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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.)

Control of gonadotropin-releasing hormone (GnRH) signalling is an effective strategy for the treatment of sex hormone-dependent diseases. GnRH analogues have been widely used for treating these diseases; however, initial stimulation or complete suppression of GnRH signalling by GnRH analogues results in the occurrence of several distinct adverse effects. Accordingly, we aimed to discover small molecule GnRH antagonists with superior pharmacokinetic and pharmacodynamic profiles. Linzagolix is a potent, orally available, and selective GnRH antagonist. Here, we reported the pharmacological characterization of linzagolix in vitro and in vivo. Linzagolix selectively binds to the GnRH receptor and inhibits GnRH-stimulated signalling, in a manner comparable to cetrorelix, a peptide GnRH antagonist. Because the inhibitory effect of the gonad axis is useful for the treatment of gynaecological conditions such as endometriosis and uterine fibroids, we investigated the effect of orally administrated linzagolix on the gonadal axis in ovariectomized and intact cynomolgus monkeys. In ovariectomized monkeys, linzagolix immediately suppressed the serum luteinizing hormone concentration at doses over 1 mg/kg, indicating dose-dependent inhibition that correlated with serum linzagolix concentrations. In intact female monkeys, repeated linzagolix administration suppressed hormone surges and ceased or prolonged menstrual cycles. Furthermore, all animals presenting arrested menstrual cycles following linzagolix treatment showed recovery of hormone secretion and regular menstrual cycles after administration periods ended. Our results demonstrated that linzagolix has potential as a novel agent for reproductive-age women suffering from sex hormone-dependent diseases., (© 2022 John Wiley & Sons Australia, Ltd.)

Background: 18 F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18 F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades., Methods: Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18 F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters., Results: A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation., Conclusions: 18 F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake., Clinical Trial Registration: NCT03036943., (© 2021. 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.)

Fibrates and omega-3 polyunsaturated acids are used for the treatment of hypertriglyceridemia but have not demonstrated consistent effects on cardiovascular (CV) risk. In this study, we investigate how these two pharmacological agents influence plasma levels of bioactive lipid mediators, aiming to explore their efficacy beyond that of lipid-lowering agents. Plasma from overweight patients with non-alcoholic fatty liver disease (NAFLD) and hypertriglyceridemia, participating in a randomized placebo-controlled study investigating the effects of 12 weeks treatment with fenofibrate or omega-3 free carboxylic acids (OM-3CA) (200 mg or 4 g per day, respectively), were analyzed for eicosanoids and related PUFA species, N-acylethanolamines (NAE) and ceramides. OM-3CA reduced plasma concentrations of proinflammatory PGE 2 , as well as PGE 1 , PGD 1 and thromboxane B2 but increased prostacyclin, and eicosapentaenoic acid- and docosahexaenoic acid-derived lipids of lipoxygenase and cytochrome P450 monooxygenase (CYP) (e.g., 17-HDHA, 18-HEPE, 19,20-DiHDPA). Fenofibrate reduced plasma concentrations of vasoactive CYP-derived eicosanoids (DHETs). Although OM-3CA increased plasma levels of the NAE docosahexaenoyl ethanolamine and docosapentaenoyl ethanolamine, and fenofibrate increased palmitoleoyl ethanolamine, the effect of both treatments may have been masked by the placebo (olive oil). Fenofibrate was more efficacious than OM-3CA in significantly reducing plasma ceramides, pro-inflammatory lipids associated with CV disease risk. Neither treatment affected putative lipid species associated with NAFLD. Our results show that OM-3CA and fenofibrate differentially modulate the plasma mediator lipidome, with OM-3CA promoting the formation of lipid mediators with potential effects on chronic inflammation, while fenofibrate mainly reducing ceramides. These findings suggest that both treatments could ameliorate chronic inflammation with possible impact on disease outcomes, independent of triglyceride reduction., (© 2021 Federation of American Societies for Experimental Biology.)

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.

Isopimaric acid (IPA) exhibits a diverse array of pharmacological activities, having been shown to function as an antihypertensive, antitumor, antibacterial, and hypocholesterolemic agent. However, few studies of the pharmacokinetics of IPA have been performed to date, and such analyses are essential to explore the in vivo mechanisms governing the biological activity of this compound. As such, we herein designed a selective LC-MS approach capable of quantifying serum IPA levels in model rats using an Agilent HC-C18 column (250 mm × 4.6 mm, 5  μ m) via isocratic elution with a mobile phase composed of methanol 0.5% formic acid (91 : 9, v/v) at a 1 mL/min flow rate. Ion monitoring at m/z 301.2 [M-H] - was used to quantify IPA levels in plasma samples from these rats, while internal standard (IS) levels were assessed at m/z 455.3 [M-H] - . After validation, this approach was employed to conduct a pharmacokinetic analysis of rats administered IPA via the oral (p.o. 50, 100, or 200 mg/kg) and intravenous (i.v. 5 mg/kg) routes. Analyses of noncompartmental pharmacokinetic parameters revealed that IPA underwent secondary absorption following oral administration to these animals, with the two tested oral doses (50 and 100 mg/kg) being associated with respective absolute bioavailability values of 11.9% and 17.5%. In summary, this study may provide a foundation for future efforts to explore the mechanistic basis for the pharmacological activity of IPA, offering insights to guide its subsequent clinical utilization., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Doudou Huang et al.)

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases. Our compound collection was mined for molecules possessing substructure features associated with S1P2 activity. The weakly potent indole hit 6 evolved into a potent phthalazone series, bearing a carboxylic acid, with the aid of a homology model. Suboptimal pharmacokinetics of a benzimidazole subseries were improved by modifications targeting potential interactions with transporters, based on concepts deriving from the extended clearance classification system (ECCS). Scaffold hopping, as a part of a chemical enablement strategy, permitted the rapid exploration of the position adjacent to the carboxylic acid. Compound 38 , with good pharmacokinetics and in vitro potency, was efficacious at 10 mg/kg BID in three different in vivo mouse models of fibrotic diseases in a therapeutic setting.

