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Spodoptera exigua , a multifeeding insect pest, has developed a high level of resistance to chlorantraniliprole, which is a benzoylurea insecticide that targets the ryanodine receptors (RyRs). Herein, the resistant strain (SE-Sel) and sensitive strain (SE-Sus) were obtained by bidirectional screening for six generations. The potential oviposited eggs and oviposition rate of the SE-Sel strain were dramatically lower than those of the SE-Sus strain; on the contrary, the weights of prepupae and preadult were significantly increased. As a post-mating response, the higher number of non-oviposited eggs in the SE-Sel strain was caused by a lower mating rate. In addition, the expression levels of vitellogenin ( SeVg ) and its receptor ( SeVgR ) in the SE-Sel strain were consistently lower than those in the SE-Sus strain. An RyR I4743M mutation, contributing to the resistance to chlorantraniliprole, was located in the S3 transmembrane segments and might have affected the release of calcium ions; it led to the upregulated expression of the neuropeptide SeNPF and its receptor SeNPFR , and the mating and oviposition rate were significantly recovered when the SeNPF was knocked down though RNA interference (RNAi) in the male adult of the SE-Sel strain. Moreover, the expression of the juvenile hormone-binding proteins SeJHBWDS3 and SeJHBAN in the male adult of the SE-Sel strain was significantly decreased, which proved the existence of a fitness cost from another angle. Therefore, these results indicate that the fitness cost accompanied by chlorantraniliprole resistance in S. exigua may be related to the decrease in mating desire due to SeNPF overexpression.

Background: Transient receptor potential vanilloid 2 (TRPV2) was previously shown to play an important role in the maintenance of cancer stem cells, and its specific inhibitor, tranilast, also has potential as a targeted therapeutic agent for esophageal squamous cell carcinoma (ESCC). The present study is being conducted to confirm the safety and efficacy of the additional use of tranilast with conventional preoperative adjuvant chemotherapy for patients with advanced ESCC., Patients and Methods: Between 56 and 59 patients aged between 20 and 74 years with clinically diagnosed Stage II or Stage III ESCC will be enrolled. Eligible patients will receive preoperative adjuvant chemotherapy, 2 cycles of combination therapy with cisplatin, 5-fluorouracil, and tranilast. Recruitment started in November 2019, with the final follow-up being planned for March 2029. One subject has been enrolled since October 21, 2020. The pathological therapeutic effect is the primary endpoint. The objective response rate, safety of preoperative adjuvant chemotherapy, recurrence-free survival (RFS), and overall survival (OS) are the secondary endpoints. RFS and OS will be calculated as the time from surgery to first recurrence and all-cause death, respectively., Ethics and Dissemination: This protocol has been approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine and all participating hospitals in August 30, 2019 (Number: CRB5180001). Written informed consent will be obtained from all patients before their registration, which is in accordance with the Declaration of Helsinki. The results of the present study will be disseminated via publication in peer-reviewed journals., Trial Registration: Trial registration number jRCTs051190076.

As for developing effective integrated pest management (IPM), it is necessary to understand the sublethal effects of common insecticides on the non-target beneficial arthropods. In this lab-scale study, the sublethal effects of two anthranilic diamide insecticides chlorantraniliprole and cyantraniliprole on the populations of 7-spot ladybird Coccinella septempunctata (Coleoptera: Coccinellidae) were determined and compared using an age-stage, TWO-SEX life table and CONSUME-MSChart computer program. Cyantraniliprole at low-lethal concentrations of 1 and 10 mg L -1 significantly prolonged the larval stages and reduced the total adult longevity, compared with the control. Additionally, the net reproductive rate (R 0 ), intrinsic rate of increase (r), finite rate of increase (λ), and mean generation time (T) were significantly reduced in the group treated with 10 mg L -1 of cyantraniliprole. Similarly, the net predation (C 0 ), the finite predation rate (ω), and stable predation rate (ψ) were significantly reduced by cyantraniliprole at 1 and 10 mg L -1 . In contrast, no significant difference in the demographic parameters above was determined for chlorantraniliprole at 1 mg L -1 . Therefore, C. septempunctata population may develop faster and possess greater predation potential against aphids under the exposure of chlorantraniliprole, compared to cyantraniliprole. Chlorantraniliprole may be a preference to cyantraniliprole as a combined alternative with ladybeetle predators in IPM framework.

