptoms, signs, or laboratory findings indicating hemolysis before administration of the drug and 4 days thereafter. In conclusion, tolfenamic acid is a strong antipyretic agent with excellent tolerance and high safety in children.

Background: Choosing an alternative anti-inflammatory agent for a patient who has suffered adverse reactions to nonsteroidal anti-inflammatory drugs is a common problem in clinical practice, and it is complicated by the possibility of non-immunologic cross reactivity among the various members of this drug class., Objective: We performed a retrospective study based on oral challenge results in 150 patients with histories of adverse reactions to one or more nonsteroidal anti-inflammatory drugs. The alternative drugs tested included floctafenine, an analgesic of the fenamic acid group, nimesulide, or paracetamol (acetaminophen)., Patients and Methods: One hundred fifty patients with histories of adverse reactions to nonsteroidal anti-inflammatory drugs received oral challenges with floctafenine; 101 were also challenged with nimesulide and paracetamol. The oral challenges were administered under single-blinded conditions. One-fourth of the therapeutic dose (floctafenine, 200 mg; nimesulide, 100 mg; and paracetamol, 500 mg) was administered initially; the remaining 3/4 was given one hour later if no symptoms had developed with the initial administration. In patients with histories of rhinitis and/or bronchial asthma unrelated to drug use and those whose adverse reactions had included bronchospastic or rhinitic symptoms, the FEV1 was measured. The response to the challenge was considered positive if any of the following symptoms developed: erythema, pruritus accompanied by erythema, urticaria/ angioedema, rhinorrhea, nasal obstruction, sneezing, dyspnea or cough associated with a decrease of at least 20% in the FEV1, hypotension., Results: Floctafenine challenges were positive in 13/150 patients (8.7%). Nimesulide and paracetamol provoked reactions in 9/101 patients (8.9%). All positive reactions occurred within 24 hours of the challenge. None of the patients reacted to more than one of the drugs tested., Conclusions: Our findings confirm those of other investigators regarding the use of nimesulide and paracetamol in patients who do not tolerate aspirin or other nonsteroidal anti-inflammatory drugs, although the percentage of reactions to nimesulide observed in the present study is somewhat higher than that reported by some other groups. The study also indicates that floctafenine, a relatively weak cyclooxygenase inhibitor, can be a valid alternative for many patients who react adversely to other nonsteroidal anti-inflammatory drugs.

Tolfenamic acid (TA) was tested in two studies to investigate its value in controlling ocular inflammation in the dog. First, TA was assayed within primary and secondary aqueous humour (AH) and in plasma 0, 4 and 24 hours after a 4 mg/kg subcutaneous injection. Secondly, an experimental ocular surgery model was set up in 10 dogs-five receiving TA two hours before surgery and five left untreated. TA was shown to diffuse into AH, reaching lower levels than in plasma: 1:126 ratio in primary AH and 1:43 in secondary AH. In the model, TA-treated dogs versus untreated dogs showed a significant reduction of miosis (P < 0.05) and a clear trend to a reduced ocular discharge and corneal oedema (P = 0.06). Prostaglandin E2 (PGE2) levels increased significantly less in AH after TA treatment (P < 0.05). These results show that TA, even if the whole concentration measured in AH is lower than in plasma, is able to limit the synthesis of the inflammatory mediator PGE2 in AH and to control ocular inflammatory symptoms induced by corneal surgery.

Nephrogenic diabetes insipidus (NDI) occurred in a 43-year-old woman who had received lobenzarit disodium for the treatment of rheumatoid arthritis (RA). Her urine output was initially 3 l/day and urine osmolarity was 203 mOsm/l. Based on a sodium chloride loading test and a vasopressin loading test, she was diagnosed as having lobenzarit-induced NDI. Seven days after the cessation of the use of lobenzarit disodium, polydipsia and polyuria disappeared, and the vasopressin test showed a normal response. These findings suggest that lobenzarit induces a reversible form of NDI as a side effect. The reports of lobenzarit-induced NDI in Japan during the past seven years are also reviewed.

