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Purpose: To compare topical nonsteroidal anti-inflammatory drug (NSAID) efficacy on intravitreal injection-induced pain reduction and determine the most efficient topical NSAID., Methods: This randomized-controlled study included 662 eyes of 662 patients. Based on the types of NSAID administered before intravitreal injection, eight subgroups were formed. In the control group, a sterile saline solution was applied instead of NSAIDs. The visual analog scale was used to assess pain scores after intravitreal injection. The visual analog scale scores were noted immediately and 6 hours following injection (sixth hour)., Results: Nepafenac 0.3%, nepafenac 0.1%, and bromfenac 0.09% had the lowest scores, immediately after and after 6 hours, with no significant differences. Diclofenac and ketorolac had higher visual analog scale scores than the first trio but lower scores than the control group. Flurbiprofen, pranoprofen, and indomethacin did not significantly affect immediate pain; however, at the sixth hour, the visual analog scale scores were significantly reduced., Conclusion: Nepafenac 0.3%, nepafenac 0.1%, and bromfenac 0.09% were the most effective NSAIDs for pain reduction. Although some NSAIDs did not have a significant effect on immediate pain, they all provided significant benefits at the sixth hour.

Purpose: To compare the efficacy of topical nepafenac 0.1% versus intravitreal triamcinolone acetonide (IVTA) at the conclusion of vitrectomy surgery versus no adjuvant therapy (NAT) in improving macular morphology post-operatively in patients undergoing vitrectomy for epiretinal membrane (ERM), as measured by optical coherence tomography (OCT) imaging and best-corrected visual acuity (BCVA)., Methods: Design: Prospective randomized clinical trial Setting: Multi-centre 80 patients scheduled to undergo vitrectomy surgery for idiopathic ERM were randomized to receive either IVTA (4 mg/0.1 cc) at the end of surgery, topical nepafenac sodium 0.1% TID for 1 month post-operation or no adjuvant treatment (NAT). Optical coherence tomography (OCT) imaging, best-corrected visual acuity and intraocular pressure (IOP) were measured before surgery, and 1 and 2 months post-operation., Results: Although all three groups showed reduction in macular thickness post-operation, the NAT group showed the most improvement, with a reduction of 136.18 ± 29.84 μm at two months. There was no statistically significant difference in macular thickness between the groups at each time point, p = 0.158. The NAT group also had the best recovery in BCVA with an improvement of 0.207 logMAR (10.35 letters) at two months post-operation. There was no statistically significant difference in BCVA between the groups, p = 0.606. There was statistically significant difference in the IOP between the three groups, p = 0.04 only at 1-month visit. The IVTA group had the highest rise in average IOP at both 1 and 2 months post-operation (2.72 and 1.58 mmHg, respectively)., Conclusion: Our study data suggest there was no advantage in the use of topical nepafenac or IVTA for post-vitrectomy ERM surgery., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption., Competing Interests: The authors would like to declare the following patents/patent applications associated with this research. Calithera Biosciences, Inc., has patent rights in several issued and pending applications related to telaglenastat and its use. Telaglenastat is in clinical development in a number of cancer indications (ClinicalTrials.gov Identifier: NCT04265534). This does not alter the authors adherence to PLOS ONE policies on sharing data and materials.

Background Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutaminase 1) activity, is mechanoactivated by matrix stiffening and the transcriptional coactivators YAP1 (yes-associated protein 1) and transcriptional coactivator with PDZ-binding motif (TAZ), resulting in pulmonary vascular proliferation and PH. Pharmacologic inhibition of YAP1 (by verteporfin) or glutaminase (by CB-839) improved PH in vivo. However, systemic delivery of these agents, particularly YAP1 inhibitors, may have adverse chronic effects. Furthermore, simultaneous use of pharmacologic blockers may offer additive or synergistic benefits. Therefore, a strategy that delivers these drugs in combination to local lung tissue, thus avoiding systemic toxicity and driving more robust improvement, was investigated. Methods and Results We used poly(lactic-co-glycolic) acid polymer-based microparticles for delivery of verteporfin and CB-839 simultaneously to the lungs of rats suffering from monocrotaline-induced PH. Microparticles released these drugs in a sustained fashion and delivered their payload in the lungs for 7 days. When given orotracheally to the rats weekly for 3 weeks, microparticles carrying this drug combination improved hemodynamic (right ventricular systolic pressure and right ventricle/left ventricle+septum mass ratio), histologic (vascular remodeling), and molecular markers (vascular proliferation and stiffening) of PH. Importantly, only the combination of drug delivery, but neither verteporfin nor CB-839 alone, displayed significant improvement across all indexes of PH. Conclusions Simultaneous, lung-specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease.

The eukaryotic elongation factor-2 kinase, eEF2K, which restricts protein translation elongation, has been identified as a potential therapeutic target for diverse types of malignancies including triple negative breast cancer (TNBC). However, the contexts in which eEF2K inhibition is essential in TNBC and its consequences on the proteome are largely unknown. Here we show that genetic or pharmacological inhibition of eEF2K cooperated with glutamine (Gln) starvation, and synergized with glutaminase (GLS1) inhibitors to suppress growth of diverse TNBC cell lines. eEF2K inhibition also synergized with depletion of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1; 4EBP1), a suppressor of eukaryotic protein translation initiation factor 4E (eIF4E), to induce c-MYC and Cyclin D1 expression, yet attenuate growth of TNBC cells. Proteomic analysis revealed that whereas eEF2K depletion alone uniquely induced Cyclin Dependent Kinase 1 (CDK1) and 6 (CDK6), combined depletion of eEF2K and 4EBP1 resulted in overlapping effects on the proteome, with the highest impact on the 'Collagen containing extracellular matrix' pathway (e.g. COL1A1), as well as the amino-acid transporter, SLC7A5/LAT1, suggesting a regulatory loop via mTORC1. In addition, combined depletion of eEF2K and 4EBP1 indirectly reduced the levels of IFN-dependent innate immune response-related factors. Thus, eEF2K inhibition triggers cell cycle arrest/death under unfavourable metabolic conditions such as Gln-starvation/GLS1 inhibition or 4EBP1 depletion, uncovering new therapeutic avenues for TNBC and underscoring a pressing need for clinically relevant eEF2K inhibitors.

The efficacy of ionizing radiation (IR) for head and neck cancer squamous cell carcinoma (HNSCC) is limited by poorly understood mechanisms of adaptive radioresistance. Elevated glutaminase gene expression is linked to significantly reduced survival (p < 0.03). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in Phase I/II cancer trials and is well tolerated by patients. This study investigated if telaglenastat enhances the cellular response to IR in HNSCC models. Using three human HNSCC cell lines and two xenograft mouse models, we examined telaglenastat's effects on radiation sensitivity. IR and telaglenastat combinatorial treatment reduced cell survival (p ≤ 0.05), spheroid size (p ≤ 0.0001) and tumor growth in CAL-27 xenograft bearing mice relative to vehicle (p ≤ 0.01), telaglenastat (p ≤ 0.05) or IR (p ≤ 0.01) monotherapy. Telaglenastat significantly reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells in the presence of glucose and glutamine (p ≤ 0.0001). Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells. These data suggest that combination treatment with IR and telaglenastat leads to an enhanced anti-tumor response. This pre-clinical data, combined with the established safety of telaglenastat justifies further investigation for the combination in HNSCC patients., (Published by Elsevier B.V.)