Cyantraniliprole is a second-generation diamide insecticide that exhibited excellent biological efficacy against a variety of pests. To assess the toxic impact of cyantraniliprole on earthworms, the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), activities of superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST), as well as DNA damage were measured after exposed to five cyantraniliprole concentrations ranging from 0 to 10.00 mg/kg for 7, 14, 21 and 28 days. In most treatment groups, the ROS levels increased significantly before exposure time of 14 days and then returned to normal levels. However, the SOD and CAT activities showed different response with activities were first significantly decreased and subsequently increased. The peroxidase (POD) activity showed no significant differences between treatment and control groups at first and then significantly increased. However, the opposite pattern characterized the GST activity. Also, maybe being dose-dependent before 14 days. The MDA concentration was used as a measure of lipid peroxidation (LPO). During experiment period, the MDA concentrations significantly increased when treated by this pesticide. The olive tail moment (OTM) was used as a measure of DNA damage. At higher concentrations of cyantraniliprole and longer exposure times, the OTM gradually increased, and DNA damage in the earthworms gradually increased. The weight of the high-dose (i.e., 5 mg/kg, 10 mg/kg) earthworms showed a significant trend of decrease phenomenon. Overall, the results suggest that sub-chronic exposure to cyantraniliprole causes DNA damage and LPO, weight loss and growth inhibition, leading to antioxidant defence responses in earthworms., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The administration of high doses of non-steroidal anti-inflammatory drugs (NSAID), such as tolfenamic acid (TA), has undesirable effects on different organs. Some novel biomarkers have been reported that can determine the gastrointestinal and renal injury caused by a high dose of NSAIDs or other toxic substances. This study was aimed at determining the changes in gastrointestinal (TFF2 and HYP), renal (NGAL and KIM-1) and cardiac (cTn-I, CK-MB) injury markers after the use of increasing intravenous doses of TA in sheep. TA was administered intravenously to groups of six sheep each, at the dose levels of 0 (Group 0, i.e., G0), 2 (G2), 4 (G4), 8 (G8) and 16 (G16) mg/kg. The concentrations of the studied biomarkers were measured at 3, 9, 18 and 36 h after administration of TA. The TFF2 and NGAL concentrations in G16 were found to be significantly higher (P < 0.05) than in the other groups except for G8 at different sampling times. HYP concentration in G16 was observed to be significantly (P < 0.05) lower than that in all other groups at 36 h. KIM-1 level in G16 was significantly (P < 0.05) higher than in all other groups at different sampling times. An increase in the renal markers, KIM-1 and NGAL, in G8 was observed before any change in plasma creatinine and urea. The cardiac marker cTn-I in G16 was significantly (P < 0.05) higher than in other groups at different sampling times. The results showed that the novel biomarkers (HYP, TFF2, NGAL, and KIM-1) can be used to determine gastric and renal injury in sheep.

The pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep with TA via different routes and doses. This crossover study was carried out with a washout period of 15 days. In the study, 16 clinically healthy sheep were randomly assigned to two equal groups. In the first group (n = 8), animals received TA by intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8), TA was administered intravenously to each sheep at 2, 4, 8, and 16 mg/kg. Plasma samples were analyzed with a high-performance liquid chromatography assay. Noncompartmental pharmacokinetic analyses were used to evaluate the data. The area under the concentration-time curves (AUC 0-∞ ), elimination half-life (t 1/2ʎz ), and the mean residence time (MRT) significantly differed among the administration routes at 2 mg/kg of TA. Following IM, SC, and OR administrations, TA demonstrated different peak concentrations (C max ) and time to reach C max (T max ), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC 0-∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC 0-∞ was linear. Both t 1/2ʎz and MRT increased depending on the dose. Although the total clearance (Cl T ) decreased depending on dose, the volume of distribution at steady-state (V ss ) increased. Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg. TA exhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus, TA may be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep., (© 2018 John Wiley & Sons Ltd.)