The effects of Ta-383 (0.016, 0.08, 0.4, 2 and 10 mg/kg) and anti-rheumatic drugs (lobenzarit 10 and 50 mg/kg, dexamethasone 0.25 mg/kg) were evaluated on type II collagen-induced arthritis in DBA/1J mice. The arthritis score was markedly suppressed in the groups treated with dexamethasone and TA-383. Serum anti-type II collagen IgG was significantly suppressed in the groups treated with dexamethasone and 0.4 mg/kg TA-383. Histopathological evaluation of the knee joints revealed suppression of the inflammatory changes in the groups treated with dexamethasone and TA-383. These findings suggest that the histopathological examination of the joints of the animal model is useful for the evaluation of anti-rheumatic drugs, and that TA-383 has suppressive effects on type II collagen-induced arthritis, an animal model for human rheumatoid arthritis.

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.

An open clinical trial was designed to examine the efficacy and safety of lobenzarit (CCA), a newly developed disease modifying anti-rheumatic drug, in combination with conventional treatment with prednisolone for patients with systemic lupus erythematosus (SLE). Fifteen patients with SLE were given CCA 40 mg b.i.d. for the first 2 weeks, 80 mg b.i.d. for the next 4 weeks, and 80 mg t.i.d. or b.i.d. until the end of the 12-month trial, in addition to prednisolone, whose doses were kept unchanged throughout the trial. The patients' clinical responses to CCA, including alterations in various laboratory parameters and the development of complications, were evaluated at the end of 12 months. Fourteen of the 15 patients completed the 12-month trial. Significant increases in the white blood cell count and CD4/CD8 ratio, as well as decreases in serum anti-DNA antibody, were noted after the trial. Five patients presented with adverse effects, including mild liver dysfunction, gastrointestinal symptoms and dizziness. Only one patient who developed dizziness withdrew at 9 months. Eleven patients could be reevaluated after discontinuation of CCA, and only 2 of them have experienced recurrence of active disease 6 months after discontinuation. In one additional patient who had not responded to prednisolone 35 mg daily, administration of CCA resulted in improvement of the disease activity. These results indicate that CCA in combination with corticosteroids is a useful adjunct in the treatment of SLE. A placebo-controlled study will be necessary to confirm these results.

In a blinded multicentre trial 313 cattle showing clinical signs of respiratory disease were allocated randomly into three groups, treated intramuscularly with a long-acting oxytetracycline formulation at a dose rate of 20 mg/kg bodyweight in combination with vehicle alone (placebo) or with tolfenamic acid at 2 mg/kg bodyweight once or on two occasions with a 48-h interdosing interval. The clinical status of the animals was monitored for 5 days using a specific scoring system and weight gain was calculated between day 0 and day 21. Relapses were monitored from day 5 until day 21. When oxytetracycline was combined with two injections of tolfenamic acid, there was a significant (P < 0.04) improvement in the clinical resolution. This regimen also produced non-significant improvements in cure rate, reduced frequency of relapses and improved weight gain.

In this open randomized study, we evaluated the efficacy of Tranilast, one of the anti-inflammatory drugs, on otitis media with effusion in children. Sixty-two patients (103 ears) were divided into two groups: Group A was given Tranilast and local treatment (nasal and tubal); Group B only received local treatment (control for Group A). The overall improvement rating assessed as "moderately improved or above" for Group A was 63.6%, Group B 47.9%. There was a significant improvement in Group A as compared to Group B (p < 0.05). In subjects who suffered from otitis media with effusion for over 2 months. Group A exhibited 50.0% of efficacy while Group B only 15.4% (p < 0.05).

Tolfenamic acid (TA) is an interesting drug for the treatment of rheumatic diseases because of its capacity to inhibit the synthesis of leukotrienes. It may have fewer upper gastrointestinal side effects than other NSAIDs which inhibit only the synthesis of prostaglandins. Several controlled and non-controlled studies on the clinical efficacy and side effects of TA have been carried out since the early seventies. These studies include about 900 patients suffering from different rheumatic diseases. The clinical efficacy of TA has proved to be at least as good as that of control drugs in all double-blind trials. We have compared the analgesic effect of ten NSAIDs in patients with rheumatoid arthritis, using a single-blind method by asking the patients which one of two drugs was the better. The study gave a rank order to the drugs favoured by the patients and the results showed that TA was among the four best drugs together with naproxen, indomethacin, and diclofenac. The side effect profile of TA is different from that of other NSAIDs. The number of upper gastrointestinal side effects during TA treatment was less than half the number during treatment with control NSAIDs in eight double-blind studies. On the other hand, dysuria was found only during TA treatment. In 1989 the official side effect registers of Denmark and Finland included a total of 462 side effect reports. The frequency of side effects per treatment day was about the same as for other NSAIDs according to these reports.(ABSTRACT TRUNCATED AT 250 WORDS)