Recent evidence suggests that kappa opioid receptors (KOR) in limbic brain regions such as the amygdala contribute to pain conditions, but underlying mechanisms remain to be determined. The amygdala is an important player in averse-affective aspects of pain and pain modulation. The central nucleus (CeA) serves output functions through projection neurons that include corticotropin releasing factor (CRF) expressing neurons. The CeA is also rich in KOR. Here we tested the novel hypothesis that KOR activation in the CeA generates pain-like behaviors through a mechanism that involves inhibition of synaptic inhibition (disinhibition) of CRF neurons. Intra-CeA administration of a KOR agonist (U-69,593) increased vocalizations of naïve rats to noxious stimuli, and induced anxiety-like behaviors in the open field test (OFT) and avoidance in the conditioned place preference test, without affecting mechanosensory thresholds. Optogenetic silencing of CeA-CRF neurons blocked the facilitatory effects of systemically applied U-69,593 in naïve rats. Patch-clamp recordings of CRF neurons in rat brain slices found that U-69,593 decreased feedforward inhibitory transmission evoked by optogenetic stimulation of parabrachial afferents, but had no effect on monosynaptic excitatory transmission. U-69,593 decreased frequency, but not amplitude, of inhibitory synaptic currents, suggesting a presynaptic action. Multiphoton imaging of CeA-CRF neurons in rat brain slices showed that U-69,593 increased calcium signals evoked by electrical stimulation of presumed parabrachial input. This study shows for the first time that KOR activation increases activity of amygdala CRF neurons through synaptic disinhibition, resulting in averse-affective pain-like behaviors. Blocking KOR receptors may therefore represent a novel therapeutic strategy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose : To quantify the intraocular inflammation, measured using laser flare photometry (LFP), after Nd:YAG capsulotomy and compare the effects of different topical anti-inflammatory regimes. Methods : A single-center, prospective, randomized controlled study, which included 90 eyes of 90 patients with visually significant posterior capsular opacification. In all patients, Nd:YAG capsulotomy was done and was then randomized into three groups: (A) Topical betamethasone 0.1%; (B) Topical nepafenac 0.1%; and (C) Control group: did not receive any anti-inflammatory agent post capsulotomy. Results : There was a significant increase in the mean LFP values 2 h following laser capsulotomy ( p < 0.001) and then declined gradually and came back to pre-laser values by 2 weeks in all three groups. The mean LFP values, central macular thickness, and best corrected visual acuity were comparable among groups. None developed central macular edema. Conclusion : Intraocular inflammation following Nd:YAG capsulotomies is minimal and transient. Routine use of prophylactic anti-inflammatory agents may be avoided.

Purpose: To determine the effect of preoperative topical Nepafenac administration on anterior chamber flare after uneventful cataract surgery in healthy subjects., Methods: Prospective randomized clinical trial. Seventy-three eyes of 73 healthy patients undergoing routine cataract surgery were randomized to receive (group A) topical nepafenac (1 mg/ml) or not to receive (group B) 1 drop 3 times per day for 3 days before surgery. All eyes received the same postoperative anti-inflammatory therapy. Clinical outcome parameters such as best corrected visual acuity, intraocular pressure, retinal central foveal thickness and aqueous flare were recorded preoperatively, 1, 15, 30 and 60 days after surgery., Results: Three patients were excluded for poor compliance, and three patients were excluded or developing pseudophakic macular oedema during the follow-up. Both groups were comparable for age, gender, and showed similar BCVA, intraocular pressure and central macular thickness values preoperatively and during the entire follow-up (p > 0.01). Aqueous flare values showed a statistically increase in both groups respect to preoperative values through follow-up evaluations (p < 0.01), while values were significantly lower in group A than in group B 30 days after surgery (p < 0.01)., Conclusion: Preoperative administration of topical Nepafenac reduces the inflammatory response in healthy patients undergoing uncomplicated cataract surgery one month after surgery respect to non-treated group., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Introduction: There are currently no approved targeted therapies for lung squamous-cell carcinoma (LSCC) and KRAS-mutant lung adenocarcinoma (LUAD). About 30% of LSCC and 25% of KRAS-mutant LUAD exhibit hyperactive NRF2 pathway activation through mutations in NFE2L2 (the gene encoding NRF2) or its negative regulator, KEAP1. Preclinical data demonstrate that these tumors are uniquely sensitive to dual inhibition of glycolysis and glutaminolysis via mammalian target of rapamycin (mTOR) and glutaminase inhibitors. This phase 1 study was designed to assess safety and preliminary activity of the mTOR inhibitor MLN0128 (sapanisertib) in combination with the glutaminase inhibitor CB-839 HCl., Methods: Phase 1 dose finding will use the queue-based variation of the 3 + 3 dose escalation scheme with the primary endpoint of identifying the recommended expansion dose. To confirm the acceptable tolerability of the recommended expansion dose, patients will subsequently enroll onto 1 of 4 expansion cohorts (n = 14 per cohort): (1) LSCC harboring NFE2L2 or (2) KEAP1 mutations, or (3) LUAD harboring KRAS/(KEAP1 or NFE2L2) coalterations, or (4) LSCC wild type for NFE2L2 and KEAP1. The primary endpoint of the dose expansion is to determine the preliminary efficacy of MLN0128/CB-839 combination therapy., Conclusion: This phase 1 study will determine the recommended expansion dose and preliminary efficacy of MLN0128 and CB-839 in advanced non-small-cell lung cancer with a focus on subsets of LSCC and KRAS-mutant LUAD harboring NFE2L2 or KEAP1 mutations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

PIK3CA encodes the p110α catalytic subunit of PI3K and is frequently mutated in human cancers, including ∼30% of colorectal cancer. Oncogenic mutations in PIK3CA render colorectal cancers more dependent on glutamine. Here we report that the glutaminase inhibitor CB-839 preferentially inhibits xenograft growth of PIK3CA -mutant, but not wild-type (WT), colorectal cancers. Moreover, the combination of CB-839 and 5-fluorouracil (5-FU) induces PIK3CA -mutant tumor regression in xenograft models. CB-839 treatment increased reactive oxygen species and caused nuclear translocation of Nrf2, which in turn upregulated mRNA expression of uridine phosphorylase 1 (UPP1). UPP1 facilitated the conversion of 5-FU to its active compound, thereby enhancing the inhibition of thymidylate synthase. Consistently, knockout of UPP1 abrogated the tumor inhibitory effect of combined CB-839 and 5-FU administration. A phase I clinical trial showed that the combination of CB-839 and capecitabine, a prodrug of 5-FU, was well tolerated at biologically-active doses. Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that PIK3CA -mutant patients with colorectal cancer might derive greater benefit from this treatment strategy as compared with PIK3CA WT patients with colorectal cancer. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA -mutant colorectal cancers and warrants further clinical evaluation. SIGNIFICANCE: Preclinical and clinical trial data suggest that the combination of CB-839 with capecitabine could serve as an effective treatment for PIK3CA -mutant colorectal cancers., (©2020 American Association for Cancer Research.)

Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLS high cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. SIGNIFICANCE: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4514/F1.large.jpg., (©2020 American Association for Cancer Research.)

Purpose: To evaluate the vitreous concentration of different nonsteroidal anti-inflammatory drugs (NSAIDs) after topical administration and the related prostaglandin E2 (PGE2) levels in patients undergoing pars plana vitrectomy., Methods: A prospective, randomized, investigator-masked study was performed. One hundred four patients scheduled for a pars plana vitrectomy for an epiretinal membrane or a macular hole were randomized to receive topical diclofenac 0.1%, indomethacin 0.5%, nepafenac 0.3%, bromfenac 0.09%, or placebo 3 days before surgery. At the beginning of surgery, a sample of undiluted vitreous was collected in each patient to assess NSAIDs concentration and PGE2 levels., Results: The median vitreous concentrations were 203.35 (interquartile range 146.54-264.18) pg/mL for diclofenac, 243.45 (interquartile range 156.96-365.37) pg/mL for nepafenac, 438.21 pg/mL (interquartile range, 282.52-645.87) for its active metabolite amfenac, 350.14 (interquartile range, 290.88-481.95) pg/mL for indomethacin, and 274.59 (245.43-358.25) pg/mL for bromfenac. Vitreous PGE2 levels were significantly lower for all the NSAIDs groups compared with the control group (P < 0.001). A statistically significant higher vitreous PGE2 level was found in the diclofenac group compared with the other NSAIDs groups (P < 0.05)., Conclusion: Topical NSAIDs achieve sufficient vitreous concentration to decrease vitreous PGE2 levels compared with the control group. The different efficacy in reducing PGE2 concentration may affect the management of posterior segment inflammation.