Introduction: Uterine myomas and endometriosis are benign hormone-dependent diseases affecting women of reproductive age. Substantial efforts have been made to develop innovative medical options for treating these gynecologic diseases. Elagolix and relugolix have been approved in some countries for treating endometriosis and myomas, respectively; however, linzagolix (OBE 2109, KLH 2109) is a new oral gonadotropin-releasing hormone (GnRH) antagonist in phase II-III trials. Treatment options for women with contraindications for hormonal therapies or who refuse particular options, are the driving force behind the development of new drugs in this area., Area Covered: This drug evaluation highlights definitive and preliminary results from previous and ongoing studies of linzagolix for the treatment of endometriosis and myomas., Expert Opinion: Linzagolix showed a dose-dependent and rapidly reversible action on the pituitary-gonadal axis. In a recent phase II trial (EDELWEISS), linzagolix significantly reduced pain related to endometriosis and improved quality of life at single daily doses of 75-200 mg. The preliminary results of international, double-blind phase III trials (PRIMROSE 1 and 2) reported its efficacy in treating heavy menstrual bleeding related to myomas with a good safety profile. Further studies will determine the necessity of add-back therapy during long-term use of linzagolix.

Cardiac safety and plasma concentration-QTc interval analyses were completed using data from 2 phase 1 studies of the selective mouse double minute chromosome 2 antagonist, KRT-232, in patients with solid tumors or multiple myeloma and acute myeloid leukemia (AML) who received KRT-232 doses of 15 to 480 mg once daily (QD; N = 130). A linear mixed-effects model related change from baseline Fridericia-corrected QT interval (ΔQTcF) to KRT-232 plasma concentrations. The final model included parameters for the intercept (with between-subject variability), KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. Mean (90% confidence interval) predicted ΔQTcF values at the maximum clinical dose (480 mg QD) were 2.04 (0.49-3.60) milliseconds for patients with solid tumors and 4.52 (2.35-6.69) milliseconds for patients with AML. Because the 90% confidence interval upper bound of the mean ΔQTcF was predicted to be below 10 milliseconds at doses up to 480 mg QD in patients with solid tumors, multiple myeloma, or AML, KRT-232 does not result in clinically meaningful QT prolongation at the doses currently under investigation in clinical trials. No significant cardiac safety concerns were identified at these doses., (© 2021 Kartos Therapeutics, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

In patients with coronary heart disease undergoing primary prevention, hypertriglyceridemia is a residual risk for cardiovascular events. Omega-3 carboxylic acid (OM3-CA), a mixture of the free fatty acid forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be beneficial in reducing triglyceride levels. As part of the clinical development program of OM3-CA in China, this phase I study evaluated the pharmacokinetics, safety, and tolerability profile of OM3-CA in healthy subjects. The pharmacokinetic results of this study were also compared with those of available data for Western populations. Fourteen healthy Chinese subjects (aged 18-45 years) received once-daily oral OM3-CA 4 g for 14 consecutive days. Pharmacokinetic parameters were assessed from both baseline-uncorrected and baseline-corrected plasma concentrations vs time profile of EPA, DHA, and EPA plus DHA. Following single and multiple oral doses of OM3-CA, the absorption of EPA, DHA, and EPA plus DHA was steady with median t max occurring at 5.5-6 hours after both single and multiple dosing. Close to steady-state concentrations in plasma were reached after 14 days of continuous once-daily dosing, and accumulation was confirmed for EPA, DHA, and EPA plus DHA. Of the 14 subjects treated with OM3-CA, 6 (42.9%) reported at least 1 adverse event (diarrhea) during the study, which was determined as mild and treatment emergent. No serious adverse events were reported. In summary, the pharmacokinetic profile of oral OM3-CA 4 g after single and multiple dosing in healthy Chinese subjects is consistent with that observed in other ethnic populations., (© 2020, The American College of Clinical Pharmacology.)

Retinoic acid receptors (RARs) α, β, and γ are members of the nuclear receptor superfamily. Compounds which bind to and activate the RARs are termed retinoids which regulate a wide variety of biological processes such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation, and apoptosis, as well as their disorders. Although many synthetic selective RARα, RARβ, and RARγ agonists have been designed and prepared, these have generally been lipophilic acids without good drug-like properties and with low oral bioavailability. Recently this has been changing and drug design approaches to highly potent and selective RARα and RARβ agonists with low lipophilicity that are orally bioavailable and less toxic have been developed, that have a range of potential therapeutic uses. This review covers these new advances., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

After oral administration to monkeys of [ 14 C]GDC-0810, an α , β -unsaturated carboxylic acid, unchanged parent and its acyl glucuronide metabolite, M6, were the major circulating drug-related components. In addition, greater than 50% of circulating radioactivity in plasma was found to be nonextractable 12 hours post-dose, suggesting possible covalent binding to plasma proteins. In the same study, one of the minor metabolites was a cysteine conjugate of M6 (M11) that was detected in plasma and excreta (urine and bile). The potential mechanism for the covalent binding to proteins was further investigated using in vitro methods. In incubations with glutathione (GSH) or cysteine (5 mM), GSH and cysteine conjugates of M6 were identified, respectively. The cysteine reaction was efficient with a half-life of 58.6 minutes ( k react = 0.04 1/M per second). Loss of 176 Da (glucuronic acid) followed by 129 Da (glutamate) in mass fragmentation analysis of the GSH adduct of M6 (M13) suggested the glucuronic acid moiety was not modified. The conjugation of N-glucuronide M4 with cysteine in buffer was >1000-fold slower than with M6. Incubations of GDC-0810, M4, or M6 with monkey or human liver microsomes in the presence of NADPH and GSH did not produce any oxidative GSH adducts, and the respective substrates were qualitatively recovered. In silico analysis quantified the inherent reactivity differences between the glucuronide and its acid precursor. Collectively, these results show that acyl glucuronidation of α , β -unsaturated carboxylic acids can activate the compound toward reactivity with GSH, cysteine, or other biologically occurring thiols and should be considered during the course of drug discovery. SIGNIFICANCE STATEMENT: Acyl glucuronidation of the α,β-unsaturated carboxylic acid in GDC-0810 activates the conjugated alkene toward nucleophilic addition by glutathione or other reactive thiols. This is the first example that a bioactivation mechanism could lead to protein covalent binding to α,β-unsaturated carboxylic acid compounds., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP)., Design: A multinational, parallel group, randomized, placebo-controlled, double-blind, dose-ranging trial., Setting: Clinical centers., Patient(s): Women aged 18-45 years with surgically confirmed endometriosis and moderate-to-severe EAP., Intervention(s): The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24 weeks., Main Outcome Measure(s): The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD)., Result(s): Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern., Conclusion(s): Linzagolix significantly reduced EAP and improved QoL at doses of 75-200 mg and decreased BMD dose-dependently., Clinical Trial Registration Number: NCT02778399., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of this prospective single-institution clinical trial (NCT02002455) was to evaluate the potential of advanced post-processing methods for 18 F-Fluciclovine PET and multisequence multiparametric MRI in the prediction of prostate cancer (PCa) aggressiveness, defined by Gleason Grade Group (GGG). 21 patients with PCa underwent PET/CT, PET/MRI and MRI before prostatectomy. DWI was post-processed using kurtosis (ADC k , K), mono- (ADC m ), and biexponential functions (f, D p , D f ) while Logan plots were used to calculate volume of distribution (V T ). In total, 16 unique PET (V T , SUV) and MRI derived quantitative parameters were evaluated. Univariate and multivariate analysis were carried out to estimate the potential of the quantitative parameters and their combinations to predict GGG 1 vs >1, using logistic regression with a nested leave-pair out cross validation (LPOCV) scheme and recursive feature elimination technique applied for feature selection. The second order rotating frame imaging (RAFF), monoexponential and kurtosis derived parameters had LPOCV AUC in the range of 0.72 to 0.92 while the corresponding value for V T was 0.85. T he best performance for GGG prediction was achieved by K parameter of kurtosis function followed by quantitative parameters based on DWI, RAFF and 18 F-FACBC PET. No major improvement was achieved using parameter combinations with or without feature selection. Addition of 18 F-FACBC PET derived parameters (V T , SUV) to DWI and RAFF derived parameters did not improve LPOCV AUC.