Tolfenamic acid (TA) is a nonsteroidal antiinflammatory drug and belongs to the group of fenamates. It is used as a potent pain reliever in the treatment of acute migraine attacks, and disorders like dysmenorrhea, rheumatoid, and osteoarthritis. TA has shown excellent in vitro antibacterial activity against certain ATCC strains of bacteria when complexed with bismuth(III). It has also been reported to block pathological processes associated with Alzheimer's disease. In the recent past, TA has also been used as a novel anticancer agent for the treatment of various cancers. In view of the clinical importance of TA, a comprehensive review of the physical and pharmaceutical properties and details of the various analytical methods used for the assay of the drug in pharmaceutical and biological systems has been made. The methods reviewed include identification tests and titrimetric, spectrophotometric, chromatographic, electrochemical, thermal, microscopic, enzymatic, and solid-state techniques. Along with the analytical profile, the stability and degradation of TA, its pharmacology and pharmacokinetics, dosage forms and dose, adverse effects and toxicity, and interactions have been discussed., (© 2018 Elsevier Inc. All rights reserved.)

Background: Tranilast (N-[3, 4-dimethoxycinnamoyl] anthranilic acid), an antiallergic drug, has been shown to attenuate scar formation possibly through inhibition of transforming growth factor beta 1 activity and consequent suppression of collagen synthesis in fibroblasts., Objective: The authors aimed at evaluating the efficacy and safety of tranilast 8% gel in improving the appearance and symptoms of new post-cesarean section surgical wounds., Methods: In this prospective double-blind split-scar study, the authors treated each half scar of 26 women with either tranilast 8% liposomal gel or tranilast-free liposomal gel (placebo). Treatment was applied twice daily for 3 months. Twenty women completed the trial. Scar halves were evaluated by 2 investigators and by the patients 9 months after the last application using the Patient and Observer Scar Assessment Scale (POSAS). The participants also rated overall satisfaction and recorded side effects of the treatment., Results: The mean POSAS scores at 9 months post-treatment were significantly lower for tranilast-treated half scars compared with placebo-treated half scars (p < .001). The women were significantly more satisfied with the tranilast-treated half-scar appearance (p = .002). Three participants reported itching and erythema on the tranilast-treated side., Conclusion: Topical tranilast 8% gel provided significantly better postcaesarian section scar cosmesis and user satisfaction compared with placebo.

Objective: The effect of naftopidil on symptoms of tranilast-induced interstitial cystitis (IC) was examined in rats., Methods: Thirty-two female rats were divided into four groups (control, naftopidil, tranilast, and combination groups). Rats in the control group were fed a standard diet, while rats in the naftopidil, tranilast, and combination groups were fed diets containing naftopidil, tranilast, or naftopidil + tranilast, respectively. After 4 weeks of treatment, locomotor activity was measured and continuous cystometry was performed., Results: During the light period, locomotor activity was lower in the tranilast group than in the control, naftopidil, and combination groups. During the dark period, locomotor activity was higher in the naftopidil group than in the other three groups. The combination group showed higher locomotor activity than the tranilast group, but significantly lower activity than the naftopidil group. Continuous cystometry revealed that the interval between bladder contractions was shorter in the tranilast group than in the other three groups. The combination group also had a shorter interval between contractions than the control group., Conclusion: Naftopidil improved the symptoms of tranilast-induced IC, such as reduced locomotor activity due to pelvic pain and a shortened interval between bladder contractions. Therefore, naftopidil may be a potential treatment for IC., (© 2015 Wiley Publishing Asia Pty Ltd.)

Background: Based on animal and human data, phosphoinositide 3-kinase (PI3K)β is a promising antithrombotic target. However, the relation between efficacy and bleeding when combined with current antiplatelet therapies is unclear., Objective: To strengthen the PI3Kβ target validation using the short-acting inhibitor AZD6482 alone and in different combinations with P2Y12 and cyclooxygenase (COX)-1 inhibition in vitro (human platelets), in vivo (dog), and in healthy subjects., Methods and Results: Evaluation of complete target inhibition of PI3Kβ (by AZD6482), P2Y12 (by ticagrelor), and COX-1 (by aspirin) alone and in the different combinations vs. concentration responses for a panel of platelet agonists in vitro (adenosine diphosphate, collagen, thrombin receptor activating peptide) indicates that the rank order of antiplatelet efficacy is P2Y12  > PI3Kβ > COX-1 as monotherapy and P2Y12 plus PI3Kβ > P2Y12 plus COX-1 > PI3Kβ plus COX-1 as dual therapy, with little additional effect with triple therapy. Use of a conscious dog model to assess ex vivo antiplatelet effect in parallel with bleeding time prolongation (standard incision in the ear) confirms the wide separation of efficacy vs. bleeding for PI3Kβ inhibition and that this separation is reduced when combined with aspirin and more reduced when combined with clopidogrel. In healthy subjects, AZD6482, in combination with aspirin, shows a potential for greater antiplatelet potency but less bleeding potential compared with clopidogrel plus aspirin., Conclusions: PI3Kβ inhibition, in comparison with P2Y12 and COX-1, delivers medium antiplatelet effect but with minimal bleeding. PI3Kβ inhibition, in combination with aspirin, in healthy subjects, provides a potential for greater overall antiplatelet effect compared with clopidogrel plus aspirin, but with significantly less bleeding potential., (© 2015 International Society on Thrombosis and Haemostasis.)