Purpose: To compare 0.1% nepafenac, a topical nonsteroidal anti-inflammatory drop, with 1% prednisolone acetate in controlling inflammation after neodymium:yttrium-aluminum-garnet laser peripheral iridotomy (LPI) in primary angle-closure suspects (PACS)., Design: Randomized controlled trial., Participants: One hundred fifty-two PACS undergoing bilateral LPI., Methods: Patients were randomized to 0.1% nepafenac or 1% prednisolone acetate eye drops in both eyes. Medications were given 4 times daily for 7 days, then twice daily for additional 7 days. Investigators were masked to the type of medication. Right eyes in patients with bilateral PACS and the PACS eye in asymmetrical disease (primary angle closure in fellow eye) were analyzed., Main Outcome Measures: Noninferior control of inflammation, defined as absence of cell in the anterior chamber at 2 weeks and absence of rebound iritis with medication discontinuation, was the primary outcome, whereas difference in the rise in intraocular pressure (IOP) was a secondary outcome., Results: Both groups were comparable in baseline characteristics, including IOP and total laser energy. Nepafenac was noninferior to prednisolone with regard to inflammation control, with 1 nepafenac-treated eye (1.3%) not meeting the primary end point because of 1+ anterior chamber cell at 2 weeks and 4 prednisolone-treated eyes (5.4%) failing to meet the primary end point because of rebound iritis (P < 0.001). A greater increase in IOP from baseline to 2 weeks was observed in the prednisolone group compared with the nepafenac group (+2.6 mmHg vs. +0.6 mmHg; P = 0.004), although at 4 weeks, IOP was not significantly different than baseline in either group (P > 0.05 for both). Two weeks after LPI, 3 nepafenac-treated eyes and 10 prednisolone-treated eyes demonstrated a 6- to 15-mmHg IOP elevation from baseline (P = 0.10), whereas 2 prednisolone-treated eyes and no nepafenac-treated eyes showed IOP elevation of more than 15 mmHg (P = 0.20). Four weeks after LPI, more prednisolone-treated eyes showed IOP elevation of 6 to 15 mmHg as compared with nepafenac-treated eyes (6 eyes vs. 1 eye; P = 0.04); no eyes showed IOP elevation of more than 15 mmHg., Conclusions: Nepafenac was noninferior to prednisolone in controlling inflammation after LPI in PACS., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1 R132H (loss of wild-type allele), heterozygous IDH1 R132H is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1 R132H biology and the underlying mechanism of the glutamate effect., Methods: RNA sequencing data of IDH1 R132H -heterozygous and IDH1 R132H -hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1 R132H -heterozygous and IDH1 R132H -hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 gene (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1 R132H -heterozygous cells., Results: In contrast to IDH1 R132H -heterozygous cells, 3D-cultured but not 2D-cultured IDH1 R132H -hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1 R132H -heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation., Conclusion: 3D culture is more relevant to IDH1 R132H glioma biology. The importance of redox homeostasis in IDH1 R132H glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1 R132H inhibitors may have counterproductive consequences in patient treatment.

Acute myeloid leukemia (AML) is an aggressive hematopoietic disease characterized by glutamine-dependent metabolism. A novel glutaminase (GLS) inhibitor, CB-839, is currently under evaluation for treatment of hematopoietic malignancies and solid tumors. Our purpose was to measure cellular changes in AML associated with CB-839 treatment and to test the ability of hyperpolarized pyruvate for interrogating these changes to OCI-AML3 cells. Our results show that treatment with CB-839 interfered with the citric acid cycle, reduced the NADH/NAD + ratio and ATP levels, reduced cell proliferation and viability, and reduced the basal and maximal respiratory capacities [oxygen consumption rate (OCR)]. We observed a reduction of the conversion of hyperpolarized pyruvate to lactate in cell lines and in a mouse AML model after CB-839 treatment. Our in vitro and in vivo results support the hypothesis that, in AML, glutamine is utilized to generate reducing equivalents (NADH, FADH 2 ) through the citric acid cycle and that reduction in redox state by GLS inhibition decreases the rate of pyruvate to lactate conversion catalyzed by lactate dehydrogenase. We propose hyperpolarized pyruvate/lactate measurement as a method for direct monitoring of metabolic changes occurring in AML patients receiving CB-839. With further optimization, this method may provide a noninvasive imaging tool to assess the early efficacy of therapeutic intervention with GLS inhibitors., (©2019 American Association for Cancer Research.)

Purpose: Pain after an intravitreal injection (IVI) can last up to 7 days and negatively impacts the patient's experience, potentially reducing treatment compliance. We prospectively evaluated topical nepafenac 0.3% suspension and patching for the reduction of pain after IVI., Design: Randomized controlled trial., Participants: Sixty patients receiving an IVI of bevacizumab, aflibercept, or triamcinolone acetonide in 1 eye., Methods: Participants were randomized equally to receive either a single drop of nepafenac 0.3%, a pressure patch for 2 hours, or a single drop of preservative-free artificial tears (control group). A single-blinded placebo-controlled design was used to mask the topical treatment used. Pain was assessed using the Numeric Pain Rating Scale that ranged from 0 to 10 (horizontal pain scale). Because pain scores were not normally distributed, statistical analysis was performed using a nonparametric randomization-based analysis of covariance., Main Outcome Measure: Pain scores., Results: Fifty-six and 53 patients of the 60 patients enrolled completed the 6- and 24-hour follow-ups, respectively. Numeric Pain Rating Scale scores at 6 and 24 hours after IVI were lower in the nepafenac group (0.8±0.3 and 0.1±0.1, respectively; n = 18) and the patching group (1.3±0.4 and 0.4±0.2, respectively; n = 19) compared with the control group (2.5±0.6 and 0.9±0.4, respectively; n = 19). After controlling for age, gender, number of prior injections, and physician administering the injection, patients in the nepafenac group reported significantly lower pain scores than those in the control group at 6 hours (1.3±0.6 less; P = 0.047) and 24 hours (0.7±0.3 less; P = 0.047). Although the patching group reported lower pain scores than the control group, this was not statistically significant (6 hours, P = 0.24; 24 hours, P = 0.29)., Conclusions: Nepafenac 0.3% was effective as a single drop in reducing pain at 6 and 24 hours after IVI compared with placebo. Limited patching was associated with lower pain scores than placebo, but the difference was not statistically significant. Additional studies are needed to determine the most effective method to maximize the patient's experience after an IVI without sacrificing outcomes., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine preoperative anti-inflammatory treatment on recovery from cataract surgery in eyes of diabetic patients., Methods: A Prospective randomized clinical trial. One hundred and three eyes of 103 patients with diabetes undergoing routine cataract surgery were randomized (1:1) not to receive any preoperative anti-inflammatory medication or to receive preoperative topical anti-inflammatory medication with a combination of prednisolone acetate (10 mg/ml) and nepafenac (1 mg/ml). All eyes received postoperative anti-inflammatory combination therapy for 3 weeks. Recovery from surgery was recorded by a structured home questionnaire. Clinical outcome parameters were recorded at 28 days and 3 months., Results: Patient age and gender distribution, and all baseline ophthalmic and systemic parameters were comparable between the study groups. After surgery, conjunctival injection lasted 2.4 ± 1.7 days (mean ± SD) and irritation of the eye 3.3 ± 3.9 days in eyes without preoperative treatment, when compared to 1.6 ± 1.6 days (p = 0.067) and 2.4 ± 4.0 days (p = 0.431), respectively, in eyes with preoperative treatment. At 28 days, central subfield macular thickness (CSMT) increased 2.2 ± 20.2 μm in eyes without preoperative treatment, when compared 0.1 ± 25.2 μm (p = 0.670) in eyes with preoperative treatment. At 3 months, the respective CSMT change from baseline was -1.5 ± 26.9 μm and -3.4 ± 26.2 μm (p = 0.762). None of the eyes were reported with pseudophakic cystoid macular oedema (PCME) in either group., Conclusion: Lack of preoperative anti-inflammatory treatment does not impair recovery from surgery or predispose diabetic patients to increased risk of PCME in eyes postoperatively treated with combination therapy of prednisolone acetate and nepafenac., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To evaluate the analgesic effect of nepafenac 0.3% in patients undergoing intravitreal injections (IVI) of antivascular endothelial growth factors., Methods: This is a single-center, prospective, randomized, blinded, triple-arm, placebo-controlled interventional study. Patients were randomized into 3 Groups. Group 1 (n = 33) received nepafenac 0.1%, Group 2 (n = 32) received nepafenac 0.3%, and Group 3 (n = 31) received placebo 40 min before IVI. Using the short form of the McGill Pain Questionnaire (SF-MPQ), pain intensity was assessed with the visual analog scale (VAS), the Main Component of the SF-MPQ, and the present pain intensity (PPI) scores immediately and 6 h postinjection., Results: Immediately after IVI, the VAS pain score was statistically significantly lower in patients treated with nepafenac 0.1% and 0.3%, compared with placebo (P < 0.001 and P = 0.001, respectively). The PPI scores were statistically significantly lower when nepafenac 0.1% or 0.3% was instilled compared with placebo (P = 0.01 and P < 0.0001, respectively). The Main Component of the SF-MPQ scores were statistically significantly lower after nepafenac 0.1% and 0.3% administration compared with placebo (P = 0.001 and P < 0.001, respectively). Six hours post-IVI the nepafenac 0.3% demonstrated statistically significantly higher analgesic effect compared with nepafenac 0.1% and placebo as this was indicated by the VAS pain score (P = 0.013 and P < 0.00001, respectively) and by the PPI score (P = 0.01 and P < 0.00001, respectively)., Conclusions: A single instillation of nepafenac 0.1% or 0.3% before IVI could effectively alleviate the IVI-related pain. The 0.3% formula exerts its analgesic effect more intensively at 6 h after the IVI.