Background: Acne is one of the most common skin problems among human populations. A facial cleanser formulated with alkyl ether carboxylate (AEC) and alkyl carboxylate (AC) can improve acne by cleansing sebum on facial skin but cannot effectively remove keratotic plugs in the skin pores. Recently, we confirmed that Tris (hydroxymethyl) aminomethane and L-arginine (Tris/Arg) is able to reduce sebum levels, disrupt keratotic plugs in vitro and decrease pore size on facial skin., Objective: To compare the efficacy of the Tris/Arg-formulated cleanser with the AEC/AC cleanser in Thai subjects with acne., Methods: We designed a randomized, double-blind, controlled, parallel trial. Thirty-four male Thai subjects with mild to moderate acne were assigned to one of two groups: one group used the Tris/Arg cleanser while the other used the AEC/AC-based cleanser twice a day for 4 weeks., Results: After 4 weeks, significant decreases in noninflammatory acne were observed in both groups, yet significant decreases in inflammatory acne were only observed in the Tris/Arg cleanser group. The sebum level prior to and 30 minutes after facial washing showed no change in either group. The average pore size with keratotic plugs on the cheeks was significantly decreased in the Tris/Arg group. More than half of subjects in both groups observed acne improvement but more subjects in the Tris/Arg group noted pore size improvement., Conclusion: The Tris/Arg formulated cleanser has a high efficacy for significantly reducing both noninflammatory and inflammatory acne accompanied by decreases in pore size with keratotic plugs in male Thai subjects., (© 2019 Wiley Periodicals, Inc.)

Organic acids (OA) and phytogenic compounds have been used in pig feeding as alternatives to antibiotic growth promoters. However, few studies have evaluated the systemic effect of the combination of these additives. The aim of this study was to assess the impact of an organic acid-based feed additive (OAFA), containing a blend of OA and cinnamaldehyde, on the tissue integrity of bacterially challenged piglets. Thirty weaned piglets 21 d old were used in a 19-d trial. Pigs received a standard diet during the first 7 d and afterward were allotted to five treatments. Dietary treatments were: Control (basal diet), Escherichia coli (basal diet and challenge with E. coli), colistin (basal diet + 200 mg colistin/kg feed + challenge with E. coli), OAFA1 (basal diet + 1 kg OAFA/ton feed + challenge with E. coli), and OAFA2 (basal diet + 2 kg OAFA/ton feed + challenge with E. coli). Seven days after the beginning of the treatment, the animals were challenged with an enterotoxic strain of E. coli (K88) for pigs. Five days after the challenge, all animals were euthanized for tissue sampling for histological and oxidative stress (intestine and liver) analysis. The reduced glutathione (GSH), ferric-reducing ability potential (FRAP), and free-radical scavenging ability (ABTS) assays were used to evaluate the intestinal antioxidant defense. Lipid peroxidation and superoxide anion production were evaluated through the levels of thiobarbituric acid-reactive substances (TBARS) and nitroblue tetrazolium (NBT) reduction assay, respectively. Animals fed the OAFA (1 and 2) diets had a decrease (P < 0.05) on histological changes in the intestine, liver, mesenteric lymph nodes, and spleen. Greater villus height (VH) and a higher ratio of VH to crypt depth (CD) were observed in animals of the OAFA2 group compared with the control and E. coli groups. The colistin and OAFA groups decreased (P < 0.05) the number of inflammatory cells in intestinal lamina propria. OAFA2 group increased (P < 0.05) intestinal cell proliferation. Colistin and OAFA2 supplementation induced a decrease (P < 0.05) in the levels of TBARS in both the intestine and liver compared with the E. coli group. In addition, an increase (P < 0.05) in GSH and FRAP ileal levels was observed in the OAFA2 group compared with E. coli group. These results show that the supplementation with OAFA in the diet of weaned piglets, especially at a dose of 2 kg/ton (OAFA2) protected tissues against enterotoxigenic Escherichia coli (ETEC) damage., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We evaluated a blend of medium-chain fatty acids (MCFA), organic acids, and a polyphenol antioxidant on gut integrity. Eighty Ross Broilers were exposed to 20-22°C (control - normothermic) or to 35-39.5°C (heat stress) for eight hours a day for a period of 1 or 5 days. Birds were fed a standard diet, or a diet supplemented with the test blend. Thereafter, birds were euthanized, and intestinal sections were excised for morphological, morphometric and gene expression analyses. Blood samples were collected for glucose-6-phosphate dehydrogenase (G6PD), glutathione peroxidase (GSH-Px) activity and trolox equivalent antioxidant capacity (TEAC) determination. Heart and liver tissues were used to quantify the expression of heat shock proteins 60 and 70 (HSP60 and HSP70, respectively) and inhibitor of kappa light chain gene enhancer in B cells alpha (IKBA). The jejunum was the most sensitive intestinal section, where heat stress modulated the expression of HSP70, of the inflammatory markers IKBA, interleukin 8 (IL-8), interferon gamma (IFNγ), and toll-like receptor 4 (TLR4). Moreover, expression of tight junctions (CLDN1, ZO1 and ZO2) and nutrient transporters (PEPT1 and EAAT3) was modulated especially in the jejunum. In conclusion, the feed additive blend protected intestines during heat stress from the decrease in villus height and crypt depth, and from the increase in villus width. Especially in the jejunum, heat stress played an important role by modulating oxidative stress and inflammation, impairing gut integrity and nutrient transport, and such deleterious effects were alleviated by the feed additive blend. RESEARCH HIGHLIGHTS Jejunum is the most sensitive intestinal segment during heat stress. Heat stress affects the expression of tight junctions and nutrient transporters. Feed management helps to alleviate the disturbances caused by heat stress. A blend of MCFA, organic acids and a polyphenol protects broilers under heat stress.