Tranilast (N-[3',4'-dimethoxycinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite. Initially, tranilast was identified as an anti-allergic agent, and used in the treatment of inflammatory diseases, such as bronchial asthma, atypical dermatitis, allergic conjunctivitis, keloids and hypertrophic scars. Subsequently, the results showed that it could be also effective in the management of a wide range of conditions. The beneficial effects of tranilast have also been seen in a variety of disease states, such as fibrosis, proliferative disorders, cancer, cardiovascular problems, autoimmune disorders, ocular diseases, diabetes and renal diseases. Moreover, several trials have shown that it has very low adverse effects and it is generally well tolerated by patients. In this review, we have attempted to accurately summarize previously published studies relating to the use of tranilast for a range of disorders and discuss the drug's possible mode of action. The major mode of the drug's efficacy appears to be the suppression of the expression and/or action of the TGF-β pathway, but the drug affects other factors as well. The findings presented in this review demonstrate the potential of tranilast for the control of a vast array of pathological situations, furthermore, it is a prescribed drug without severe side effects., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Based on in vitro and animal data, PI3Kβ is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear., Objective: To strengthen the PI3Kβ target validation using the novel, short-acting inhibitor AZD6482., Methods and Results: AZD6482 is a potent, selective and ATP competitive PI3Kβ inhibitor (IC(50) 0.01 μm). A maximal anti-platelet effect was achieved at 1 μm in the in vitro and ex vivo tests both in dog and in man. In dog, in vivo AZD6482 produced a complete anti-thrombotic effect without an increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3-h infusion. The ex vivo anti-platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin-induced human adipocyte glucose uptake in vitro (IC(50) of 4.4 μm). In the euglycemic hyperinsulinemic clamp model, in rats, glucose infusion rate was not affected at 2.3 μm but reduced by about 60% at a plasma exposure of 27 μm. In man, the homeostasis model analysis (HOMA) index increased by about 10-20% at the highest plasma concentration of 5.3 μm., Conclusions: This is the first human target validation for PI3Kβ inhibition as anti-platelet therapy showing a mild and generalized antiplatelet effect attenuating but not completely inhibiting multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at 'supratherapeutic' plasma concentrations may attenuate insulin signaling, most likely through PI3Kα inhibition., (© 2012 International Society on Thrombosis and Haemostasis.)

Backgrounds and Aim: As circumferential or near-circumferential endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms might evoke refractory strictures, multiple sessions of endoscopic balloon dilation (EBD) are required. We aimed to assess the effectiveness and safety of oral agent tranilast with EBD for improving the efficacy of stricture dilation after esophageal ESD., Methods: In an open-label prospective study at a single institution, 31 asymptomatic consecutive patients with superficial esophageal squamous cell carcinomas were enrolled from April 2007 to October 2010. After ESD, we performed scheduled EBD (twice weekly for 4 wk) with or without administration of oral agent tranilast for 8 weeks. Thereafter, we added additional EBD on the basis of solid criteria-for example, patient's awareness of vomiting >1/wk and inability of passage of routine endoscope through the ESD site. We compared the rates of post-ESD strictures and the numbers of additional EBD sessions for 48 weeks after ESD and the Dysphagia score between tranilast (T)-group and none (N)-group, based on patients' subjective symptoms, at 16, 24, and 48 weeks after ESD., Results: The percentage of post-ESD strictures in T-group was significantly lower than that in N-group (P=0.04). The median numbers of additional EBD sessions and Dysphagia score at 16 and 24 weeks after ESD in T-group were significantly smaller than those in N-group (P=0.0138, 0.002, 0.005, respectively). No adverse events and no recurrence were observed., Conclusions: We demonstrated for the first time that scheduled EBD combined with oral agent tranilast might be effective and safe for improving the efficacy of stricture dilation after esophageal ESD.