FLZ is a novel anti-Parkinson's disease candidate drug. The main active metabolite is FLZ O-dealkylation (M1) in preclinical studies. A reliable ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) quantitation method was developed for the simultaneous determination of FLZ and M1 with low limits of quantitation in human plasma (0.1 ng/mL) and urine (0.5 ng/mL). The plasma and urine samples were both purified by full-automatic solid phase extraction (SPE) method with ensured high extraction recovery and little matrix effect for both analytes, and then separated on a BEH C 18 column (2.1 × 50 mm, 1.7 μm). Detection and quantification were performed using an electrospray ionization (ESI) source in positive mode by multiple reaction monitoring (MRM). The precursor to product ion transitions were monitored at m/z 450.3 + →313.2 + for FLZ, m/z 436.3 + →299.1 + for M1, m/z 462.6 + →142.0 + for [D 12 ]-FLZ (internal standard of FLZ) and m/z 447.2 + →125.2 + for [D 11 ]-M1 (internal standard of M1), respectively. This method showed good linearity, accuracy, precision and stability in the range of 0.1-100 ng/mL in plasma and 0.5-500 ng/mL in urine of two analytes. Finally, the developed method was successfully applied to a pharmacokinetic research in Chinese healthy volunteers after oral administration of FLZ tablets., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: To compare patient-reported tolerability, impact on quality of life, interference with activities of daily life, and ocular surface toxicity of branded nepafenac 0.3% and generic ketorolac 0.5% after cataract surgery., Setting: Harvard Eye Associates, Laguna Hills, California, and the Cincinnati Eye Institute, Ohio, USA., Design: Prospective case series., Methods: One eye of each patient was randomized to receive ketorolac 0.5% or nepafenac 0.3% topical eyedrops for 3 days preoperatively and 28 days postoperatively. Additional medications were moxifloxacin 0.5% 4 times a day 3 days preoperatively and 7 days postoperatively and difluprednate 0.05% twice a day for 1 week postoperatively. Primary endpoints were patient-reported tolerability of each drug, the related impact on quality of life, and activities of daily life. Secondary endpoints were differences in conjunctival hyperemia, anterior chamber inflammation, tear breakup time (TBUT), and corneal staining., Results: Baseline characteristics were similar between the nepafenac group (n = 91) and the ketorolac group (n = 90). Burning and stinging lasted longer in the ketorolac group, while blurry/hazy/foggy vision and a film or coating on the eye lasted longer in the nepafenac group (all P < .0001). All objective measures were statistically significant for ketorolac 0.5% versus nepafenac 0.3% as follows: corneal staining (64% versus 28%); Oxford grade 2 or greater staining (28% versus 4%); Schulze grade 30 or greater conjunctival erythema (65% versus 36%, respectively); abnormal TBUT greater than 10 seconds (77% versus 51%) (all P < .0001)., Conclusion: Branded nepafenac 0.3%-treated patients had significantly better objective and subjective outcomes after cataract surgery than generic ketorolac 0.5%-treated patients., (Copyright © 2018 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Nepafenac is a water-insoluble nonsteroidal antiinflammatory drug that is available as an ophthalmic suspension (Nevanac®). Suspensions are undesirable for 2 reasons: they tend to cause foreign body sensation and lacrimation, which could limit residence time and drug bioavailability. This decreases the amount of time the drug has to reach the site of action, the cornea. Previously, we improved the solubility and ocular permeability of nepafenac by complexing the drug with hydroxypropyl-β-cyclodextrin. In this study, we used the complex to formulate an ion-activated in situ gel system using sodium alginate, Protanal PH 1033, to increase the residence time and to reduce repeat eye drop instillation. Rheological properties of the formulations revealed that the viscosity of the optimized formulation was increased 30-fold when exposed to the simulated tear fluid (35°C). Permeation studies showed that the drug concentration of the in situ formulations were approximately 10 times higher than the commercial product, Nevanac® (p < 0.001). In addition, the in situ gel formulations had 5-fold higher concentrations of nepafenac retained in the cornea when compared to Nevanac® (p <0.001). Finally, ex vivo drug distribution studies in the porcine eye perfusion model revealed a higher drug retention in various ocular tissues such as cornea, sclera, retina, as compared to Nevanac®., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Current cataract surgery guidelines recommend routine use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing pseudophakic cystoid macular oedema (PCME). Here, we compare the clinical efficacy and tolerability of two potent NSAIDs, nepafenac and preservative-free diclofenac following cataract surgery., Methods: Randomized, double-blind, prospective single-centre study. Ninety-six eyes of 95 patients undergoing routine cataract surgery were randomized 1:1 either to nepafenac (Nevanac, 1 mg/ml) or diclofenac (Dicloabak, 1 mg/ml) for 3 weeks. Seventy-three patients accounting for 73 eyes completed the entire follow-up. Aqueous flare and central retinal thickness (CRT) analysis were conducted preoperatively and at control visits 28 days and 3 months after surgery. A structured home questionnaire and interview were used to record any adverse effects of the topical medications, subjective visual recovery and the dispenser's ease of use., Results: No differences were observed between the groups for aqueous flare, CRT, speed of recovery or visual acuity gain. Seven patients (16%) on nepafenac and 20 patients (48%) on preservative-free diclofenac reported symptoms related to topical use of NSAID medications (p = 0.001)., Conclusion: No differences in clinical efficacy were found between potent NSAIDs, while tolerability might be an issue., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To investigate the effectiveness of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of cystoid macular edema (CME) post Descemet's stripping automated endothelial keratoplasty (DSAEK)., Study Design: Retrospective observational study METHODS: In this study of 334 patients who underwent DSAEK at the Baptist Eye Institute, Kyoto, Japan between July 2011 and December 2015, 18 patients with postoperative CME (determined by optical coherence tomography) treated with topical NSAIDs after the onset of CME were included., Results: At CME onset, 17 of the 18 patients were treated with bromfenac eye drops and 1 was treated with nepafenac eye drops. Post initiation of treatment with topical NSAIDs, CME in 17 (94.4%) of the 18 patients improved at 1 month and all cases completely recovered within 3 months. At 12-months post initiation of treatment, 61.1% (n = 11) of patients achieved a visual acuity (VA) of 20/40 or better, and there was no significant difference of VA between the patients with or without an episode of postoperative CME (P = 0.55)., Conclusion: The administration of topical NSAID eye drops was found to be effective in treating patients with CME post DSAEK.