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI., (© 2018, The American College of Clinical Pharmacology.)

Background: National Comprehensive Cancer Network guidelines consider 18 F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18 F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL)., Methods: This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent 18 F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT02940262, and is complete., Findings: Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with 18 F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2-19] with 18 F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estimable [95% CI non-estimable], p=0·0078)., Interpretation: With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of miridesap (GSK2315698) following an intravenous (IV) infusion in healthy Japanese men. Subjects in Cohort 1 received 1-hour IV infusions of 10, 20, and 40 mg of miridesap or placebo, and subjects in Cohort 2 received a 15-hour IV infusion of 20 mg/h of miridesap or placebo. No treatment-related adverse events were reported. No new safety signals were identified for either vital signs or clinical laboratory parameters. A dose-dependent increase was observed in miridesap exposure (area under the concentration-time curve and maximum observed drug concentration) in the 10 to 40 mg/h dose range after a 1-hour IV infusion of miridesap. Rapid depletion of circulating serum amyloid P component was observed after the initiation of miridesap infusion. Serum amyloid P component concentrations fell in a dose-dependent manner following administration of miridesap., (© 2018, The American College of Clinical Pharmacology.)

The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose. In a multiple-dose escalation study, doses of 5-50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1-3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half-life of 6.84-12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose-linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once-daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti-remodeling drug with existing standard of care in patients with left-ventricular dysfunction after acute myocardial infarction., (© 2018, The American College of Clinical Pharmacology.)

Purpose: The prospective, multicenter LOCATE (F Fluciclovine [FACBC] PET/CT in Patients with Rising PSA after Initial Prostate Cancer Treatment) trial assessed the impact of positron emission tomography/computerized tomography with F-fluciclovine on treatment plans in patients with biochemical recurrence of prostate cancer after primary therapy with curative intent., Materials and Methods: Men who had undergone curative intent treatment of histologically confirmed prostate cancer but who were suspected to have recurrence based on rising prostate specific antigen levels were enrolled prospectively. Each man had negative or equivocal findings on standard of care imaging. F-fluciclovine positron emission tomography/computerized tomography was performed according to standardized protocols. Treating physicians completed a questionnaire regarding the patient treatment plan before and after scanning, recording changes to the treatment modality (eg salvage radiotherapy to systemic androgen deprivation therapy) as major and changes in a modality (eg modified radiotherapy fields) as other., Results: Between June 2016 and May 2017, 213 evaluable patients with a median age of 67 years and median prostate specific antigen 1.00 ng/ml were enrolled in study. F-fluciclovine avid lesions were detected in 122 of the 213 patients (57%). Overall 126 of the 213 patients (59%) had a change in management after the scan, which were major in 98 of 126 (78%) and in 88 (70%) were informed by positive positron emission tomography/computerized tomography findings. The most frequent major changes were from salvage or noncurative systemic therapy to watchful waiting (32 of 126 cases or 25%), from noncurative systemic therapy to salvage therapy (30 of 126 or 24%) and from salvage therapy to noncurative systemic therapy (11 of 126 or 9%)., Conclusions: F-fluciclovine positron emission tomography/computerized tomography detected 1 or more recurrence sites in the majority of men with biochemical recurrence, frequently resulting in major changes to management plans. Future studies will be planned to determine whether a management change leads to improved outcomes.

Perfluorocarboxylic acid compounds (PFCAs) and copper have been regarded as ubiquitous environmental contaminants in aquatic ecosystems worldwide. However, data on their possible joint toxic effects on microorganisms are still lacking. To study the combined effects of four PFCAs with different carbon chain lengths and copper, a series of experiments were conducted to explore the acute toxicity of these PFCAs in the absence and presence of copper on a metal-resistant Arthrobacter strain GQ-9 by microcalorimetry. The thermokinetic parameters, including growth rate constant ( k ), inhibitory ratio ( I ), and half inhibitory concentration ( IC 50 ), were calculated and compared using the data obtained from the power-time curves. Our work revealed that GQ-9 is more resistant to perfluorooctanoic acid (PFOA) than Escherichia coli . The single and joint toxicity of PFCAs with copper are dose- and carbon chain length-dependent. The longer the carbon chain length of PFCAs, the higher the toxicity. In addition, PFCAs interacted synergistically with copper. This work could provide useful information for the risk assessment of co-exposure to perfluorinated compounds and heavy metals in natural environments.

CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters. DILIsym predicted that single doses of CKA caused serum ALT >3xULN in a subset of the simulated rat population, while single doses in a simulated human population did not produce serum ALT elevations. Species differences were largely attributed to differences in liver exposure, but increased sensitivity to inhibition of mitochondrial respiration in the rat also contributed. We conclude that mechanistic modeling can elucidate species differences in the hepatotoxic potential of drug candidates.

Aims/hypothesis: The EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA), individually or combined, on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD)., Methods: This randomised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21), 4 g OM-3CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial)., Results: Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m 2 (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, -15%; dapagliflozin, -13%; OM-3CA + dapagliflozin, -21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, -24%, p = 0.037) in comparison with placebo. There was an interaction between the PNPLA3 I148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase (γ-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in γ-GT correlated with changes in liver PDFF (ρ = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments., Conclusions/interpretation: Combined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD., Trial Registration: ClinicalTrials.gov NCT02279407 FUNDING: The study was funded by AstraZeneca.

