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Purpose: Whole-pelvis (WP) radiation therapy (radiation) improved biochemical relapse-free survival (bRFS) compared with prostate bed (PB)-only radiation in the Radiation Therapy Oncology Group 0534, but was performed in an era prior to positron emission tomography (PET) staging. Separately, 18F-fluciclovine PET/CT-guided postprostatectomy radiation improved 3-year bRFS versus radiation guided by conventional imaging alone. We hypothesized that patients who were changed from WP to PB-only radiation after PET would have bRFS that was: (a) no higher than patients initially planned for PB-only radiation; and (b) lower than patients planned for WP radiation without PET guidance., Methods and Materials: We conducted a post hoc analysis of a prospective, randomized trial comparing conventional (arm 1) versus PET-guided (arm 2) postprostatectomy radiation. In arm 2, pre-PET treatment field decisions were recorded and post-PET fields were defined per protocol; pathologic node negative (pN0) without pelvic or extrapelvic PET uptake received PB-only radiation. Three-year bRFS was compared in patients planned for WP with change to PB-only radiation (arm 2 [WP:PB]) vs arm 2 patients planned for PB-only with final radiation to PB-only (arm 2 [PB:PB]) and arm 1 pN0 patients treated with WP radiation (arm 1 [WP]) using the Z test and log-rank test. Demographics were compared using the chi-square test, Fisher exact test, or analysis of variance, as appropriate., Results: We identified 10 arm 2 (WP:PB), 31 arm 2 (PB:PB) and 11 arm 1 (WP) patients. Androgen deprivation was used in 50.0% of arm 2 (WP:PB) and 3.2% of arm 2 (PB:PB) patients, P < .01. Median preradiation prostate-specific antigen was higher in arm 2 (WP:PB) vs arm 2 (PB:PB) patients (0.4 vs 0.2 ng/mL, P = .03); however, there were no significant differences in T stage, Gleason score, or margin positivity. Three-year bRFS was 80% in arm 2 (WP:PB) vs 87.4% in arm 2 (PB:PB), P = .47, respectively. Arm 1(WP) patients had significantly worse 3-year (23%) bRFS vs arm 2 (WP:PB), P < .01., Conclusions: Patients initially planned for WP radiation with field decision change to PB-only radiation after PET showed (1) no significant difference in 3-year bRFS compared with patients initially planned for PB-only radiation; and (2) improved bRFS compared with patients receiving WP radiation without PET guidance. PET-guided volume de-escalation in selected patients may be 1 approach to mitigating toxicity without compromising outcomes., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: According to the National Comprehensive Cancer Network Guidelines, 18F-fluciclovine PET/CT is considered appropriate after negative standard of care (SOC) imaging., Objective: To prospectively compare 18F-fluciclovine to SOC imaging, investigate whether it should be done when SOC imaging is (+), and evaluate its detection rate in patients receiving androgen deprivation therapy., Methods: We recruited 57 prostate cancer patients with biochemical recurrence with 18F-fluciclovine PET/CT and SOC imaging within 30 days. Prostate-specific antigen (PSA) level, Gleason score (GS), history of radical prostatectomy (RP), radiation therapy (RT) or hormone therapy (HT) were reviewed., Results: The 57 patients had a median PSA of 2.6 and average GS of 7.4; 27 (47.4%) had RP, 28 (49.1%) had RT, 1 (1.75%) had HT and 1 (1.75%) observation only. 18F-fluciclovine identified disease recurrence in 45/57 patients (78.9%), including oligometastasis in 18/45 (40%). SOC imaging identified recurrent disease in 12/57 patients (21.1%) while 18F-fluciclvoine identified additional sites of disease in 11/12 (91.7%). The (+) 18F-fluciclovine studies had a median PSA 2.6 ng/ml compared to 6.0 ng/ml in the (+) SOC studies., Conclusion: 18F-fluciclovine was superior to SOC imaging for lesion detection, identification of oligometastasis and identification of additional sites of disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The early identification of responsive and resistant patients to androgen receptor-targeting agents (ARTA) in metastatic castration-resistant prostate cancer (mCRPC) is not completely possible with prostate-specific antigen (PSA) assessment and conventional imaging. Considering its ability to determine metabolic activity of lesions, positron emission tomography (PET) assessment might be a promising tool., Patients and Methods: We carried out a monocentric prospective study in patients with mCRPC treated with ARTA to evaluate the role of different PET radiotracers: 49 patients were randomized to receive 11 C-Choline, Fluorine 18 fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid - FACBC) ( 18 F-FACBC), or Gallium-68-prostate-specific-membrane-antigen ( 68 Ga-PSMA) PET, one scan before therapy and one 2 months later. The primary aim was to investigate the performance of three novel PET radiotracers for the early evaluation of response to ARTA in metastatic CRPC patients; the outcome evaluated was biochemical response (PSA reduction ≥50%). The secondary aim was to investigate the prognostic role of several semiquantitative PET parameters and their variations with the different radiotracers in terms of biochemical progression-free survival (bPFS) and overall survival (OS). The study was promoted by the Italian Department of Health (code RF-2016-02364809)., Results: Regarding the primary endpoint, at log-rank test a statistically significant correlation was found between metabolic tumor volume (MTV) (P = 0.018) and total lesion activity (TLA) (P = 0.025) percentage variation among the two scans with 68 Ga-PSMA PET and biochemical response. As for the secondary endpoints, significant correlations with bPFS were found for 68 Ga-PSMA total MTV and TLA at the first scan (P = 0.001 and P = 0.025, respectively), and MTV percentage variation (P = 0.031). For OS, statistically significant correlations were found for different 68 Ga-PSMA and 18 F-FACBC parameters and for major maximum standardized uptake value at the first 11 C-Choline PET scan., Conclusions: Our study highlighted that 11 C-Choline, 68 Ga-PSMA, and 18 F-FACBC semiquantitative PET parameters and their variations present a prognostic value in terms of OS and bPFS, and MTV and TLA variations with 68 Ga-PSMA PET a correlation with biochemical response, which could help to assess the response to ARTA., Competing Interests: Disclosure FM has received research support and/or honoraria from Astellas, BMS, Janssen, Ipsen, MSD, and Pfizer outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. This epithelial anion channel regulates the active transport of chloride and bicarbonate ions across membranes. Mutations result in reduced surface expression of CFTR channels with impaired functionality. Correctors are small molecules that support the trafficking of CFTR to increase its membrane expression. Such correctors can have different mechanisms of action. Combinations may result in a further improved therapeutic benefit. We describe the identification and optimization of a new pyrazolol3,4-bl pyridine-6-carboxylic acid series with high potency and efficacy in rescuing CFTR from the cell surface. Investigations showed that carboxylic acid group replacement with acylsulfonamides and acylsulfonylureas improved ADMET and PK properties, leading to the discovery of the structurally novel co-corrector GLPG2737. The addition of GLPG2737 to the combination of the potentiator GLPG1837 and C1 corrector 4 led to an 8-fold increase in the F508del CFTR activity.