Purpose: To evaluates analgesic effectiveness of 0.1% nepafenac during cataract surgery., Methods: This prospective randomized randomized double-masked, placebo-controlled study comprised 80 eyes of 40 consecutive patients who underwent bilateral cataract surgery and implantation of foldable intraocular lens with topical anesthesia with and without topical nepafenac drops. Each eye of patients was assigned to group 1 and group 2. Topical anesthesia combined with 0.1% nepafenac used three times a day the day before the surgery and once half an hour just before the surgery was group 1, consisting of 40 eyes, and topical anesthesia with using placebo was group 2 consisting of 40 eyes. Patients were asked to score their pain using a visual analog scale (VAS) and verbal pain scale (VPS) immediately following the surgery. When the patient moved or squeeze the eye during surgery, the surgical comfort was evaluated as bad and otherwise, it was evaluated as good., Results: When the intensity of pain during the surgery was evaluated, the percentage of patients reporting mild or no pain in group 1 was %825 and in group 2 was %45. Mean VAS pain score and mean VPS pain score in group 1 was significantly lower than that in group 2(p = 0.024, p < 0.001). Surgical comfort in group 1 was %825 and in group 2%65(P = 0.075)., Conclusion: 0.1% nepafenac reduces pain of patients who undergone routine clear corneal phacoemulsification with topical anesthesia and may increase patient comfort during the surgery when used preoperatively., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: To evaluate the analgesic effect of nepafenac 0.1%, a topical non-steroidal anti-inflammatory agent, in patients undergoing treatment with intravitreal injections (IVIs)., Material and Methods: It is a single center, prospective, randomized, double-blinded, placebo-controlled, crossover interventional study. Fifty-two patients scheduled to undergo IVI of anti-vascular endothelial growth factors were included in the study. Patients were randomized in a 1:1 ratio to receive topical nepafenac 0.1% or placebo 1 h before subsequent IVIs. Using the short form of the McGill Pain Questionnaire (SF-MPQ), pain intensity was assessed with the Visual Analogue Scale (VAS), the Main Component of the SF-MPQ (MC-SF-MPQ), and the Present Pain Intensity (PPI) scores immediately and 6-h post-injection., Results: The VAS pain score was statistically significant lower immediately and 6-h post-IVI in patients treated with nepafenac (p = 0.001 and < 0.001, respectively). The MC-SF-MPQ scores were also statistically significant lower after nepafenac administration at both time points (p < 0.001). Finally, the PPI score was statistically significant lower when nepafenac was instilled before IVI (p = 0.015 immediately and p < 0.001 at 6-h post-injection)., Conclusions: A single drop of nepafenac 0.1% before IVI could effectively alleviate the IVI-related pain immediately and up to 6 h after the injection.

Lung cancer is the leading cause of cancer deaths. Epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small cell lung cancers (NSCLCs), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the anti-EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib initially, but soon develop resistance to them in about half of the cases due to the emergence of the gatekeeper mutation T790M. The third-generation TKIs such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to the EGFR kinase through Cys 797, but ultimately lose their efficacy upon emergence of the C797S mutation that abolishes the covalent bonding. Therefore to develop new TKIs to overcome EGFR drug-resistant mutants harboring T790M/C797S is urgently demanded. EAI001 and EAI045 are a new type of EGFR TKIs that bind to EGFR reversibly and not relying on Cys 797. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR L858R/T790M and L858R/T790M/C797S. Here we report the crystal structure of EGFR T790M/C797S/V948R in complex with EAI045, and compare it to EGFR T790M/V948R in complex with EAI001. The complex structure reveals why EAI045 binds tighter to EGFR than does EAI001, and why EAI001 and EAI045 prefer binding to EGFR T790M. The knowledge may facilitate future drug development studies targeting this very important cancer target., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A10, (3-phenylacetylamino-2,6-piperidinedione), is a natural peptide with broad antineoplastic activity. Recently, in vitro antitumor effect of a new A10 analog [3-(4-methoxybenzoylamino)-2,6-piperidinedione] (MPD) has been verified. However, poor aqueous solubility represents an obstacle towards intravenous formulation of MPD and impedes successful in vivo antitumor activity. To surmount such limitation, MPD microemulsion (MPDME) was developed. A 3 1 2 2 full factorial design using Design-Expert® software was adopted to study the influence of different parameters and select the optimum formulation (MPDME1). Transmission electron microscopy (TEM) displayed spherical droplets of MPDME1. The cytotoxicity of MPDME1 in Michigan Cancer Foundation 7 (MCF-7) breast cancer cell line exceeded that of MPD solution (MPDS) and tamoxifen. Compatibility with injectable diluents, in vitro hemolytic studies and in vivo histopathological examination confirmed the safety of parenteral application of MPDME1. Molecular docking results showed almost same binding affinity of A10, MPD and 125 I-MPD with histone deacetylase 8 (HDAC8) receptor. Accordingly, radioiodination of MPDME1 and MPDS was done via direct electrophilic substitution reaction. Biodistribution of 125 I-MPDME1 and 125 I-MPDS in normal and tumor (ascites and solid) bearing mice showed high accumulation of 125 I-MPDME1 in tumor tissues. Overall, the results proved that MPDME represents promising parenteral delivery system capable of improving antineoplastic activity of MPD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study is to determine factors predicting resolution of acute pseudophakic cystoid macular edema (PCME) after 6 weeks of topical prednisolone and nepafenac application., Methods: Case records of patients with a clinical and optical coherence tomography (OCT)-based diagnosis of acute PCME were retrospectively reviewed for best-corrected visual acuity and OCT-based parameters at the time of presentation with PCME. In addition, demographic variables, intraoperative and early postoperative factors, and type of treatment prescribed (tapering vs. nontapering prednisolone, generic vs. branded prednisolone and nepafenac) were recorded from case records for analysis. Complete and any successes were defined and baseline factors predicting complete success at 6 weeks were analyzed., Results: We analyzed 69 eyes of 69 patients out of which complete success with topical medications was seen in 37 eyes (54%) and any success was seen in 55 eyes (80%) at 6 weeks. Multivariable logistic regression showed that eyes with lower vision at presentation had a significantly lower likelihood of experiencing both, complete (odds ratio [OR] = 0.83 with one-line decrement in baseline vision, 95% confidence interval [CI] = 0.61-0.89, P = 0.003) and any success (OR = 0.61, 95% CI = 0.4-0.9, P = 0.007). Baseline OCT thickness did not influence success rates., Conclusion: Topical prednisolone and nepafenac lead to resolution in PCME in half of the eyes at 6 weeks. Baseline vision is the only factor predicting rates of success and PCME resolution with topical medications., Competing Interests: There are no conflicts of interest

Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes for therapeutic targeting. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3α/β signaling pathway, which upregulates glutaminolysis. Phospho-GSK3α/β protein levels are predictive of response to single-therapy mTOR inhibition while combinatorial treatment with the glutaminase inhibitor CB-839 effectively overcomes therapy resistance. In addition, we identified a conserved metabolic signature in a broad spectrum of hypermetabolic human tumors that may be predictive of patient outcome and response to combined metabolic therapies targeting mTOR and glutaminase., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To compare the antiinflammatory efficacy of topical nepafenac 0.3% for prophylaxis of macular edema after cataract extraction., Setting: São Paulo University, São Paulo, Brazil., Design: Prospective randomized clinical trial., Methods: Patients with bilateral cataract were included in this study. Each patient was assigned randomly to receive nepafenac 0.3% drops in 1 eye and a placebo in the fellow eye. The primary outcome measure was the change in the mean spectral-domain optical coherence tomography central subfield thickness 5 weeks postoperatively. The secondary outcome measures were the total macular volume 1, 5, and 12 weeks postoperatively; the percentage of patients in both groups who developed macular edema, and the corrected distance visual acuity within 5 weeks and 12 weeks after cataract surgery., Results: The study comprised 224 eyes of 112 patients. For all retinal thickness measurements, a significant increase in both groups was detected starting from the first postoperative week until 12 weeks. At 5 weeks, there was a statistically significant difference in central subfield thickness and total macular volume between the nepafenac group and control group (P = .01 and P < .001, respectively). At the fifth postoperative week, no eye in the nepafenac group and 4 eyes (3.57%) in the control group had macula edema, highlighting a trend toward a greater incidence in the control group. The between-group differences in visual outcomes were not statistically significant., Conclusion: Used prophylactically after cataract surgery, nepafenac 0.3% was efficacious in reducing macular thickness compared with a placebo 5 weeks postoperatively, without a difference in final visual acuity., (Copyright © 2018 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess changes in retinal vascular caliber in response to short-term use of nepafenac eye drops in patients with mild diabetic macular edema., Materials and Methods: Thirty-four patients with previously untreated bilateral mild diabetic macular edema were included in this prospective study. For each participant, one eye was randomly assigned to nepafenac treatment (0.1%, three times/day) and the other eye was left untreated throughout the study. Using digital fundus photographs, retinal vascular calibers were calculated and compared in treated and untreated eyes at the baseline, week 1, and week 6., Results: Baseline vessel diameters did not differ in treated and fellow eyes (p > 0.05). Over the 6 weeks of the study, significant vasoconstriction of the retinal arteriolar caliber was observed at weeks 1 (p < 0.05) and 6 (p < 0.05), while an unchanged retinal venular caliber was noted between the treated and untreated eyes (p > 0.44). Significant macular thickness difference was only observed at week 6 (p = 0.002)., Conclusions: Topical nepafenac has a significant narrowing effect on the retinal arteriolar diameter and a significant reductive effect on central macular thickness in eyes with mild diabetic retinopathy.

Purpose: To evaluate the incidence of pseudophakic cystoid macular edema (PCMO) in patients treated with corticosteroids alone or in combination with bromfenac or nepafenac eyedrops after uneventful cataract surgery., Materials and Methods: Prospective, randomized, open-label, placebo-controlled clinical trial. Patients who underwent routine cataract surgery with intraocular lens (IOL) implant were randomly divided into three groups receiving either bromfenac or nepafenac in association with dexamethasone or dexamethasone alone (control group) postoperatively. Best-corrected visual acuity (BCVA) measurement, slit lamp and fundus examination and optical coherence tomography (OCT) were performed preoperatively, 1 and 5 weeks after surgery. Primary outcome was defined as patients (%) in whom macular edema developed within 5 weeks after cataract surgery; secondary end points were patients (%) with BCVA improvement from pre-op through 5 weeks after surgery and corneal toxicity., Results: A total of 144 patients completed the study, 48 for each group. In all groups, mean central subfield thickness at OCT increased significantly 5 weeks after surgery (p < 0.01). However, at this time point, four patients (8.3%) of the control group and none in nepafenac and bromfenac groups developed PCMO (p = 0.016). Compared with baseline, mean BCVA significantly improved both at 1 and 5 weeks in all groups (p < 0.01). At 1 week, the nepafenac group showed a mean BCVA significantly lower compared with both the control (p = 0.038) and bromfenac group (p = 0.002)., Conclusions: Co-administration of nepafenac or bromfenac and steroids in patients who underwent routine cataract surgery is associated with a lower incidence of PCMO compared with steroid monotherapy.

Objective: We present an interesting case of accidental overdose of latanoprost eye drops., Case Report: A 71-year-old patient underwent an uncomplicated cataract surgery in his right eye. During the first postsurgical week he mistakenly used latanoprost eye drops six times daily instead of the prescribed tobramycin/dexamethasone eye drops. The patient experienced gradually decreasing visual acuity and was diagnosed with cystoid macular edema seven weeks after surgery. The cystoid macular edema resolved 4 weeks later after treatment with nepafenac 0.3% eye drops and oral acetazolamide. The cystoid macular edema recurred 2 weeks after rechallenge with latanoprost. The rechallenge-induced cystoid macular edema once again resolved after cessation of latanoprost and retreatment with nepafenac eye drops. A Naranjo assessment score of 7 was obtained, indicating a probable relationship between the patient's symptoms and the suspect drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose: Retrospective, pilot study to determine whether nepafenac treatment pre- and postcataract surgery in glaucoma patients using topical hypotensive agents minimized cystoid macular edema by comparing pre- and postsurgical foveal characteristics, as in some cases these agents cannot be withdrawn and, hypothetically, their inflammatory effect on the fovea could be neutralized by the addition of nepafenac., Methods: Patients were divided into two subgroups depending on whether or not topical nepafenac was added to the surgical protocol (NEP = nepafenac group and nNEP = non nepafenac group). All had undergone phacoemulsification and data on pre- and postoperative macular status were recorded., Results: In the nNEP group, there was a significant increase in foveal thickness (FT) in the first month postoperative visit with respect to the preoperative status (p = 0.006), and this situation did not change at the third postoperative month (p = 0.9411). In the NEP group, the increase in FT was not significant at the first month after surgery (p = 0.056) nor at the final visit (p = 0.268), in contrast to the nNEP group., Conclusion: This study of the possible prophylactic effect of nepafenac on postoperative macular edema supports the results of other studies that confirm subclinical edema post phacoemulsification, and found a significantly lower gradient in the increase in FT in patients treated pre- and postoperatively with nepafenac.

Purpose: To compare the efficacy and safety of subtenon triamcinolone acetonide (TA) injection with topical nepafenac 0.1% for the treatment of pseudophakic cystoid macular edema (CME)., Methods: In this prospective study, the TA group comprised 24 eyes and the nepafenac group 24 eyes. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure measurements, and slit-lamp fundoscopy were performed in all subjects at baseline, 1, 2, 3, and 6 months., Results: Changes in BCVA and CRT over four follow-up visits were statistically significant (p<0.001). The mean CRT decreased from 513.3 to 318.9 μm in the TA group and from 483.7 to 278.0 μm in the nepafenac group. This reduction was statistically significant (p<0.001 for both groups)., Conclusions: Our visual and OCT results suggest that both treatment modalities are effective with few side-effects. However, nepafenac is more efficacious than subtenon TA in terms of visual gain and its correlation with the reduction in CRT.