OM3-CA (omega-3-carboxylic acids) is a complex mixture of omega-3 carboxylic acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which is approved in the United States for the treatment of hypertriglyceridemia. As part of its clinical development in Japan, we performed a phase 1 study to investigate the safety, tolerability, and pharmacokinetics after single and multiple doses of OM3-CA in healthy male Japanese subjects. Eighteen Japanese subjects were allocated to receive 2 or 4 g/day OM3-CA, or placebo (n = 6 per group). In addition, 6 white subjects received 4 g/day OM3-CA. The primary objective was to determine the safety and tolerability of OM3-CA. Plasma concentrations of EPA and DHA were adjusted for baseline values for pharmacokinetic analysis. Overall, OM3-CA was well tolerated in healthy Japanese subjects. Two Japanese subjects in each group and 5 white subjects experienced adverse events (AEs). Alanine aminotransferase increase was the most common AE in Japanese subjects, also seen with placebo, and diarrhea was the most common AE in white subjects. The maximum plasma concentrations of EPA and DHA were observed 5-6 hours postdose. The pharmacokinetic profiles of EPA and DHA after administration of OM3-CA were comparable between Japanese and white subjects., (© 2017, The American College of Clinical Pharmacology.)

For efficient and deeper drug delivery into the lungs via dry powder inhalers (DPIs), we designed porous spray-dried particles (SDPs) containing anti-tuberculosis drugs and sugar-based excipients. The SDPs were prepared by spray-drying ethanol solutions containing isoniazid and/or rifampicin and sucrose, maltose, or highly branched cyclic dextrin (HBCD). Solid-state fluorescence emission spectroscopy showed that 1-naphthoic acid (1-NPA), a model drug, was dispersed in a molecular dispersion/solid solution, suggesting high potential of HBCD as an excipient in DPIs. 1-NPA was dispersed not only as active pharmaceutical ingredient (API) molecules with HBCD, but also as fine crystals. Morphological examination showed that the fine particles of HBCD/anti-tuberculosis drugs were porous, indicating high aerodynamic performance. Isoniazid and rifampicin could also be incorporated into the HBCD matrix. HBCD formulations exhibited higher released doses and fine-particle fractions than sucrose and maltose formulations, and could incorporate both hydrophilic and hydrophobic drugs.

Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 μM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.

Although exogenous agonists for cannabinoid (CB) receptors are clinically effective for treating chronic pain, global activation of brain CB receptors causes frequent central nervous system (CNS) side-effects. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide (AEA), an endogenous CB. Recently, we discovered a novel FAAH inhibitor, 3-pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477). In vitro studies demonstrated that ASP8477 inhibited human FAAH-1, FAAH-1 (P129T) and FAAH-2 activity with IC 50 values of 3.99, 1.65 and 57.3nM, respectively. ASP8477 at 10µM had no appreciable interactions with 65 different kinds of receptors, ion channels, transporters and enzymes, including CB 1 and CB 2 receptors and monoacylglycerol lipase. In adolescent rats, orally administered ASP8477 (0.3-10mg/kg) elevated AEA concentrations in both plasma and brain. In a capsaicin-induced secondary hyperalgesia model, a pretreatment with ASP8477 significantly improved mechanical allodynia and thermal hyperalgesia at 0.3-3mg/kg p.o. ASP8477 also significantly improved mechanical allodynia in an L5/L6 spinal nerve ligation neuropathic pain model, with an ED 50 value of 0.63mg/kg, and in a streptozotocin-induced diabetic neuropathy model at 3 and 10mg/kg p.o. Furthermore, ASP8477 significantly attenuated the reduction in rearing events at 1 and 3mg/kg p.o. in a monoiodoacetic acid-induced osteoarthritis model. Importantly, ASP8477 had no significant effect on motor coordination up to 30mg/kg p.o. These results indicate that ASP8477 is a potent, selective, and oral active FAAH inhibitor with activity in the CNS, with the potential to be a new analgesic agent with a wide safety margin., (Copyright © 2017 Elsevier B.V. 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.)

A class of substituted 1-thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives was found to have potent anti-proliferative activity against a broad range of tumor cell lines. A compound from this class (14) was profiled across a broad panel of hematologic and solid tumor cancer cell lines demonstrating cell cycle arrest at the G0/G1 interphase and has potent anti-proliferative activity against a distinct and select set of cancer cell types with no observed effects on normal human cells. An example is the selective inhibition of human B-cell lymphoma cell line (BJAB). Compound 14 was orally bioavailable and tolerated well in mice. Synthesis and structure activity relationships (SAR) in this series of compounds are discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aims: Omega-3-carboxylic acids (OM3-CA) contain omega-3 free fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as carboxylic acids. Food intake is known to affect the bioavailability of ethyl ester fatty acid formulations. We conducted a phase I study to investigate the effects of the timing of OM3-CA administration relative to food intake on the pharmacokinetics of EPA and DHA., Methods: In this randomized, open-label, three-period crossover study, Japanese healthy male subjects were administered 4×1 g OM3-CA capsules with continued fasting, before a meal, or after a meal. All subjects fasted for ≥10 h prior to drug/meal administration. The primary objective was to examine the effect of meal timing on the pharmacokinetics of EPA and DHA after OM3-CA administration. The secondary objectives were to examine the safety and tolerability of OM3-CA., Results: A total of 42 Japanese subjects was enrolled in the study. The baseline-adjusted maximum concentration and area under the concentration-time curve from 0 to 72 h for EPA, DHA, and EPA +DHA were lower in the fasting and before meal conditions than in the after meal condition. The maximum total EPA, total DHA, and total EPA+DHA concentrations were reached later when administered in fasting conditions than in fed conditions, indicating slower absorption in fasting conditions. Diarrhea was reported by five, six, and no subjects in the fasting, before meal, and after meal conditions, respectively., Conclusions: The timing of OM3-CA administration relative to food intake influences the systemic bioavailability of EPA and DHA in healthy Japanese male subjects., Trial Registration: NCT02372344.