Carboxylic organic acids are intermediates of central carbon metabolic pathways (e.g. acetic, propionic, citric, and lactic acid) long known to have potent antimicrobial potential, mainly at acidic pHs. The food industry has been leveraging those properties for years, using many of these acids as preservatives to inhibit the growth of pathogenic and/or spoilage fungal and bacterial species. A few of these molecules (the most prominent being acetic acid) have been used as antiseptics since Hippocratic medicine, mainly to treat infected wounds in patients with burns. With the growth of antibiotic therapy, the use of carboxylic acids (and other chemical antiseptics) in clinical settings lost relevance; however, with the continuous emergence of multi-antibiotic/antifungal resistant strains, the search for alternatives has intensified. This prospective article raises awareness of the potential of carboxylic acids to control infections in clinical settings, considering not only their previous exploitation in this context (which we overview) but also the positive experience of their safe use in food preservation. At a time of great concern with antimicrobial resistance and the slow arrival of new antimicrobial therapeutics to the market, further exploration of organic acids as anti-infective molecules may pave the way to more sustainable prophylactic and therapeutic approaches., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational β-lactam and β-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-β-lactamases., Methods: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority., Results: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups., Conclusions: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Uterine fibroids constitute a significant health problem in the United States, affecting upward of 11 million people., Objective: Characterize the literature regarding the incidence of amenorrhea and reductions in abnormal uterine bleeding and fibroid size and to report on clinically relevant safety outcomes of oral medications that may be used to manage symptomatic uterine fibroids to assist in choice of therapeutic options., Methods: A literature search was conducted through December 31, 2021, using Embase, MEDLINE, and International Pharmaceutical Abstracts databases. Primary literature reporting on safety or efficacy data of any oral medication for the treatment of symptomatic uterine fibroids was included. Relevant study characteristics, outcomes, and safety data were extracted. Data extraction was performed in duplicate with any discordant data reconciled by the entire investigative team., Results: A total of 41 studies met inclusion criteria-28 randomized control trials (RCTs), 11 prospective observational studies, 1 phase-1 pharmacokinetic study, and 1 pooled study. The majority of literature involved the study of mifepristone (n = 26, [63.4%]), followed by vilaprisan (n = 5, [12.2%]), elagolix (n = 5, [12.2%]), relugolix (n = 4, [9.8%]), and linzagolix (n = 1 [2.4%]). A total of 33 articles (80.5%) reported results pertaining to the efficacy objectives of this review with all medications statistically significantly improving at least one of these domains. Hot flashes, liver function test abnormalities, and endometrial hyperplasia were the most often reported adverse events. Of the RCTs, 7 of 28 (25%) had a moderate-high risk of bias (RoB), whereas 10 of 11 (90.9%) observational studies had a moderate-high RoB. The majority of moderate-high RoB studies involved the study of mifepristone (15 of 18, 83.3%)., Conclusions: Given higher quality of evidence, confirmed therapeutic efficacy, and a milder adverse effect profile, the contemporary gonadotropin releasing hormone antagonists (elagolix, relugolix, linzagolix) and vilaprisan represent preferred oral treatment options for the management of uterine fibroids., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Introduction: Uterine fibroids (UFs) are the most prevalent benign neoplastic threat originating from myometria of reproductive age women, with a profound financial load valued in hundreds of billions of dollars. Unfortunately, there is no curative treatment so far except surgery and available pharmacological treatments are restricted for short-term treatment options. Thus, there is a large unmet need in the UF space for noninvasive therapeutics., Areas Covered: The authors reviewed the literature available for the utility of gonadotropin-releasing hormone (GnRH) analogs in women with UFs. We also focused on clinical studies exploring the therapeutic benefits of novel oral non-peptide GnRH antagonists that were recently approved by the U.S. Food and Drug Administration (FDA) in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with UFs in premenopausal women., Expert Opinion: The results regarding the efficacy of new-generation oral GnRH-antagonists, such as elagolix, relugolix and linzagolix, are promising and offer potential prospect for the future therapy of UFs. However, these antagonists must be combined with hormonal add-back therapy to minimize the resultant hypoestrogenic side effects such as bone loss.

Background: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis., Methods: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [ 89 Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [ 89 Zr]Zr-dezamizumab cardiac uptake assessed via PET., Results: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [ 89 Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks., Conclusions: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)., (© 2022. The Author(s).)