The objective of this study was to evaluate the effects of the nonsteroidal anti-inflammatory drugs vedaprofen and tolfenamic acid on renal function after oral administration for 2 weeks in healthy cats. Experiments were performed using nineteen domestic short-haired cats randomly divided into one control (n=6) and two treatment groups. All cats in the first (n=6) and second treatment groups (n=7) received vedaprofen (0.5 mg/kg/day) and tolfenamic acid (4 mg/kg/day), respectively. During the experiment, renal function was evaluated using percent renal uptakes of (99m)Technetium-diethylenetriamine-pentaacetic acid ((99m)Tc-DTPA) collected from renal scintigraphy and blood samples used to determine complete blood count and biochemical profiles. Renal scintigraphy and blood collections were performed at days 0, 5, 11, 15, and 45. The percent of renal uptake after the administration of vedaprofen and tolfenamic acid were not significantly different compared to pretreatment (day 0) and control group levels. In addition, significant changes were not observed in hematological and biochemical profiles within or between groups, with the exception of slightly lower numbers in red blood cell counts compared to the normal value on day 45 in the tolfenamic acid-treated group. Taken together, we conclude 14-day administration of vedaprofen and tolfenamic acid might not cause any adverse effects on renal function, hematological and serum biochemical variables., (© 2011 Blackwell Publishing Ltd.)

Simple, three classes of new anthranilic acid derivatives were aimed at, synthesized and tested for their toxicity, anti-inflammatory, analgesic, antipyretic activity. Also, their potential protective role against ulcerative colitis in rats was performed. Furthermore, their effect on liver and kidney functions was detected through measurement of the serum level of alanine transaminase (ALT), aspartate aminotransferase (AST), urea, creatinine and other parameters. Compounds 4, 5, 6b, 6c, 7c and 7e showed significant anti-inflammatory activity. From those 6b and 7e best improved the inflammatory indices even producing better reduction in the intensity of lesion score, ulcer area and wet weight/length ratio and showed good analgesic activity. Fortunately, none of the tested compounds showed any hepatotoxicity or nephrotoxicity. None of the tested compounds showed any antipyretic activity. Conclusively, presence of a phenyl ring in the substituent added is a must, since any alteration in its nature led to decrease in activity. Also, the presence of an extra halogen in addition to the one already embedded in the main structure was detrimental to activity.

Background: Tranilast is a therapeutic agent used in treatment of allergic diseases. It has been reported previously that tranilast has antitumour effects on prostate cancer cells. This study examined whether tranilast has clinical benefit for prostate cancer patients., Patients and Methods: Twenty-one Japanese patients with advanced castration-resistant prostate cancer (CRPC) were administered tranilast orally., Results: All patients had already been treated with combined androgen blockade followed by one or more salvage therapies and their prostate-specific antigen (PSA) continued to increase before starting tranilast. Median follow-up time was 14 months and median tranilast treatment time was 5 months. PSA progression was inhibited in 5 CRPC patients with bone metastasis. The survival rates at 12 and 24 months were 74.5% and 61.5%, respectively., Conclusion: Although this study involved only pilot data, it indicates that tranilast may improve the prognosis of patients with advanced CRPC.

The response of field-collected populations of the obliquebanded leafroller, Choristoneura rosaceana (Harris) (Lepidoptera: Tortricidae), to chlorantraniliprole, spinetoram, spinosad, and azinphosmethyl was assessed using a diet incorporation bioassay. Populations of obliquebanded leafroller were collected from nine orchards in Chelan, Douglas, Grant, and Okanogan counties of Washington. The neonates of the F1 or F2 generation were used in all assays. The parameters of probit regression lines were estimated and lethal concentration ratios were calculated for all populations compared with a susceptible laboratory population. Significant variation was detected in response to all four insecticides including chlorantraniliprole and spinetoram, which had never been used in the field, lethal concentration ratios were 3.9-39.7 for azinphosmethyl, 0.5-3.6 for spinosad, 1.2-5.3 for chlorantraniliprole, and 0.5-4.1 for spinetoram. Correlation analysis indicated possibility of cross-resistance between spinosad and spinetoram, which are both members of spinosyn class. The occurrence of low but significant levels of resistance against chlorantraniliprole and spinetoram in field-collected populations of C. rosaceana before their first field application indicates that the risk of resistance evolution against these two new reduced-risk insecticides exists. However, it is likely that these low levels of resistance can be managed if the insecticides are used judiciously in conjunction with sound resistance management programs. Implications of these results for developing and implementing resistance management strategies are discussed.