In this proof of concept study, 50 lesions from 15 patients with multiple seborrheic keratoses (SKs) were treated with a novel aqueous solution containing nitric acid, zinc and copper salts, and organic acids (acetic, lactic, and oxalic acid). Treatment consisted in the application of an amount of the solution sufficient to obtain a whitening/yellowish reaction. Application of the nitric-zinc solution was performed every other week until clinical and dermoscopic clearance or crust formation, for a maximum of 4 applications. Efficacy evaluation was performed at 8 weeks (T1) and 6 months (T2). All subjects, who reported no or minimal discomfort during and after the application of the solution, completed the study. At T1, a complete clinical and dermoscopic resolution was observed in 37 lesions after an average of 3 applications/lesion (range 2-4). A partial response, with minimal persistent residual spots, was detected in the remaining 13 lesions. All patients with complete clearance showed no relapses at a 6-month follow-up (T2). The positive preliminary results indicate that this novel solution may represent a promising alternative option for SKs especially in patients not keen or eligible to undergo invasive tissue-destructive procedures., (© 2017 Wiley Periodicals, Inc.)

Background: Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels., Objective: Our objective was to assess the effects of OM3-CA on warfarin pharmacokinetics and pharmacodynamics and on acetylsalicylic acid (ASA)-dependent and independent platelet activation when co-administered with ASA in two phase I studies., Methods: In ECLIPSE II (NCT01431690), 26 participants received warfarin 25 mg on days 1 and 22 and OM3-CA 4 g once daily from day 8 to day 28. In OM-EPA-007 (NCT01486433), 52 participants received simvastatin 40 mg plus ASA 81 mg once daily for 14 days, with or without OM3-CA 4 g. Lack of a drug-drug interaction was indicated when 90% confidence intervals (CIs) fell entirely within the range 80-125% for least-squares mean (LSM) ratios of area under the concentration-time curve (AUC), maximum observed plasma concentration (C max ), international normalized ratio (INR) AUC to 168 h and maximum INR., Results: In ECLIPSE II, 90% CIs for LSM ratios of with:without OM3-CA fell within 80-125% for AUC and C max of S- and R-warfarin enantiomers. The 90% CIs for LSM ratios of with:without OM3-CA fell within 80-125% for INR AUC to 168 h after dosing and for maximum INR of warfarin. In OM-EPA-007, no significant effect of OM3-CA was observed on ASA-dependent or ASA-independent platelet activation. No deaths or serious adverse events occurred in either study., Conclusion: OM3-CA did not affect the pharmacokinetics or pharmacodynamics of warfarin or the pharmacodynamic effects of ASA. OM3-CA did not affect platelet function when co-administered with ASA.

18 F-Fluciclovine ( trans -1-amino-3- 18 F-fluorocyclobutanecarboxylic acid; anti - 18 F-FACBC) is a positron emission tomography (PET) tracer for diagnosing cancers (e.g., prostate and breast cancer). The most frequent metastatic organ of these cancers is bone. Fluciclovine-PET can visualize bony lesions in clinical practice; however, such lesions have not been described histologically. Methods: We investigated the potential of 14 C-fluciclovine in aiding the visualization of osteolytic and osteoblastic bone metastases (with histological analyses), compared with 3 H-2-deoxy-2-fluoro-D-glucose ( 3 H-FDG), 3 H-choline chloride ( 3 H-choline), and 99m Tc-hydroxymethylene diphosphonate ( 99m Tc-HMDP) by using triple-tracer autoradiography in rat breast cancer osteolytic (on day 12 ± 1 postinjection of MRMT-1) and prostate cancer osteoblastic (on day 20 ± 3 postinjection of AT6.1) metastatic models. Results: The distribution patterns of 14 C-fluciclovine, 3 H-FDG, and 3 H-choline, but not 99m Tc-HMDP, were similar in both models, and the lesions where these tracers accumulated were, histologically, typical osteolytic and osteoblastic lesions. 99m Tc-HMDP accumulated mostly in osteoblastic lesions. 14 C-fluciclovine could visualize the osteolytic lesions as early as day 6 postinjection of MRMT-1. However, differential distributions in 14 C-fluciclovine and 3 H-FDG existed, based on histological differences: low 14 C-fluciclovine and high 3 H-FDG accumulation in osteolytic lesions with inflammation. In the osteoblastic metastatic model, visualization of osteoblastic lesions with 14 C-fluciclovine was not clear, yet clearer than with 3 H-FDG. Although half of the osteoblastic lesions with 14 C-fluciclovine accumulation showed negligible 3 H-choline accumulation in comparison, they were histologically similar to lesions with marked 14 C-fluciclovine and 3 H-choline accumulation. Conclusion: These results suggest that fluciclovine-PET can visualize true osteolytic and osteoblastic bone metastatic lesions., Competing Interests: Conflict of interest: Shuntaro Oka, Masaru Kanagawa, Yoshihiro Doi, and Hirokatsu Yoshimura are employees of Nihon Medi-Physics (Tokyo, Japan). We are collaborating with Mark M. Goodman and David M. Schuster for nonclinical and clinical studies on 18F-fluciclovine. Mark M. Goodman and Emory University are eligible to receive royalties from Nihon Medi-Physics. David M. Schuster is receiving research support through Emory University from Nihon Medi-Physics and Blue Earth Diagnostics (Oxford, United Kingdom). There is no other potential conflict of interest relevant to this article to declare.

Purpose: [ 18 F]Fluciclovine PET imaging shows promise for the assessment of prostate cancer. The purpose of this PET/MRI study is to optimise the PET imaging protocol for detection and characterisation of primary prostate cancer, by quantitative evaluation of the dynamic uptake of [ 18 F]Fluciclovine in cancerous and benign tissue., Methods: Patients diagnosed with high-risk primary prostate cancer underwent an integrated [ 18 F]Fluciclovine PET/MRI exam before robot-assisted radical prostatectomy with extended pelvic lymph node dissection. Volumes-of-interest (VOIs) of selected organs (prostate, bladder, blood pool) and sub-glandular prostate structures (tumour, benign prostatic hyperplasia (BPH), inflammation, healthy tissue) were delineated on T2-weighted MR images, using whole-mount histology samples as a reference. Three candidate windows for optimal PET imaging were identified based on the dynamic curves of the mean and maximum standardised uptake value (SUV mean and SUV max , respectively). The statistical significance of differences in SUV between VOIs were analysed using Wilcoxon rank sum tests (p<0.05, adjusted for multiple testing)., Results: Twenty-eight (28) patients [median (range) age: 66 (55-72) years] were included. An early (W1: 5-10 minutes post-injection) and two late candidate windows (W2: 18-23; W3: 33-38 minutes post-injection) were selected. Late compared with early imaging was better able to distinguish between malignant and benign tissue [W3, SUV mean : tumour vs. BPH 2.5 vs. 2.0 (p<0.001), tumour vs. inflammation 2.5 vs. 1.7 (p<0.001), tumour vs. healthy tissue 2.5 vs. 2.0 (p<0.001); W1, SUV mean : tumour vs. BPH 3.1 vs. 3.1 (p=0.771), tumour vs inflammation 3.1 vs. 2.2 (p=0.021), tumour vs. healthy tissue 3.1 vs. 2.5 (p<0.001)] as well as between high-grade and low/intermediate-grade tumours (W3, SUV mean : 2.6 vs. 2.1 (p=0.040); W1, SUV mean : 3.1 vs. 2.8 (p=0.173)). These differences were relevant to the peripheral zone, but not the central gland., Conclusion: Late-window [ 18 F]Fluciclovine PET imaging shows promise for distinguishing between prostate tumours and benign tissue and for assessment of tumour aggressiveness.