Background: Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease., Methods: We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values., Findings: The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4·53 [95% CI 1·49-13·79]), infliximab combined with azathioprine (7·49 [2·04-27·49]), adalimumab (3·01 [1·25-7·27]), and ustekinumab (2·63 [1·10-6·28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3·76 [1·01-14·03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2·82 [95% CI 1·20-6·62]; low confidence), and risankizumab (2·10 [1·12-3·92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias., Interpretation: Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission., Funding: None., Competing Interests: Declaration of interests SS has received personal fees from Pfizer for ad hoc grant review, and his institute has received research grants from AbbVie and Janssen. MF has received consulting fees or lecture fees, or both, from AbbVie, Amgen, Ferring, Fresenius Kabi, Janssen, Takeda, Pfizer, Tillots, Celgene, Celltrion, MSD, Biogen, Gilead, and Galapagos; and research support from Pfizer, Sandoz, AbbVie, and Takeda. RS has received consulting fees from Alimentiv. VJ has received consulting and advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genetech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda, and Topivert; and speaker's fees from AbbVie, Ferring, Galapagos, Janssen Pfizer Shire, and Takeda. RP has received consulting and advisory board fees from AbbVie, Abbott, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pandion Pharma, Pendopharm, Pfizer, Progenity, Protagonist Therapeutics, Roche, Satisfai Health, Sandoz, Schering-Plough, Shire, Sublimity Therapeutics, Theravance Biopharma, UCB, and Takeda Pharmaceuticals; speaker's fees from AbbVie, Arena Pharmaceuticals, Celgene, Eli Lilly, Ferring, Gilead Sciences, Janssen, Merck, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and research and educational support from AbbVie, Ferring, Janssen, Pfizer, and Takeda. WJS has received research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, and Theravance Biopharma; consulting fees from AbbVie, Abivax, Admirx, Alfasigma, Alimentiv, Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech–Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma (acquired by Ventyx Biosciences), Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, and Zealand Pharma; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (acquired by Ventyx Biosciences), Prometheus Biosciences, Prometheus Laboratories Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Biosciences; and an employee at Shoreline Biosciences. WJS' spouse is an employee at Prometheus Biosciences and a consultant at Iveric Bio, Oppilan Pharma (acquired by Ventyx Biosciences), and Prometheus Laboratories; and holds stocks or stock options, or both, in Iveric Bio, Progenity, Oppilan Pharma (acquired by Ventyx Biosciences), Prometheus Biosciences, Prometheus Laboratories, Ventyx Biosciences, and Vimalan Biosciences. CM has received consulting fees from AbbVie, Amgen, AVIR Pharma, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pfizer, Roche, Alimentiv; and speaker's fees from AbbVie, Amgen, AVIR Pharma, Janssen, Takeda, and Pfizer; and research support from Pfizer. MHM declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: 18F-fluciclovine (fluciclovine) is an amino acid analog approved by the Food and Drug Administration for use as a radiotracer in positron emission tomography (PET) in men with biochemical recurrence of suspected prostate cancer. The purpose of this study was to investigate the initial institutional experience with 18F-fluciclovine in the evaluation of prostate cancer with biochemical recurrence., Methods: This study was a retrospective review of 135 patients who underwent 18F-fluciclovine PET-computed tomography (PET-CT) at a single institution from August 2018 through January 2020. Prognostic information, including prostate-specific level antigen (PSA) at the time of diagnosis, initial risk, initial Gleason score, and initial stage, was reviewed as well as the PSA level at the time of the scan. The images were reviewed by two radiologists with fellowship training in nuclear medicine and additional training to interpret the fluciclovine studies. A minority of studies were reviewed by a third fellowship-trained radiologist under the guidance of the two nuclear medicine-trained radiologists. In cases with abnormal radiopharmaceutical uptake in lymph nodes, the short-axis dimension of the lymph node or largest lymph node with abnormal uptake was noted. If CT or bone scan was performed within 4 months of the 18F-fluciclovine PET-CT, findings on the alternate imaging were compared with the results of the 18F-fluciclovine PET-CT., Results: Our institutional positivity rate was 75.6%, with 64 (67.4%) patients with metastatic disease and 71 (52.6%) patients with local recurrence detected by fluciclovine. As expected, the rate of positive examinations increased with increasing PSA values measured at the time of imaging ( P < 0.001). Of the 54 patients with nodal disease, 35 had nonpathologically enlarged lymph nodes measuring <1 cm in maximum short-axis dimension. In more than half of the patients in this study, with conventional imaging, fluciclovine either discovered otherwise undetectable metastatic disease or suggested the presence of local recurrence., Conclusions: Our single-institution experience with 18F-fluciclovine PET-CT has the largest number of patients to date in the literature and demonstrates the ability of fluciclovine to help guide clinical management in the detection of early recurrent disease.

Ethnopharmacological Relevance: Trichodesma indicum (L.) R. Br. (family: Boraginaceae) is a medicinal herb largely used to treat arthralgia, rheumatoid arthritis, wound healing, dysentery, etc. It's mechanism of anti-inflammatory activity has not been systematically analyzed yet., Aim of the Study: The present study was undertaken to examine the anti-inflammatory effects of successive solvent extracts (n-hexane extract (HE), ethyl acetate extract (EA), ethanol extract (EE), aqueous extract (AE) and fractions of HE) from the aerial parts of Trichodesma indicum (TI) against lipopolysaccharide (LPS) stimulated inflammatory reaction using mouse macrophage RAW 264.7 cells., Materials and Methods: Cytotoxic effects of the extracts and fractions of TI were assessed by MTT assay. The effect of extracts and fractions on the production of nitric oxide (NO) in RAW 264.7 macrophages were measured using the Griess reagent method. IL - 6, IL - 1β, TNF-α, iNOS and COX-2 gene expressions were examined by a qRT-PCR method., Results: RAW 264.7 macrophages pretreated with HE, EA, EE and AE of TI showed a significant decrease in the production of proinflammatory cytokines and NO without exhibiting cytotoxicity. The potent HE was fractionated using flash chromatography into FA, FB, FC, FD and FE. Among the five fractions, FE displayed a stronger ability to reduce IL - 1β, TNF-α, iNOS, COX2 and NO importantly no cytotoxicity was observed. The phytochemical compounds present in FE were further screened by Gas chromatography - Mass spectroscopy (GC-MS). GC-MS analysis revealed that 1,2-benzenedicarboxylic acid diisooctyl ester is the major compound in FE. Molecular docking analysis showed good inhibition of 1,2-benzenedicarboxylic acid diisooctyl ester against TLR-4, NIK and TACE., Conclusion: Our results suggested that 1,2-benzenedicarboxylic acid diisooctyl ester could be a potential candidate in alleviating inflammatory reactions in TI., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In this work, an iron self-boosting polymer nanoenzyme was prepared by using pyrrole-3-carboxylic acid as a monomer and iron as an oxidizing agent via a simple and one-step method [hereafter referred to as FePPy nanoparticles (NPs)]. In fact, researchers previously paid negligible attention on the iron element during the polymerization reaction of polypyrrole, thus the intrinsically catalytic functions and enzymatic activities of the high iron content (wt %: 21.11%) are ignored and not fully explored. As expected, results demonstrate that the as-synthesized FePPy NPs can decompose H 2 O 2 to generate hydroxyl radicals ( • OH) which exhibit enzyme characteristics, further inducing a nonapoptotic ferroptosis pathway. Moreover, the nanoenzyme shows impressive photothermal properties which can accelerate the Fenton reactions to enhance ferroptosis. The combined photothermal and ferroptosis therapy of FePPy NPs was found to have high efficacy. With the properties of easy synthesis, high efficacy, and good biocompatibility, the FePPy NPs are considered as potential agents for cancer treatments.