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.

Purpose: To evaluate the safety and efficacy of a sustained-release agent designed to reduce posterior capsule opacification (PCO)., Setting: Department of Ophthalmology, EENT Hospital, Fudan University, Shanghai, Peoples Republic of China., Methods: Free tranilast (TFree) was incorporated into polylactic acid microspheres and then tested using a rabbit model of PCO. Twenty-nine rabbits were randomized into 5 groups treated with balanced saline solution (BSS control); TFree; or 0.5, 1.0, or 2.0 mg tranilast microspheres (TMicro). Standard phacoemulsification cataract surgery, including manual aspiration of all visible soft lens matter, was performed in all groups. The selected test agent was then injected into the lens capsule. Postoperative clinical examinations were performed at 1, 3, 7, 14, 30, 60, and 90 days. Posterior capsule opacification was quantified using high-resolution computer image analysis at 1, 2, and 3 months. Histological examination was performed at 3 months., Results: Eyes treated with TMicro had significantly less PCO than the eyes in the BSS and TFree groups. While the BSS control eyes had increased PCO over 3 months, eyes in the TMicro group had reduced PCO over time in a dose-dependent fashion. Histological examination showed reduced lens epithelial cell proliferation in the TMicro groups, with no manifest damage to the cornea, iris, or retina compared with the BSS controls. There was a transient increase in postoperative inflammation in all tranilast-treated groups compared with the BSS controls., Conclusion: Sustained-release intracapsular tranilast reduced PCO in an experimental model of PCO, suggesting further investigation of its therapeutic potential is justified.

Tolfenamic acid esters with nitrooxyalcohols are synthesized. They are anti-inflammatory agents reducing carrageenan rat paw edema, with low gastrointestinal and general toxicity. In vitro, they are nitric oxide donors, inhibitors of lipoxygenase and cyclooxygenases. A two to three carbon chain between carboxylic and nitric ester groups seems optimal for activity.

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.

Unlabelled: Summary Background In the clinical practice patients with a history of acute urticaria induced by a single non-steroidal anti-inflammatory drug (NSAID) and seeking for safe alternative drugs generally undergo tolerance tests with alternative NSAIDs that have little or no cyclooxygenase-1 (COX-1) enzyme inhibitory activity. This practice does not allow for the detection of single NSAID reactors and may lead to unnecessary avoidance of many potentially useful NSAIDs., Objective: Evaluate aspirin challenge as a means to distinguish single from multiple NSAID intolerance in patients with a clinical history of acute urticaria induced by a single NSAID. Methods One hundred and seventeen otherwise normal subjects with a history of acute urticaria following the ingestion of a single NSAID (pyrazolones (n=58), nimesulide (n=17), propionic acid derivatives (n=13), aryl acetic acid derivatives (n=14), acetaminophen (n=9), piroxicam (n=5), and indometacin (n=1)) underwent single-blind placebo-controlled oral challenges with aspirin. Aspirin-intolerant subjects underwent further tolerance tests drugs exerting little or no inhibitory activity on COX-1 enzyme (including paracetamol, nimesulide, rofecoxib, tramadol, and floctafenine). Results Aspirin induced urticaria in 28/117 (24%) patients. Five out of 28 (18%) aspirin reactors did not tolerate alternative NSAID on subsequent oral challenges. Conclusion In subjects with a history of urticaria induced by a single NSAID (other than aspirin) the diagnostic workup should start with an aspirin challenge in order to detect single/multiple NSAID reactors.