Nanoparticle (NP) interactions with biological tissues are affected by the size, shape and surface chemistry of the NPs. Here we use in vivo (zebrafish) and in vitro (HUVEC) models to investigate association of quantum dots (QDs) with endothelial cells and the effect of fluid flow. After injection into the developing zebrafish, circulating QDs associate with endothelium and penetrate surrounding tissue parenchyma over time. Amino-functionalized QDs cluster, interact with cells, and clear more rapidly than carboxy-functionalized QDs in vivo, highlighting charge influences. QDs show stronger accumulation in slow-flowing, small caliber venous vessels than in fast-flowing high caliber arterial vessels. Parallel-plate flow experiments with HUVEC support these findings, showing reduced QD-EC association with increasing flow. In vivo, flow arrest after nanoparticle injection still results in venous accumulation at 18 h. Overall our results suggest that both QD charge and blood flow modulate particle-endothelial cell interactions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Treating plantar, periungual, and external genital warts can be challenging. A prospective study from four centers in Italy evaluated 37 immunocompetent patients with single or multiple warts and treated each lesion with a nitric-zinc topical solution composed of organic and inorganic acids meant to devitalize tissue and destroy HPV DNA in infected keratinocytes. Thirty of the 37 patients had external genital warts, two had plantar warts, two had palm and finger warts, and three had subungual warts for a total of 55 lesions treated. Nitric-zinc aqueous solution was applied over each wart utilizing a 30 µL capillary tube until a whitening response was observed. Additional applications as needed were accomplished at 2-week intervals until the wart was gone. In those with hand, plantar, and subungual warts, there was a 100% clearance after two to three sessions. Three with external genital warts had only a partial response and one no benefit after four applications. Thus, this approach was effective in external genital and other "difficult-to-treat" warts in 90% of patients after one to four applications. It also was easy to use with no adverse events noted., (© 2016 Wiley Periodicals, Inc.)

Hemorrhagic shock/resuscitation involves overwhelming reactive oxygen species (ROS) that cause oxidative stress, inflammation, and subsequent tissue injury. We investigated the effects of the potent antioxidant carboxyfullerene (C 3 ) on acute liver injury during hemorrhage shock/resuscitation. C 3 infusion reduced the alanine aminotransferase (ALT) activity, methemoglobin content, malondialdehyde content, myeloperoxidase activity and expression levels of tumor necrosis factor -α and interleukin-6; it increased superoxide dismutase activity in the liver. The histologic injury score and apoptotic index were also markedly decreased after C 3 treatment compared with the vehicle group. Additionally, C 3 -treated rats showed a significant decrease in nuclear factor-κB DNA binding capacity, which was preceded by reduced phosphorylation of the nuclear factor κB (NF-κB) p65 subunit in the liver. C 3 nanoparticles ameliorate oxidative stress, the inflammatory response, and subsequent acute liver injury after hemorrhagic shock/resuscitation. These protective effects appear to be mediated through the inhibition of the nuclear factor-κB pathway. C 3 treatment may be a promising strategy to improve tissue injury in hemorrhagic shock/resuscitation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Improvement of water solubility, dissolution rate, oral bioavailability, and reduction of first pass metabolism of OL (OL), were the aims of this research. Co-amorphization of OL carboxylic acid dispersions at various molar ratios was carried out using rapid solvent evaporation. Characterization of the dispersions was performed using differential scanning calorimetry (DSC), Fourier transform infrared spectrometry (FTIR), X-ray diffractometry (XRD), and scanning electron microscopy (SEM). Dispersions with highest equilibrium solubility were formulated as fast dissolving oral films. Modeling and optimization of film formation were undertaken using artificial neural networks (ANNs). The results indicated co-amorphization of OL-ascorbic acid through H-bonding. The co-amorphous dispersions at 1:2 molar ratio showed more than 600-fold increase in solubility of OL. The model optimized fast dissolving film prepared from the dispersion was physically and chemically stable, demonstrated short disintegration time (8.5 s), fast dissolution (97% in 10 min) and optimum tensile strength (4.9 N/cm 2 ). The results of in vivo data indicated high bioavailability (144 ng h/mL) and maximum plasma concentration (14.2 ng/mL) compared with the marketed references. Therefore, the optimized co-amorphous OL-ascorbic acid fast dissolving film could be a valuable solution for enhancing the physicochemical and pharmacokinetic properties of OL.

Background: Functionalization is believed to have a considerable impact on the biodistribution of fullerene in vivo. However, a direct comparison of differently functionalized fullerenes is required to prove the hypothesis. The purpose of this study was to investigate the influences of surface modification on the biodistribution of fullerene following its exposure via several routs of administration., Methods: (13)C skeleton-labeled fullerene C60 ((13)C-C60) was functionalized with carboxyl groups ((13)C-C60-COOH) or hydroxyl groups ((13)C-C60-OH). Male ICR mice (~25 g) were exposed to a single dose of 400 μg of (13)C-C60-COOH or (13)C-C60-OH in 200 μL of aqueous 0.9% NaCl solution by three different exposure pathways, including tail vein injection, gavage and intraperitoneal exposure. Tissue samples, including blood, heart, liver, spleen, stomach, kidneys, lungs, brain, large intestine, small intestine, muscle, bone and skin were subsequently collected, dissected, homogenized, lyophilized, and analyzed by isotope ratio mass spectrometry., Results: The liver, bone, muscle and skin were found to be the major target organs for C60-COOH and C60-OH after their intravenous injection, whereas unmodified C60 was mainly found in the liver, spleen and lung. The total uptakes in liver and spleen followed the order: C60 > > C60-COOH > C60-OH. The distribution rate over 24 h followed the order: C60 > C60-OH > C60-COOH. C60-COOH and C60-OH were both cleared from the body at 7 d post exposure. C60-COOH was absorbed in the gastrointestinal tract following gavage exposure and distributed into the heart, liver, spleen, stomach, lungs, intestine and bone tissues. The translocation of C60-OH was more widespread than that of C60-COOH after intraperitoneal injection., Conclusions: The surface modification of fullerene C60 led to a decreased in its accumulation level and distribution rate, as well as altering its target organs. These results therefore demonstrate that the chemical functionalization of fullerene had a significant impact on its translocation and biodistribution properties. Further surface modifications could therefore be used to reduce the toxicity of C60 and improve its biocompatibility, which would be beneficial for biomedical applications.