The G-protein coupled receptors (GPCRs) activated by free fatty acids (FFAs) have emerged as new and exciting drug targets, due to their plausible translation from pharmacology to medicines. This perspective aims to report recent research about GPR120/FFAR4 and its involvement in several diseases, including cancer, inflammatory conditions, and central nervous system disorders. The focus is to highlight the importance of GPR120 in Type 2 diabetes mellitus (T2DM). GPR120 agonists, useful in T2DM drug discovery, have been widely explored from a structure-activity relationship point of view. Since the identification of the first reported synthetic agonist TUG-891, the research has paved the way for the development of TUG-based molecules as well as new and different chemical entities. These molecules might represent the starting point for the future discovery of GPR120 agonists as antidiabetic drugs.

Lambertianic acid (LA) is a diterpene bioactive compound mainly purified from different species of Pinus . It is an optical isomer of another natural compound daniellic acid and was firstly purified from Pinus lambertiana . LA can be synthesized in laboratory from podocarpic acid. It has been reported to have potential health benefits in attenuating obesity, allergies and different cancers including breast, liver, lung and prostate cancer. It exhibits anticancer properties through inhibiting cancer cell proliferation and survival, and inducing apoptosis, targeting major signalling components including AKT, AMPK, NFkB, COX-2, STAT3, etc. Most of the studies with LA were done using in vitro models, thus warranting future investigations with animal models to evaluate its pharmacological effects such as antidiabetic, anti-inflammatory and neuroprotective effects as well as to explore the underlying molecular mechanisms and toxicological profile. This review describes the chemistry, source, purification and therapeutic potentials of LA and it can therefore be a suitable guideline for any future study with LA., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Based on the SAR of both α 1 -AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [C 6 min]Br as solvent, the yield of 4aaa was increased to 75.1% from 16.0% and the reaction time was shortened in 1.5 h from 48 h. 25 derivatives structurally based on arylpiperazine and indolyl butyric acid with alkyl linker were prepared. The protocol was futher extended to get another 14 derivatives wherein O-alkylation was involved, and applied to the synthesis of biologically efficient molecules DPQ and Aripiprazole. Expectedly, compound 4aaa exhibited dual inhibition of α 1 -AR and 5α-reductase, and exhibited no obvious cytotoxicity against human cells. The pharmacokinetic properties of 4aaa was also determined., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Despite major advances in the β-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii . Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 ( 35 ). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a β-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.

Objectives: To evaluate various Prostate-Specific Antigen (PSA) thresholds at which a 18 F-fluciclovine PET scan could be considered in the setting of biochemical recurrent prostate cancer after definitive treatment., Methods: We analyzed available records of men who underwent a 18 F-fluciclovine PET scan after definitive therapy at a single academic institution between November 2016 to May 2018. The primary outcome was the rate of positive imaging findings at specific PSA thresholds. We then employed empiric strategies including a ROC curve and decision curve analysis to identify a specific threshold for which obtaining a positive result would be optimized., Results: A total of 115 men underwent imaging with 18 F-fluciclovine PET. No concerning lesions were identified in 25 (21.7%) patients, 32 (27.8%) had a solitary lesion identified, 45 (39.1%) had 2 to 5 lesions, and 13 (11.3%) had greater than 5 suspicious lesions identified. At PSA thresholds of less than 0.5, 0.5 to 2.0, and greater than 2, lesions were detected in 55.5% (12/22), 70.6% (24/34), and 91.5% (54/59) of patients respectively [P < 0.001]. Our ROC analysis yielded a PSA threshold of 2.10 while our decision curve analysis provided a PSA cutoff of 1.38., Conclusion: This study constitutes an early single institution series evaluating the use of 18 F-fluciclovine PET scans in the assessment of biochemically recurrent prostate cancer after definitive treatment. The probability of having positive imaging findings and increasing numbers of suspicious lesions rises with increasing PSA. Utilization of a lower PSA threshold of 0.5 may allow earlier intervention with salvage therapies in biochemical recurrence. However, using a threshold below 1 carries a higher risk of negative scans. Employing a higher PSA threshold of 1 to 2 carries greater sensitivity and specificity and may maximize identifying individuals with early BCR who may benefit from early intervention, while minimizing negative scans., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 ( 2 ) and OZ165 ( 3 ). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para -substituted carboxymethoxy and N -benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.

Objective: PQA-18 (Prenylated quinolinecarboxylic acid-18) has been reported to be a novel immunosuppressant that attenuates the production of various cytokines, and the differentiation of macrophages by inhibiting PAK2. In this study, we investigated the function of this drug mainly on macrophages using a rat small intestinal transplant model., Methods: Male Dark Agouti (DA) and Lewis rats (LEW), 7-9 weeks of age, were used as donor and recipient, respectively. Approximately 15 cm intestinal grafts were heterotopically transplanted to the recipient rats. The recipient rat was treated with PQA-18 (4 mg/kg/day) by intraperitoneal injection (ip) from postoperative day 1 for 2 weeks. The in vivo effects of this drug were evaluated based on changes in body weight, and the population of each type of blood cell. Mixed lymphocyte reaction (MLR) was also assessed, using the T cells from intestinal mesenteric lymph nodes (MLN) of the grafts on POD6. Total cells from MLN and graft Payer's patch (PP) were next collected on POD6, and the number of infiltrated macrophages was determined., Results: While the survival time was 7.0 ± 0.77 days for the control group (n = 9), that for the PQA-18 group was 10.7 ± 1.26 days (n = 10) (p < .001). Histological examinations showed a relatively clear difference in the grafts for both groups. In addition, the MLR response was significantly lower in recipients treated with PQA-18, suggesting PQA-18 well suppressed the T cells. Moreover, while a significant increase of both MHC class II and CD11b/c positive cells, estimated as differentiated/polarized macrophages, in MLN & PP was observed in the control group, PQA-18-administration significantly suppressed the differentiation of macrophages in the MLN & PP., Conclusion: PQA-18 significantly prolonged the survival of the rats with intestinal grafts, and also suppressed the infiltration of lymphocytes, and macrophages to the grafts., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC 50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 μM. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.