Biomarkers of nephrotoxicity range from plasma and urine biochemistry, enzymic assays for brush border and lysosomal markers plus new protein markers by immunoassay. Because of the complexity of the nephron and regional sensitivity to xenobiotics, it is important to co-localise sites of marker release with pathological lesions. Han Wistar rats were treated p.o.for up to 14 days with compounds causing selective nephrotoxicity. Compounds used were cyclosporin A ,a signal transduction inhibitor and N-phenylanthranylic acid (NPAA). Plasma and urine was collected for biochemistry and urinalysis (including proteomics and metabonomics) and at termination kidneys were fixed for standard H&E pathology and immunohistochemistry examinations for D28 k calbindin, calmodulin, phospho-erk, Cox 1, Cox 2 and other markers. Cyclosporin A treatment caused injury to the thick ascending limb (TAL) of the nephron and was associated with a down-regulation of calbindin protein expression in cortical distal tubules (mean score 75% reduction) and TALs (21% reduction). Inhibition of signal transduction used p-erk as a downstream marker of activity. P-erk was highly expressed in the collecting ducts and inhibition of signalling caused a 39% reduction in IHC score. There was no evidence of direct renal injury by there was a hypercalcaemia (9% increase) and hyperphosphataemia (24% increase) at 24 hrs post-dose and metastatic calcification by 7 days. NPAA treatment caused renal papillary necrosis in some treated rats (sometimes unilateral) with some secondary dilation of distal tubules. Unlike NSAID treatment, there was no evidence of Cox 1 or 2 dysregulation on IHC and the Cox1 positive interstitial cells did not loose integrity before the onset of necrosis. There were a number of urinary proteomic and metabonomic alterations which are being characterised. The 3 model nephrotoxicants studied demonstrated the linkage of protein expression on IHC to nephron segment-specific sites as important for urinary biomarker validation and linkage to mechanisms.

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.

Tranilast (N-(3'4'-demethoxycinnamoyl)-anthranilic acid (N-5)) is an investigational drug for the prevention of restenosis following percutaneous transluminal coronary revascularization. An increase in bilirubin levels was observed in 12% of patients upon administration of tranilast in a phase III clinical trial. To identify the potential genetic factors that may account for the drug-induced hyperbilirubinemia, we examined polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in over a thousand patients. Our results suggested that the TA repeat polymorphism in UGT1A1, which predisposes some individuals to Gilbert's syndrome, predicted the susceptibility to tranilast-induced hyperbilirubinemia. The (TA)(7)/(TA)(7) genotype was present in 39% of the 127 hyperbilirubinemic patients vs 7% of the 909 controls (P=2 x 10(-22)). Rapid identification of genetic factors accounting for the observed adverse effect during the course of a double-blind clinical trial demonstrated the potential application of pharmacogenetics in the clinical development of safe and effective medicines.

N-Phenylanthranilic acid (NPAA) causes renal papillary necrosis (RPN) in the rat following repeated oral dosing. Non-invasive early detection of RPN is difficult, but a number of potential biomarkers have been investigated, including phospholipid and uronic acid excretion. This study used 1H-nuclear magnetic resonance (NMR) spectroscopic analysis of urine to investigate urinary metabolic perturbations occurring in the rat following exposure to NPAA. Male Alderley Park rats received NPAA (300, 500 or 700 mg kg(-1) day(-1) orally) for 7 days, and urine was collected on days 7-8, 14-15, 21-22 and 28-29. In a separate study, urine was collected on days 1-2, 3-4, 5-6 and 7-8 from rats receiving 500 mg kg(-1) day(-1). Samples were analysed by 1H NMR spectroscopy combined with multivariate data analysis and clinical chemistry. Histopathology and clinical chemistry analysis of terminal blood samples was carried out following termination on days 4, 6, 8 and 29 (4 week time course) and days 2, 4, 6 and 8 (8 day study). Urine analysis revealed a marked, though variable, excretion of beta-hydroxybutyrate, acetoacetate and acetone (ketone bodies) seen on days 3-4, 5-6 and 7-8 of the study. It is postulated that the ketonuria might be secondary to an alteration in fatty acid metabolism due to inhibition of prostaglandin synthesis. In addition, an elevation in urinary ascorbate was observed during the first 8 days of the study. Ascorbate is considered to be a biomarker of hepatic response, probably reflecting an increased hepatic activity due to glucuronidation of NPAA.

The authors retrospectively examined whether long-term administration of tranilast improves semen parameters in severe oligoasthenozoospermia. Fifty-two patients presenting with sperm concentration of less than 10 x 10(6) sperm/mL were enrolled. Subjects were partitioned into 3 groups as follows: patients displaying an atrophic testis with elevated (FSH) (group 1), patients exhibiting normal testicular volume with elevated FSH (group 2), and patients with normal testicular volume and normal FSH levels (group 3). Tranilast (300mg/day) was administered until pregnancy was achieved or for a period of up to 12 months. Sperm concentration was significantly increased at 3 months in 16 subjects (44%) in groups 1 and 3. In group 2, sperm concentration was increased at 12 months (5 of 16 subjects; 31%). Total sperm count was obviously elevated at 3 months in groups 1 and 2, and at 6 months in group 3. Six pregnancies were achieved via natural intercourse. Tranilast, a mast cell blocker, demonstrates a certain clinical benefit in terms of improvement of semen parameters involving severe oligoasthenozoospermia, but it does not appear to afford clinical benefit in long-term administration.