Purpose: To demonstrate the efficacy and safety of once-daily nepafenac 0.3% ophthalmic suspension versus vehicle, based on clinical outcomes, after cataract surgery in patients with diabetes., Design: Two prospective, randomized, multicenter, double-masked, vehicle-controlled phase 3 studies., Participants: Total, 615 patients in study 1 and 605 patients in study 2., Methods: Patients were randomized (1:1) to topical nepafenac 0.3% or vehicle once-daily starting the day before surgery and continuing for 90 days thereafter., Main Outcome Measures: Key efficacy variables were: patients (%) in whom macular edema (ME) developed (≥30% increase from preoperative baseline central subfield macular thickness) within 90 days after cataract surgery and the patients (%) with a best-corrected visual acuity (BCVA) improvement of ≥15 letters from preoperative baseline through day 14 maintained through day 90. Secondary end points included: patients (%) with a BCVA improvement of ≥15 letters from preoperative baseline through days 90 and 60 and safety over 3 months., Results: A significantly lower percentage of patients demonstrated ME within 90 days after surgery with nepafenac 0.3% versus vehicle (study 1: 2.3% vs. 17.3%; P < 0.001; study 2: 5.9% vs. 14.3%; P = 0.001; pooled: 4.1% vs. 15.9%; P < 0.001). The percentage of patients achieving a ≥15-letter improvement from baseline through day 14 maintained through day 90 with nepafenac 0.3% versus vehicle was 61.7% versus 43.0% (P < 0.001) in study 1, 48.8% versus 50.5% (P = 0.671) in study 2, and 55.4% versus 46.7% (P = 0.003) in the pooled analysis. A greater percentage of patients treated with nepafenac 0.3% versus vehicle in study 1 and similar percentage in study 2 had a BCVA improvement of ≥15 letters from preoperative baseline through day 90 (77.2% vs. 67.7% [P = 0.009] and 65.4% vs. 65.9% [P = 0.888]) and through day 60 (76.2% vs. 64.7% [P = 0.002] and 68.9% vs. 62.1% [P = 0.092]). No unanticipated adverse events were observed., Conclusions: These studies demonstrated the clinical benefits of nepafenac 0.3% over vehicle in reducing the risk of postoperative ME, with the integrated analysis showing improved BCVA after cataract surgery in patients with diabetic retinopathy, with no unanticipated safety events., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the lowering effects of ketorolac 0.4% and nepafenac 0.1% on aqueous and vitreous humor prostaglandin E 2 (PGE 2 ) levels in rabbits., Methods: Ketorolac and nepafenac ophthalmic solutions were administered to the right eyes of 24 healthy rabbits after randomized division into two groups. The left eyes of these rabbits were considered as controls for the two groups. On the 4th day of the experiment, the samples were taken from the aqueous and vitreous humors of the rabbits bilaterally, and PGE 2 levels were measured by an enzyme immune assay kit., Results: Ketorolac and nepafenac achieved a statistically significant decrease (p<0.001, for each) in PGE 2 levels in the aqueous (11.75 ± 6.15 and 14.75 ± 7.60 pg/mL, respectively) and the vitreous humor (6.58 ± 4.62 and 9.83 ± 4.55 pg/mL, respectively)., Conclusions: Both ketorolac and nepafenac inhibited PGE 2 levels in both the aqueous and vitreous humors of rabbits. Although PGE 2 -lowering effects were similar in the aqueous humor, nepafenac seemed to be more potent than ketorolac in the vitreous humor.

To determine the effect of piragliatin on the QTcS (QT-corrected study-specific) interval, a double-blind, double-dummy, placebo-controlled, active-comparator, 4-period, 4-treatment, 4-sequence randomized crossover trial was performed in 42 patients with type 2 diabetes mellitus who received 100 and 200 mg piragliatin twice daily, placebo, and 400 mg moxifloxacin (on day 1 and day 5 only) for 5 days. In the categorical analyses, piragliatin did not have a clinically significant effect on the QTcS interval at either dose, and the majority of patients were categorized with low risk for maximum change from baseline (≤30 milliseconds) and a maximum postbaseline QTcS interval as normal (≤450 milliseconds). However, in the analysis of variance model, both piragliatin doses crossed the 10-millisecond threshold (100 mg twice daily on day 5, hour 1; 200 mg twice daily on days 1 and 5, hours 1 and 2) with P values indicating statistical significance. Headache and mild hypoglycemia were the most frequent adverse events associated with piragliatin treatment. There appeared that the effect of piragliatin treatment on the QTc interval was dose/exposure dependent following short-term multiple doses. Longer-term monitoring of electrocardiograms with pharmacokinetic exposure should continue, especially at conditions for potentially higher pharmacokinetic exposure., (© 2016, The American College of Clinical Pharmacology.)

Purpose: To compare the effectiveness of three different topical nonsteroidal anti-inflammatory drugs (NSAIDs) in inhibiting surgically induced miosis during uncomplicated cataract phacoemulsification., Methods: Prospective, randomized, double-masked comparative study of patients aged 40 years or older with grades II to III cataracts (Lens Opacities Classification System) and no other comorbidities. Participants were randomized into four groups: 0.1% nepafenac, 0.03% flurbiprofen, 0.4% ketorolac, or lubricant (control group). Medications were applied three times, starting 90 minutes before surgery at 30-minute intervals. Phacoemulsification was performed by the same surgeon using the stop-and-chop technique. Pupillary area and vertical and horizontal pupil diameters were measured at five surgical stages and analyzed with a computerized image system. Multiple comparison tests were performed to analyze intergroup differences. A P value of less than .05 was considered statistically significant., Results: A total of 88 eyes were included in the study (22 eyes per group). Maximum pupillary area at the end of surgery was observed in the nepafenac group (62.72 ± 9.75 mm 2 ) versus the ketorolac, flurbiprofen, and control groups (P = .003, P =.001, and P < .001, respectively). The percentage of pupillary area loss at the end of surgery was 7.50% with nepafenac, 9.84% with flurbiprofen, 10.09% with ketorolac, and 13.83% with control. A trend to larger pupillary area and diameters was found in the nepafenac, flurbiprofen, and ketorolac groups compared with the control group, with better performance in maintaining larger pupil diameters and area in the nepafenac group at all surgical stages., Conclusions: All NSAIDs were effective in maintaining intraoperative mydriasis during uncomplicated cataract phacoemulsification compared to the control group. [J Refract Surg. 2017;33(4):236-242.]., (Copyright 2017, SLACK Incorporated.)

Background: Define the effectiveness of a topical non-steroidal anti-inflammatory drug (NSAID) added to topical steroid use after uncomplicated phacoemulsification for the prevention of pseudophakic cystoid macular edema (PCME) using a prospective, randomized, double-masked, placebo-controlled clinical study., Methods: Eyes (1000) were randomized to placebo (497) or nepafenac 0.3% (503) used once daily, post-operatively for 5 weeks at two ophthalmology clinics. Diagnosis of PCME was made by clinical, ocular coherence tomography (OCT), and with fluorescein angiography confirmation. Correlation of PCME to NSAID use and the presence of pre-operative risk factors for PCME were assessed including, contralateral PCME, diabetic retinopathy, retinal vein occlusion, macular hole, epiretinal membrane, macular degeneration, retinal detachment repair, and prostaglandin use., Results: PCME was the most common complication associated with routine cataract surgery (4.2% with PCME risk factors, 2.0% with risk factors excluded). Topical nepafenac 0.3% significantly reduces the incidence of PCME compared to placebo when used after routine cataract surgery (p = .0001). When patients with pre-operative risk factors are excluded, the incidence of PCME between treatment and placebo groups is equivalent (p = 0.31). PCME relative risk (RR) was most significant in contralateral PCME (RR 19.5), diabetic retinopathy (RR 13.1), retinal vein occlusion (RR 12.9), macular hole (RR 7.7), and epiretinal membrane (RR 5.7). Prostaglandin use and previous retinal detachment were not shown to increase risk., Conclusion: Pseudophakic cystoid macular edema is common after phacoemulsification cataract surgery. Topical nepafenac 0.3% reduces PCME in patients with pre-operative risk factors for PCME compared to placebo but shows no benefit in patients without pre-operative risk factors., Trial Registration: NIH ClincalTrials.gov retrospectively registered January 15, 2017, NCT03025945 .

Purpose: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the prevention and treatment of inflammation and pain following cataract surgery. Preservative-free diclofenac and nepafenac drops are commonly used ophthalmic NSAIDs. The purpose of this study was to compare the tolerability of diclofenac to that of nepafenac., Methods: In this prospective patient-blinded study, consecutive patients undergoing cataract surgery were included. One drop of nepafenac 0.1% and diclofenac sodium 0.1% were instilled in the right and left eyes, respectively, one immediately after the other, 1 day before surgery. Visual analog scale (scale 0-10) was used to measure patient discomfort, itching, burning, and pain at 1 second (s), 15 s, 1 minute (min), and 5 min postadministration., Results: Overall, 44 eyes of 22 patients were included in this study. Diclofenac and nepafenac had high and similar tolerability at all time points with no significant difference regarding all aspects of tolerability. A vast majority of patients (72%) did not prefer 1 drop over the other in terms of overall comfort., Conclusions: Both diclofenac and nepafenac seem to have similar high tolerability. Diclofenac may be an affordable alternative to nepafenac and therefore should be considered by prescribing physicians, specifically in preoperative cataract patients.