Urea carboxylic acids, products of aryl hydantoin hydrolysis, were recently identified as a new antischistosomal chemotype. We now describe a baseline structure-activity relationship (SAR) for this compound series. With one exception, analogs of lead urea carboxylic acid 2 were quite polar with Log D 7.4 values ranging from -1.9 to 1.8, had high aqueous solubilities in the range of 25-100 µg/mL, and were metabolically stable. None of the compounds had measurable in vitro antischistosomal activity or cytotoxicity, but four of these had moderate worm burden reduction (WBR) values of 42-70% when they were administered as single 100 mg/kg oral doses to S. mansoni-infected mice. These data indicate that with the exception of the gem-dimethyl substructure and the distal nitrogen atom of the urea functional group, the rest of the structure of 2 is required for in vivo antischistosomal activity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels., (© 2018 Wiley Periodicals, Inc.)

A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneration (AMD) and therefore may be one of several pathogenic factors contributing to AMD progression. Lipofuscin bisretinoid synthesis in the retina depends on the influx of serum retinol from the circulation into the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)-transthyretin-retinol complex in the serum is required for this influx. Herein, we report the pharmacological effects of the non-retinoid RBP4 antagonist, BPN-14136. BPN-14136 dosing in the Abca4 -/- mouse model of increased lipofuscinogenesis significantly reduced serum RBP4 levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors. BPN-14136 administration at doses inducing maximal serum RBP4 reduction did not produce changes in the rate of the visual cycle, consistent with minimal changes in dark adaptation. Abca4 -/- mice exhibited dysregulation of the complement system in the retina, and BPN-14136 administration normalized the retinal levels of proinflammatory complement cascade components such as complement factors D and H, C-reactive protein, and C3. We conclude that BPN-14136 has several beneficial characteristics, combining inhibition of bisretinoid synthesis and reduction in retinaldehydes with normalization of the retinal complement system. BPN-14136, or a similar compound, may be a promising drug candidate to manage Stargardt disease and dry AMD., (© 2018 Racz et al.)

Herein, poly(pyrrole-3-carboxylic acid) (PPyCOOH) nanoneedles with abundant carboxyl groups were synthesized by aqueous dispersion polymerization method using pyrrole-3-carboxylic acid as conductive polymer monomer. The PPyCOOH nanoneedles not only owned good photothermal performance, but also more importantly showed enhanced tumor cell uptake efficiency (1.64 fold) compared with size and zeta-potential matched nanospheres. After loading photosensitizer aluminum phthalocyanine tetrasulfonate (AlPCS 4 ) and modifying with poly(allylamine hydrochloride) (PAH) and poly(acrylic acid) (PAA) onto the PPyCOOH nanoneedles, novel nanoneedle complexes (AlPCS 4 @PPyCONH-PAH-PAA) integrating photodynamic therapy (PDT) and photothermal therapy (PTT) were successfully fabricated. The as-prepared nanoneedle complexes improved uptake efficiency of AlPCS 4 both in vitro and in vivo. Moreover, the nanoneedle complexes have infrared thermal and fluorescent properties. By combined PDT/PTT under the guiding of dual modal imaging, the tumors in mice were completely eliminated and no recurrence was observed in 30 days after treatment, indicating that PPyCOOH nanoneedles have great potential as a novel drug carrier for constructing multifunctional nanoplatform used for cancer treatment., (Copyright © 2018. Published by Elsevier Ltd.)

A significant number of patients radically treated for prostate cancer (PCa) will develop prostate-specific antigen recurrence (27-53%). Localizing the anatomical site of relapse is critical, in order to achieve the optimal treatment management. To date the diagnostic accuracy of standard imaging is low. Several desirable features have been identified for the amino-acid-based PET agent, fluciclovine ( 18 F) including: long 18 F half-life which allows more practical use in centers without a cyclotron onsite; acting as a substrate for amino acid transporters upregulated in PCa or associated with malignant phenotype; lacking of incorporation into protein; and limited urinary excretion. Fluciclovine ( 18 F) is currently approved both in USA and Europe with specific indication in adult men with suspected recurrent PCa based on elevated prostate-specific antigen following prior treatment.

Background: Positron emission tomography/computed tomography (PET/CT) has recently emerged as a promising diagnostic imaging platform for prostate cancer. Several radiolabelled tracers have demonstrated efficacy for cancer detection in various clinical settings. In this review, we aim to illustrate the diverse use of PET/CT with different tracers for the detection of prostate cancer., Methods: We searched MEDLINE using the terms 'prostate cancer', 'PET', 'PET/CT' and 'PET/MR'). The current review was limited to 18 F-NaF PET/CT, choline-based PET/CT, fluciclovine PET/CT and PSMA-targeted PET/CT, as these modalities have been the most widely adopted., Results: NaF PET/CT has shown efficacy in detecting bone metastases with high sensitivity, but relatively low specificity. Currently, choline PET/CT has been the most extensively studied modality. Although having superior specificity, choline PET/CT suffers from low sensitivity, especially at low PSA levels. Nevertheless, choline PET/CT was found to significantly improve upon conventional imaging modalities (CIM) in the detection of metastatic lesions at biochemical recurrence (BCR). Newer methods using fluciclovine and PSMA-targeted radiotracers have preliminarily demonstrated great promise in primary and recurrent staging of prostate cancer. However, their superior efficacy awaits confirmation in larger series., Conclusions: PET/CT has emerged as a promising staging modality for both primary and recurrent prostate cancer. Newer tracers have increased detection accuracies for small, incipient metastatic foci. The clinical implications of these occult PET/CT detected disease foci require organized evaluation. Efforts should be aimed at defining their natural history as well as responsiveness and impact of metastasis-directed therapy.