Background: Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI., Methods and Results: In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups (P=0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo (P=0.061 for intent-to-treat population). The primary reason for not completing treatment was > or =1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo, P<0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76+/-0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78+/-0.76 to 80 mm, P=0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm(3), respectively; P=0.16 to 0.72)., Conclusions: Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.

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.

Introduced in the 1930s, the sun filters (chemical screens) are very widely used as they are contained in photo-protective creams and in many other cosmetics. Allergy to sun filters seems to be rare in the general population (< 2%), but more frequent in populations which are suspected of photo-dermatosis (2 to 25%). It is composed of contact allergies, but also photo contact allergies in 45 to 85% of cases. Photo-biological exploration is comprised of application of photopatches and thus is necessary together with epidermotests. Crossed allergies, though rare, may be seen between filters, but also with substances that have a close chemical structure. Treatment such as prevention, if photo-protection is necessary, rest in discarding the causal filter and use of non-allergenic mineral screens.

Tranilast (Rizaben)-induced thrombocytopenia occurring in a 17-year-old man was reported. After withdrawal of the drug, he recovered within a week with oral prednisolone administration. Serological examination revealed no anti-platelet antibody, but platelet-associated IgG (PAIgG) was found. After incubation of peripheral blood of the patient with the drug in vitro, the level of PAIgG was significantly increased. These findings suggest the presence of a drug-dependent anti-platelet IgG in the patient's serum. This is the first report of immune thrombocytopenia caused by Tranilast. Our method for detecting drug-dependent platelet antibody in vitro is safe and useful for diagnosing drug-induced thrombocytopenia.

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.

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 prophylactic effect of tolfenamic acid and propranolol was studied in a randomized double-blind cross-over trial of 76 patients with migraine with or without aura. After a 4-week run-in period patients were randomly allocated to treatment with either tolfenamic acid 100 mg three times daily or propranolol 40 mg three times daily for 12 weeks. After a placebo wash-out period of 4 weeks the patients got the alternative drug for 12 weeks; 56 patients completed the study. Both drugs significantly reduced migraine attacks as judged from the reduction in the efficacy parameters (migraine hours, migraine days, and migraine intensity) in the treatment periods compared with the run-in period. No statistical significant difference in any efficacy parameter was found between the two drugs (level 2 alpha = 0.05, alpha = 0.10). The adverse effects showed no statistical difference in frequency between the 2 treatments. Twenty patients discontinued the study: 12 patients on propranolol and 8 patients on tolfenamic acid. Side effects were the cause of premature discontinuation of study medicine in 9 patients during propranolol treatment (dizziness, fatigue, and fall in blood pressure) and in 5 patients during tolfenamic acid treatment (gastrointestinal symptoms).

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.

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)

Anthranilic acid derivatives are a group of nonsteroidal antiinflammatory drugs that include glafenine and fenamates. We report a woman who had immediate adverse reactions to glafenine and meclofenamate sodium. Skin prick and intradermal tests were performed with solutions of glafenine and meclofenamate in phosphate-buffered saline (PBS) and with the drugs bound to human serum albumin (HSA). Prick and intradermal tests with PBS solutions were negative for both drugs as were prick tests with HSA solutions. Intradermal tests with HSA-glafenine, however, were positive at 20 minutes, and at 6 and 24 hours. Intradermal tests with HSA-meclofenamate elicited a positive response at 6 and 24 hours. These tests were negative when performed in control subjects. A leukocyte histamine release test and a RAST assay were negative for both drugs. The patient was challenged following a double-blind placebo-controlled oral procedure and tolerated therapeutic doses of aspirin, indomethacin, ibuprofen, dipyrone, diclofenac, piroxicam, and acetaminophen. The oral challenge with glafenine and meclofenamate reproduced the reactions (eliciting doses: 50 mg and 15 mg, respectively), and the patient also reacted to 30 mg of mefenamic acid, an anthranilic acid derivative she had never previously received. This is an exceptional case of selective adverse reactions to glafenine and fenamates, anthranilic acid derivatives, in a patient tolerating aspirin and other cyclooxygenase inhibitors. Our study implicates an immunologic mechanism, and the existence of cross-reactivity between the drugs (or some active metabolite generated in vivo).