Background: The amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells., Methods: We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored., Results: There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed., Conclusions: Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.).

A rapid and sensitive liquid chromatography quadrupole time of flight method has been established for the determination of total naphthenic acid concentrations in aqueous samples. This is the first methodology that has been adopted for routine, high resolution, high throughput analysis of total naphthenic acids at trace levels in unprocessed samples. A calibration range from 0.02 to 1.0μgmL(-1) total Merichem naphthenic acids was validated and demonstrated excellent accuracy (97-111% recovery) and precision (1.9% RSD at 0.02μgmL(-1)). Quantitative validation was also demonstrated in a non-commercial oil sands process water (OSPW) acid extractable organics (AEOs) fraction containing a higher percentage of polycarboxylic acid isomers than the Merichem technical mix. The chromatographic method showed good calibration linearity of ≥0.999 RSQ to 0.005μgmL(-1) total naphthenic acids with a precision <3.1% RSD and a calculated detection limit of 0.0004μgmL(-1) employing Merichem technical mix reference material. The method is well suited to monitoring naturally occurring and industrially derived naphthenic acids (and other AEOs) present in surface and ground waters in the vicinity of mining developments. The advantage of the current method is its direct application to unprocessed environmental samples and to examine natural naphthenic acid isomer profiles. It is noted that where the isomer profile of samples differs from that of the reference material, results should be considered semi-quantitative due to the lack of matching isomer content. The fingerprint profile of naphthenic acids is known to be transitory during aging and the present method has the ability to adapt to monitoring of these changes in naphthenic acid content. The method's total ion scan approach allows for data previously collected to be examined retrospectively for specific analyte mass ions of interest. A list of potential naphthenic acid isomers that decrease in response with aging is proposed and a quantitative assay of an adamantane carboxylic acid is reported., (Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.)

Selective inhibition of glycogen synthase kinase-3 (GSK3) has been targeted as a novel therapeutic strategy for diabetes mellitus. We investigated the anti-diabetic efficacy and molecular mechanisms of KICG1338 (2-(4-fluoro-phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid(4-methyl-pyridin-3-yl)-amide), a GSK3β inhibitor, in three animal models: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, leptin receptors-deficient db/db mice, and diet-induced obese (DIO) mice. Biochemical parameters including glucose tolerance tests and gene expressions associated with glucose metabolism were investigated. Glucose excursion decreased significantly by KICG1338-treated OLETF rats, accompanied by increase in insulin receptor substrate-1 and glucose transporter (GLUT)-4 expressions in muscle and decreased GLUT-2 expression in liver. Glucose-lowering effects were similarly observed in KICG1338-treated db/db and DIO mice. KICG1338 treatment increased adiponectin levels and decreased TNF-α levels. KICG1338 therapy also led to greater β-cell preservation and less hepatic fat infiltration with decreased expressions of genes involved in inflammation and endoplasmic reticulum stress. These data demonstrate anti-diabetic efficacy of KICG1338, a novel GSK3β inhibitor., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background/objectives: The zeta-1 family isoform of GST biotransforms the investigational drug dichloroacetate (DCA) and certain other halogenated carboxylic acids. Haplotype variability in GSTZ1 influences the kinetics and, possibly, the toxicity of DCA. DCA metabolism correlates with expression of the GSTZ1 protein, so it is important to document variables that affect expression. Following up on a limited previous study, we tested the hypothesis that a coding single nucleotide polymorphism (SNP), the lysine (K) amino acid (E32>K) in GSTZ1 haplotypes linked to a promoter region SNP results in lower hepatic expression of GSTZ1., Materials and Methods: The influence of K carrier and non-K carrier haplotypes on GSTZ1 expression was determined by analyzing 78 liver samples from individuals aged 7-84 years of various racial and ethnic backgrounds. GSTZ1 expression data were analyzed on the basis of the presence or absence of lysine 32., Results: GSTZ1 protein expression differed significantly between K carrier and non-K carrier haplotypes (P=0.001) in Whites, but not in African-Americans (P=0.277). We attribute this difference in GSTZ1 expression among K carrier haplotypes in Whites to the linkage disequilibrium between the K or A allele from the G>A SNP (rs7975), within the promoter G>A-1002 SNP (rs7160195) A allele. There is no linkage disequilibrium between these two polymorphisms in African-Americans., Conclusion: We conclude that the lower expression of GSTZ1 in Whites who possess the K carrier haplotype results in lower enzymatic activity and slower metabolism of DCA, compared with those who possess the non-K carrier haplotype. These results further define safe, genetics-based dosing regimens for chronic DCA administration.

Background/purpose: Washing the face with a mild cleanser is generally recommended for acne care. Occasionally, the general public has the misconception that acne is exacerbated by cleansers and furthermore it has concerns about inducing skin irritation and xerosis by intensive washing. Recently, we developed a new cleanser based on sodium laureth carboxylate and alkyl carboxylates (AEC/soap) that cleans sebum well without penetrating the stratum corneum., Methods: We designed a controlled clinical trial conducted on adult Japanese males with moderate or less acne. Twenty subjects washed their faces with AEC/soap base cleanser twice a day for 4 weeks. Assessment of the efficacy was conducted prior to the start of the study, and at the end of weeks 2 and 4., Results: Significant improvement of the acne was observed within 2 weeks, and acne lesions were not detectable in 25% of the subjects at week 4. Sebum secretion levels on the skin significantly increased on the forehead, but significantly decreased on the cheek which correlated with the improvement. No complaints of dryness or irritation occurred during the study., Conclusion: Washing the face twice a day with facial cleanser based on AEC/soap is an effective care for moderate or less grade facial acne., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)