In current study, a series of shikonin derivatives were synthesized and its anticancer activity was evaluated. As a result, PMMB232 showed the best antiproliferation activity with an IC 50 value of 3.25±0.35μM. Further, treatment of HeLa cells with a variety of concentrations of target drug resulted in dose-dependent event marked by apoptosis. What's more, the mitochondrial potential (Δym) analysis was consistent with the apoptosis result. In addition, PARP was involved in the progress of apoptosis revealed by western blotting. To identify the detailed role and mechanism of PMMB232 in the progression of human cervical cancer, we detected the expression of HIF-1α and E-cadherin in HeLa cells. Results showed that expression of HIF-1α was downregulated, while E-cadherin protein was upregulated. Meanwhile, glycolysis related protein PDK1 was decreased in HeLa cells. Conversely, the expression of PDH-E1α was upregulated. Docking simulation results further indicate that PMMB232 could be well bound to HIF-1α. Taken together, our data indicate that compound PMMB232 could be developed as a potential anticancer agent., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids [aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco)] to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid-modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111 In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111 In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco-PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111 In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca 2+ . An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Epilepsy is one of the most common neurological diseases, with between 34 and 76 per 100,000 people developing epilepsy annually. Epilepsy therapy for the past 100 + years is based on the use of antiepileptic drugs (AEDs). Despite the availability of more than twenty old and new AEDs, approximately 30% of patients with epilepsy are not seizure-free with the existing medications. In addition, the clinical use of the existing AEDs is restricted by their side-effects, including the teratogenicity associated with valproic acid that restricts its use in women of child-bearing age. Thus, there is an unmet clinical need to develop new, effective AEDs. In the present study, a novel class of carbamates incorporating phenethyl or branched aliphatic chains with 6-9 carbons in their side-chain, and 4-benzenesulfonamide-carbamate moieties were synthesized and evaluated for their anticonvulsant activity, teratogenicity and carbonic anhydrase (CA) inhibition. Three of the ten newly synthesized carbamates showed anticonvulsant activity in the maximal-electroshock (MES) and 6 Hz tests in rodents. In mice, 3-methyl-2-propylpentyl(4-sulfamoylphenyl)carbamate(1), 3-methyl-pentan-2-yl-(4-sulfamoylphenyl)carbamate (9) and 3-methylpentyl, (4-sulfamoylphenyl)carbamate (10) had ED 50 values of 136, 31 and 14 mg/kg (MES) and 74, 53, and 80 mg/kg (6 Hz), respectively. Compound (10) had rat-MES-ED 50  = 13 mg/kg and ED 50 of 59 mg/kg at the mouse-corneal-kindling test. These potent carbamates (1,9,10) induced neural tube defects only at doses markedly exceeding their anticonvuslnat-ED 50 values. None of these compounds were potent inhibitors of CA IV, but inhibited CA isoforms I, II and VII. The anticonvulsant properties of these compounds and particularly compound 10 make them potential candidates for further evaluation and development as new AEDs.

Microtubule Targeting Agents (MTAs) induce cell death through mitotic arrest, preferentially affecting rapidly dividing cancer cells over slowly proliferating normal cells. Previously, we showed that Methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) acts as a potential MTA. In this study, we demonstrated that MBIC exhibits greater toxicity towards non-aggressive breast cancer cell-line, MCF-7 (IC50 = 0.73 ± 0.0 μM) compared to normal fibroblast cell-line, L-cells (IC50 = 59.6 ± 2.5 μM). The IC50 of MBIC against the aggressive breast cancer cell-line, MDA-MB-231 was 20.4 ± 0.2 μM. We hypothesized that the relatively high resistance of MDA-MB-231 cells to MBIC is associated with p53 mutation. We investigated p53 and three of its downstream proteins: survivin, cyclin dependent kinase (Cdk1) and cyclin B1. Following treatment with MBIC, survivin co-immunoprecipitated with caspases with higher affinity in MDA-MB-231 compared to MCF-7 cells. Furthermore, silencing survivin caused a 4.5-fold increase in sensitivity of MDA-MB-231 cells to MBIC (IC50 = 4.4 ± 0.3). In addition, 4 weeks of MBIC administration in MDA-MB-231 cells inoculated BALB/c nude mice resulted in 79.7% reduction of tumor volume compared to the untreated group with no severe sign of toxicity. Our results demonstrated MBIC has multiple anti-tumor actions and could be a potential drug in breast cancer therapy.

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management placed greater emphasis on statin therapy given the well-established benefits in primary and secondary prevention of cardiovascular disease. Residual risk may remain after statin initiation, in part because of triglyceride-rich lipoprotein cholesterol. Several large trials have failed to show benefit with non-statin cholesterol-lowering medications in the reduction of cardiovascular events. Yet, subgroup analyses showed a benefit in those with hypertriglyceridemia and lower high-density lipoprotein cholesterol level, a high-risk pattern of dyslipidemia. This review discusses the benefits of omega-3 carboxylic acids, a recently approved formulation of omega-3 fatty acid with enhanced bioavailability, in the treatment of dyslipidemia both as monotherapy and combination therapy with a statin., Competing Interests: Michael H Davidson was the Chief Medical Officer of Omthera until June of 2015. Omthera Pharmaceuticals clinically developed omega-3 carboxylic acid for FDA approval and was acquired by Astra Zeneca in July, 2013. The authors report no other conflicts of interest in this work.