Compound FLZ is a synthetic novel derivate of natural squamosamide, which has potent neuroprotective effects based on our previous study. We are now aiming to investigate the effects of FLZ on cerebral blood flow (CBF), infarct volume, neurological function, heat shock protein 70 (Hsp70), and Hsp27 expression in transient focal ischemia. For this goal, an animal model of middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion was used, and animals received low or high doses of FLZ (150 or 300mg/kg), orally 10min after MCAO onset. The results show that the infarct volume was 32.7% for the vehicle control group, and reduced to 17.6 and 12.8% for the low and high dose FLZ-treated groups, respectively. FLZ treatment also significantly improved the neurobehavioral score from 2.6 in the vehicle control group to 1.0 and 0.9 in the low and high dose groups, respectively. Further, FLZ significantly induced Hsp27 over-expression and reduced over-expression of HSP70, a sensitive marker of acute ischemia, in ipsilateral cortex by a dose-dependent manner. In addition, CBF was quantified using laser-Doppler flowmetry. During ischemia, regional CBF (rCBF) was improved from approximately 30% to over 50% of the baseline and the reperfusion-induced hyperemia was reduced in both FLZ dosage groups. Particularly, high dose FLZ reduced rCBF during hyperemia by 30%. In conclusion, FLZ (150 and 300mg/kg) can significantly reduce the infarct volume and improve neurobehavioral deficits in a rat MCAO model, most likely through improving CBF in the penumbra and enhancing Hsp27 expression., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: To assess vitreous concentrations of nonsteroidal anti-inflammatory drugs (NSAIDs) and prostaglandin E2 (PGE2) in patients treated with NSAIDs before vitrectomy for macular pucker., Methods: A prospective, investigator-masked, randomized study was performed in 64 patients scheduled to undergo vitrectomy. The patients were randomized 1:1:1:1 to receive indomethacin 0.5%, bromfenac 0.09%, nepafenac 0.1%, or placebo three times a day. NSAIDs and PGE2 levels were evaluated in vitreous samples collected at the beginning of surgery., Results: Mean (SD) vitreous concentrations of the study drugs were 503.13 (241.1) pg/mL for indomethacin, 302.5 (91.03) pg/mL for bromfenac, and 284.38 (128.2) pg/mL for nepafenac. Mean (SD) vitreous PGE2 levels were 247.9 (140.9) pg/mL for indomethacin, 322.12 (228.1) pg/mL for bromfenac, 448.8 (261.1) pg/mL for nepafenac, and 1,133 (323.9) pg/mL for placebo. All three NSAIDs reduced vitreous PGE2 levels to a statistically significant extent, without a significant difference among them., Conclusion: All assessed NSAIDs penetrated the vitreous and lowered basal PGE2 levels. A greater penetration was associated with pseudophakic eyes. The important inhibition of prostaglandins in the retina may have a clinical effect on the management of inflammatory retina diseases.

To evaluate the potential pharmacokinetic (PK) and pharmacodynamic (PD, glucose-lowering effect) interaction between simvastatin and piragliatin, both CYP3A substrates, 30 patients with type 2 diabetes mellitus participated in this open-label, randomized, 6-sequence, 3-way crossover (William's design) study. During 3 periods, patients were randomized to receive a single dose of 80 mg simvastatin alone, a single dose of 100 mg piragliatin alone, as well as single doses of 80 mg simvastatin and 100 mg piragliatin together. Primary PK and PD parameters were AUCs on dosing days. The ratio of geometric means (90% confidence intervals) of the AUCinf of piragliatin coadministered with simvastatin compared with piragliatin alone was 0.98 (0.92-1.05), whereas that of the AUCinf of simvastatin acid (active metabolite) coadministered with piragliatin compared with simvastatin alone, was 1.02 (0.90-1.16), suggesting lack of pharmacokinetic interaction between piragliatin and simvastatin. Piragliatin's glucose-lowering effect was not affected by coadministration of simvastatin. Overall, administration of piragliatin with simvastatin was without additional clinically relevant adverse effects as well as abnormality in laboratory tests, vital signs, and electrocardiogram parameters. Concomitant administration of simvastatin and piragliatin, both CYP3A substrates, has no clinically relevant effect on the pharmacokinetics of either piragliatin or simvastatin or on the pharmacodynamics for piragliatin., (© 2015, The American College of Clinical Pharmacology.)

Nepafenac ophthalmic suspensions, 0.1% (NEVANAC(®)) and 0.3% (ILEVRO™), are topical nonsteroidal anti-inflammatory drug (NSAID) products approved in the United States, Europe and various other countries to treat pain and inflammation associated with cataract surgery. NEVANAC is also approved in Europe for the reduction in the risk of postoperative macular edema (ME) associated with cataract surgery in diabetic patients. The efficacy against ME suggests that topical administration leads to distribution of nepafenac or its active metabolite amfenac to the posterior segment of the eye. This article evaluates the ocular distribution of nepafenac and amfenac and the extent of local delivery to the posterior segment of the eye, following topical ocular instillation in animal models. Nepafenac ophthalmic suspension was instilled unilaterally in New Zealand White rabbits as either a single dose (0.1%; one drop) or as multiple doses (0.3%, one drop, once-daily for 4 days, or 0.1% one drop, three-times daily for 3 days and one morning dose on day 4). Nepafenac (0.3%) was also instilled unilaterally in cynomolgus monkeys as multiple doses (one drop, three-times daily for 7 days). Nepafenac and amfenac concentrations in harvested ocular tissues were measured using high-performance liquid chromatography/mass spectrometry. Locally-distributed compound concentrations were determined as the difference in levels between dosed and undosed eyes. In single-dosed rabbit eyes, peak concentrations of locally-distributed nepafenac and amfenac showed a trend of sclera > choroid > retina. Nepafenac peak levels in sub-samples posterior to the eye equator and inclusive of the posterior pole (E-PP) were 55.1, 4.03 and 2.72 nM, respectively, at 0.25 or 0.50 h, with corresponding amfenac peak levels of 41.9, 3.10 and 0.705 nM at 1 or 4 h. By comparison, peak levels in sclera, choroid and retina sub-samples in a band between the ora serrata and the equator (OS-E) were 13- to 40-fold (nepafenac) or 11- to 23-fold (amfenac) higher, indicating an anterior-to-posterior directional concentration gradient. In multiple-dosed rabbit eyes, with 0.3% nepafenac instilled once-daily or 0.1% nepafenac instilled three-times daily, cumulative 24-h locally-distributed levels of nepafenac in E-PP retina were similar between these groups, whereas exposure to amfenac once-daily dosing nepafenac 0.3% was 51% of that achieved with three-times daily dosing of 0.1%. In single-dosed monkey eyes, concentration gradients showed similar directionality as observed in rabbit eyes. Peak concentrations of locally-distributed nepafenac were 1580, 386, 292 and 13.8 nM in E-PP sclera, choroid and retina, vitreous humor, respectively, at 1 or 2 h after drug instillation. Corresponding amfenac concentrations were 21.3, 11.8, 2.58 and 2.82 nM, observed 1 or 2 h post-instillation. The data indicate that topically administered nepafenac and its metabolite amfenac reach pharmacologically relevant concentrations in the posterior eye segment (choroid and retina) via local distribution, following an anterior-to-posterior concentration gradient. The proposed pathway involves a choroidal/suprachoroidal or periocular route, along with an inward movement of drug through the sclera, choroid and retina, with negligible vitreal compartment involvement. Sustained high nepafenac concentrations in posterior segment tissues may be a reservoir for hydrolysis to amfenac., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)