Fitness Costs of Chlorantraniliprole Resistance Related to the SeNPF Overexpression in the Spodoptera exigua (Lepidoptera: Noctuidae).

Spodopteraexigua, 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 RyRI4743M 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.

Clinical safety and efficacy of neoadjuvant combination chemotherapy of tranilast in advanced esophageal squamous cell carcinoma: Phase I/II study (TNAC).

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.

Sublethal effects of anthranilic diamide insecticides on the demographic fitness and consumption rates of the Coccinella septempunctata (Coleoptera: Coccinellidae) fed on Aphis craccivora.

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 (R0), 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 (C0), 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.

Growth, DNA damage and biochemical toxicity of cyantraniliprole in earthworms (Eisenia fetida).

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.

Changes in novel gastrointestinal and renal injury markers in the blood plasma of sheep following increasing intravenous doses of tolfenamic acid.

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.

Pharmacokinetics and bioavailability of tolfenamic acid 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 (AUC0-∞ ), elimination half-life (t1/2ʎz ), 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 (Cmax ) and time to reach Cmax (Tmax ), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC0-∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC0-∞ was linear. Both t1/2ʎz and MRT increased depending on the dose. Although the total clearance (ClT ) decreased depending on dose, the volume of distribution at steady-state (Vss ) 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.

Tolfenamic Acid.

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.

The Effect of Tranilast 8% Liposomal Gel Versus Placebo on Post-Cesarean Surgical Scars: A Prospective Double-Blind Split-Scar Study.

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.

Naftopidil Improves Symptoms in a Rat Model of Tranilast-Induced Interstitial Cystitis.

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.

Exploration of efficacy and bleeding with combined phosphoinositide 3-kinase ß inhibition and aspirin in man.

BACKGROUND: Based on animal and human data, phosphoinositide 3-kinase (PI3K)ß is a promising antithrombotic target. However, the relation between efficacy and bleeding when combined with current antiplatelet therapies is unclear. OBJECTIVE: To strengthen the PI3Kß 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 PI3Kß (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  > PI3Kß > COX-1 as monotherapy and P2Y12 plus PI3Kß > P2Y12 plus COX-1 > PI3Kß 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 PI3Kß 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: PI3Kß inhibition, in comparison with P2Y12 and COX-1, delivers medium antiplatelet effect but with minimal bleeding. PI3Kß 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.

Tranilast: a review of its therapeutic applications.

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-ß 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.

A pilot study of scheduled endoscopic balloon dilation with oral agent tranilast to improve the efficacy of stricture dilation after endoscopic submucosal dissection of the esophagus.

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.

Design, synthesis and anti-inflammatory activity of structurally simple anthranilic acid congeners devoid of ulcerogenic side effects.

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.

Human target validation of phosphoinositide 3-kinase (PI3K)ß: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kß inhibitor.

BACKGROUND: Based on in vitro and animal data, PI3Kß is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear. OBJECTIVE: To strengthen the PI3Kß target validation using the novel, short-acting inhibitor AZD6482. METHODS AND RESULTS: AZD6482 is a potent, selective and ATP competitive PI3Kß 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 PI3Kß 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.

Evaluating the effects of 14-day oral vedaprofen and tolfenamic acid treatment on renal function, hematological and biochemical profiles in healthy cats.

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.

Preliminary results of tranilast treatment for patients with advanced castration-resistant prostate cancer.

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.

Susceptibility of Choristoneura rosaceana (Lepidoptera: Tortricidae) to two new reduced-risk insecticides.

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.

Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats.

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.

Safety and efficacy of intracapsular tranilast microspheres in experimental posterior capsule opacification.

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.