New derivatives of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepin-3-carboxylate (HIE-124, 3), were synthesized as continuation to our previous patented efforts. Compounds 15 and 20 showed marginal hypnotic potency compared to 3. Compounds 15 (0.78mmol/kg) and 20 (0.39mmol/kg) showed remarkable 100% protection against PTZ induced convulsions with two and four fold increase in activity than sodium valproate (1.38mmol/kg), respectively. Molecular modeling studies showed hydrogen bonding interaction between 15 and Thr56 residues at the binding site of GABAA. Superposition, flexible alignment and surface mapping of 15, 20 and diazepam supports their biological resemblance where ADMET study suggested that those compounds could be used as oral anticonvulsants., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Skp2 is frequently overexpressed in many human cancers and plays a key role in tumorigenesis. As a component of the SCFSkp2ubiquitin E3 ligase complex, Skp2 is responsible for recruiting substrate proteins for their ubiquitination and subsequent degradation by the 26S proteasome. Thus, Skp2 promotes the cell cycle by down-regulating cell cycle proteins such as the tumor suppressor p27. Alternatively, Skp2 suppresses p53-dependent apoptosis by outcompeting p53 for binding to p300, thereby perturbing p300-mediated p53 acetylation and stabilization. Taken together, inhibition of Skp2 functions (either proteolytic function or non-proteolytic function) is emerging as a promising and novel anti-cancer strategy. In the present review, we highlight the development of Skp2 inhibitors with different mechanisms of action.

Chlorogenic acids (CGAs) are esters formed between caffeic and quinic acids, and represent an abundant group of plant polyphenols present in the human diet. CGAs have different subgroups that include caffeoylquinic, p-coumaroylquinic, and feruloyquinic acids. Results of epidemiological studies suggest that the consumption of beverages such as coffee, tea, wine, different herbal infusions, and also some fruit juices is linked to reduced risks of developing different chronic diseases. These beverages contain CGAs present in different concentrations and isomeric mixtures. The underlying mechanism(s) for specific health benefits attributed to CGAs involves mitigating oxidative stress, and hence the related adverse effects associated with an unbalanced intracellular redox state. There is also evidence to show that CGAs exhibit anti-inflammatory activities by modulating a number of important metabolic pathways. This review will focus on three specific aspects of the relevance of CGAs in coffee beverages; namely: (1) the relative composition of different CGA isomers present in coffee beverages; (2) analysis of in vitro and in vivo evidence that CGAs and individual isomers can mitigate oxidative and inflammatory stresses; and (3) description of the molecular mechanisms that have a key role in the cell signaling activity that underlines important functions.

Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.

We previously showed that activity of the large conductance calcium-activated potassium (Big-K; BK) channels is suppressed in 3xTg Alzheimer disease (AD) model mice. However, its behavioral significance is not known. In the present report, ventricular injection of the BK channel activator isopimaric acid (ISO) was conducted to examine whether BK channel activation ameliorates cognition in 3xTg mice. The novel object recognition (NOR) test revealed that chronic injection of ISO improved non-spatial memory in 3xTg mice. In the Morris water maze, the probe test demonstrated an improved spatial memory after ISO injection. Electrophysiological underpinnings of the ISO effect were then examined in slices obtained from the mice after behavior. At hippocampal CA1 synapses, the basic synaptic transmission was abnormally elevated and long-term potentiation (LTP) was partially suppressed in 3xTg mice. These were both recovered by ISO treatment. We then confirmed suppressed BK channel activity in 3xTg mice by measuring the half-width of evoked action potentials. This was also recovered by ISO treatment. We previously showed that the recovery of BK channel activity accompanies reduction of neuronal excitability in pyramidal cells. Here again, pyramidal cell excitability, as assessed by calculating the frequency of evoked spikes, was elevated in the 3xTg mouse and was normalized by ISO. ELISA experiments demonstrated an ISO-induced reduction of Aβ1-42 content in hippocampal tissue in 3xTg mice. The present study thus suggests a potential therapeutic utility of BK channel activators for AD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Current Letter presents design, synthesis and biological evaluation of a novel series of pyrazolylthiazole carboxylates 1a-1p and corresponding acid derivatives 2a-2p. All 32 novel compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema method as well as for in vitro antimicrobial activity. All the tested compounds exhibited excellent AI activity profile. Three compounds 1p (R=Cl, R(1)=Cl), 2c (R=H, R(1)=F) and 2n (R=Cl, R(1)=OCH3) were identified as potent anti-inflammatory agents exhibiting edema inhibition of 93.06-89.59% which is comparable to the reference drug indomethacin (91.32%) after 3h of carrageenan injection while most of the other compounds displayed inhibition ⩾80%. In addition, pyrazolylthiazole carboxylic acids (2a-2p) also showed good antimicrobial profile. Compound 2h (R=OCH3, R(1)=Cl) showed excellent antimicrobial activity (MIC 6.25μg/mL) against both Gram positive bacteria comparable with the reference drug ciprofloxacin (MIC 6.25μg/mL)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

1, 8-naphthyridine-3-carboxylic acid analogs were synthesized and found to possess potential 5-HT3 receptor antagonism as well as antidepressant-like activity. Initially, 5-HT3 receptor antagonism of all the compounds was determined in the form of pA2 value against agonist 2-methyl 5-HT in longitudinal muscle-myenteric plexus preparation from guinea-pig ileum. Among all the compounds tested, compound 7a demonstrated most promising pA2 value of 7.6. Subsequently, all the compounds were evaluated for antidepressant activity using forced swim test and tail suspension test in mice. Compounds 7a, 7d, 7f, 7h, and 7i exhibited significant (p < 0.05) antidepressant-like activity as compound to vehicle-treated group. Importantly, none of the tested compound affected locomotor activity of mice at tested dose levels., (© 2014 John Wiley & Sons A/S.)

Omega-3 carboxylic acids (Epanova) [OM3-CA] is the first free fatty acid form of long-chain marine omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid being the most abundant) to be approved by the US FDA as an adjunct to diet to lower triglyceride levels in patients with severe hypertriglyceridemia (≥ 500 mg/dL). Oral OM3-CA has greater bioavailability than ethyl ester forms of omega-3 and, unlike omega-3 acid ethyl esters, does not require co-ingestion of a high-fat meal, as it does not need pancreatic enzyme activity for absorption. In the 12-week EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial, OM3-CA 2 or 4 g/day significantly reduced serum triglyceride levels relative to placebo. Other lipid parameters, including non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, and very low-density lipoprotein cholesterol (VLDL-C) levels, were also reduced significantly with OM3-CA relative to placebo. Low-density lipoprotein cholesterol levels were increased significantly with OM3-CA relative to placebo; however, these increases were not accompanied by increases in the circulating concentrations of non-HDL-C, VLDL-C, or apolipoprotein B. OM3-CA was generally well tolerated in this study, with most adverse events being of mild or moderate severity. Although additional comparative data are needed to position OM3-CA with respect to other formulations of omega-3 fatty acids, current evidence suggests that OM3-CA is a useful addition to the treatment options available for patients with severe hypertriglyceridemia.

The incidence of hypertriglyceridemia has grown alongside that of obesity. Statin therapy has been widely recommended for the treatment of dyslipidemias. Omega-3 (OM3) fatty acid concentrates are commonly prescribed concurrently with statins in patients with persistent hypertriglyceridemia for additional lowering of triglyceride and non-HDL cholesterol. The bioavailability of currently available OM3 ethyl ester drugs is limited by their need for hydrolysis by pancreatic lipases, largely stimulated by dietary fat, prior to intestinal absorption. This review will discuss the chemistry, pharmacokinetics and clinical efficacy of a novel OM3 carboxylic acid drug that provides polyunsaturated docosahexaenoic and eicosapentaenoic acids in the free fatty acid form, which is readily absorbed by the intestine. This drug was approved in May 2014 as an adjunct to diet to reduce triglyceride levels in adults with severe (≥500 mg/dl) hypertriglyceridemia.

Scope: The potential benefit of vitamin K as a therapeutic in osteoporosis is controversial and the vitamin K regimen being used clinically (45 mg/day) employs doses that are many times higher than required to ensure maximal gamma-carboxylation of the vitamin K-dependent bone proteins. We therefore tested the hypothesis that vitamin K catabolites, 5-carbon (CAN5C) and 7-carbon carboxylic acid (CAN7C) aliphatic side-chain derivatives of the naphthoquinone moiety exert an osteotrophic role consistent with the treatment of osteoporosis., Methods and Results: Osteoblast-like MG63 cell cultures were challenged with lipopolysaccharide and the levels of interleukin-6, an osteoclastogenic cytokine, measured with and without catabolites; low concentrations of CAN7C significantly inhibited interleukin-6 release, but CAN5C did not. In models of bone loss induced by ovariectomy or sciatic neurectomy in C57BL/6 mice, we found that the rarer CAN7C catabolite markedly restricted ovariectomy-induced bone loss and possibly limited sciatic neurectomy-induced bone loss. CAN7C activity depends on a free carboxylic acid and its particular side-chain structure., Conclusion: These in vivo data indicate for the first time that the clinical utility of vitamin K for osteoporosis may reside in an unusual catabolite., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer's disease. Compounds that act as positive allosteric modulators at GABA(A) α5 receptors might be useful in targeting this condition because GABA(A) α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABA(A) α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABA(A) α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 μg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. This article is part of a Special Issue entitled 'Cognitive Enhancers'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Arthritis involves joint inflammation, synovial proliferation and damage of cartilage. Interleukin-1 undergoes acute and chronic inflammatory mechanisms of arthritis. Non-steroidal anti-inflammatory drugs can produce symptomatic relief but cannot act through mechanisms of arthritis. Diseases modifying anti-rheumatoid drugs reduce the symptoms of arthritis like decrease in pain and disability score, reduction of swollen joints, articular index and serum concentration of acute phage proteins. Recently, some literature references are obtained on molecular modeling of antirheumatic agents. We have tried chemometric modeling through 2D-QSAR studies on a dataset of fifty-one compounds out of which forty-four 5-Phenylthiophenecarboxylic acid derivatives have IL-1 inhibitory activity and forty-six 5-Phenylthiophenecarboxylic acid derivatives have %AIA suppressive activity. The work was done to find out the structural requirements of these anti-rheumatic agents. 2D QSAR models were generated by 2D and 3D descriptors by using multiple linear regression and partial least square method where IL-1 antagonism was considered as the biological activity parameter. Statistically significant models were developed on the training set developed by k-means cluster analysis. Sterimol parameters, electronic interaction at atom number 9, 2D autocorrelation descriptors, information content descriptor, average connectivity index chi-3, radial distribution function, Balaban 3D index and 3D-MoRSE descriptors were found to play crucial roles to modulate IL-1 inhibitory activity. 2D autocorrelation descriptors like Broto-Moreau autocorrelation of topological structure-lag 3 weighted by atomic van der Waals volumes, Geary autocorrelation-lag 7 associated with weighted atomic Sanderson electronegativities and 3D-MoRSE descriptors like 3D-MoRSE-signal 22 related to atomic van der Waals volumes, 3D-MoRSE-signal 28 related to atomic van der Waals volumes and 3D-MoRSE-signal 9 which was unweighted, were found to play important roles to model %AIA suppressive activity.

Amyloidosis is a clinical disorder caused by extracellular deposition of proteins that are normally soluble as insoluble fibrils that damage different organs. More than 20 proteins can form amyloid deposits. All types of amyloid fibrils have a secondary structure with a β folded shape that is characteristic and makes them to adopt a green birefringence after stained with Congo red and viewed under cross-polarized light. Amyloidosis can be acquired or hereditary, systemic or localized, and are classified by the fibril precursor protein. Advances in the knowledge of the pathogenesis of amyloidosis allows the development of new diagnostic and therapeutical schemes that are currently under investigation., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

A series of new quinolone-3-carboxylic acids featuring a hydroxyl group at C-5 position were synthesized and evaluated for their in vitro activity against HIV in C8166 cell culture. All the compounds showed anti-HIV-1 activity with low micromolar to submicromolar EC(50) values. The most active compound 2k exhibited activity against wild-type HIV-1 with an EC(50) value of 0.13 μΜ. Preliminary structure-activity relationship of the newly synthesized quinolone analogues was also investigated. Further docking study revealed that the anti-HIV activity of these compounds might involve a two-metal chelating mechanism., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Starting with a subtle blood glucose-lowering effect of a TGF-β inhibitor, we designed and synthesized a series of benzoylpyrrole-based carboxylic acids as PPARs activators. Among these compounds, 10sNa exhibited favorable blood glucose-lowering effect without body weight gain. We assume that the beneficial effect of 10sNa is attributed to not only its compound PPARα agonistic activity but also its PPARγ partial agonistic activity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)